京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19560号 / 医博第4067号 / 新制||医||1013(附属図書館) / 32596 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 小川 修, 教授 長澤 丘司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Indiana University-Purdue University Indianapolis (IUPUI) / More than 200,000 American women are diagnosed with breast cancer each year. Although therapies effective in treating metastatic breast cancer currently exist, each year approximately 40,000 women die from this disease. Current evidence indicates that anti-cancer immune responses can be induced by vaccination in situ to the growth of metastasis and protect patients from the tumor recurrence. However, induction of anticancer immune responses may be limited in their efficacy due to immune suppression mechanisms induced by the developing cancer. Myeloid-derived suppressor cells are one population of immune regulators comprised of immature cells of myeloid origin with important roles in blocking immune activation and promoting tumor progression. Elimination or maturation of these cells has been found to promote enhanced anti-tumor effects and improve overall survival. This thesis identifies a new role for interleukin-12 as a modulator of myeloid-derived suppressor cell activity. Interleukin-12 was found to promote up-regulation of cell maturation markers on the surface of myeloid-derived suppressor cells with an accompanying decrease in factors responsible for conferring suppressive activity such as nitric oxide synthase 2 and arginase I. The alterations in myeloid-derived suppressor cells were observed following both in vitro and in vivo treatment with interleukin-12. Further analysis of the anti-tumor efficacy of interleukin-12 revealed that at least part of its suppression of tumor growth can be linked to reductions in myeloid-derived suppressor cell populations in the tumor microenvironment and an influx of active CD8+ T cells into the tumor microenvironment. The findings outlined in this thesis show that interleukin-12 alters the suppressive function of myeloid-derived suppressor cells leading to significant immune infiltration and activation resulting in increased overall survival and a reduction in metastasis.

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Mit der Entwicklung und Einführung ökologischer Bauweise im Neubau sowie neuen Baustoffsystemen in Sandwichbauweise wird es zunehmend erforderlich, neue effektive Befestigungsvarianten zu entwickeln, die eine dauerhafte Fixierung auch unter sicherheitstechnischen Bestimmungen sowie aus Garantie- bzw. haftungsrechtlichen Gründen ermöglichen. Die aus der Praxis bisher bekannten chemischen Befestigungssysteme (Zweikomponentenverbundmörtel, Verbundankerpatronen) weisen hinsichtlich der Applikation unter bautechnischen Bedingungen noch einige Nachteile auf. Dazu gehören vor allem längere Aushärtungszeiten zur Realisierung der abschließenden Verbundfestigkeit, Inhomogenitäten im Verbund, der Einsatz toxischer Verbindungen und eine Limitierung der Applikationsmöglichkeiten in horizontalen und Überkopf-Einsatzbereichen sowie Hohlkammersystemen. Alle zuvor genannten Punkte haben bis jetzt die Nutzung solcher Verbundwerkstoffe als universale Anwendungsmöglichkeit verhindert. Ein neues chemisches Befestigungssystem, welches aus Novolak gehärteten mit Hexamethylentetramin (Hexa) und anorganischen Füllstoff besteht, wurde für Applikationen in Beton entwickelt. Das Bindemittel härtet bei der Temperaturzuführung aus. Die unkatalysierte Befestigungsmasse zeigt bei einer Temperatur zwischen 150-300 °C eine hohe Reaktivität. Die Vorteile dieses Systems sind die unbegrenzte Lagerfähigkeit der vorgemischten härtbaren Masse sowie die Gewährleistung einer homogenen Netzwerkstruktur im gesamten Verbund und sie ist frei von giftigen und flüchtigen Substanzen. Auf den Einsatz toxischer Substanzen wurde verzichtet. In dieser Arbeit wurde die Gesamtkinetik der Reaktion während des Aushärtungsprozesses dieser Polymerkomposite untersucht. Die DSC- (nicht-isothermen, isothermen) und MDSC-Untersuchungen haben sich als ein sicheres Verfahren zur Qualitätskontrolle des Aushärtezustands der Befestigungssysteme herausgestellt. Parallel zur nicht-isothermischen und isothermischen DSC wurden Leitfähigkeitsmessungen durchgeführt, um den Endpunkt der Aushärtungsreaktion zu bestimmen. / The development and introduction of ecological construction methods and the use of sandwich materials make it necessary to develop new fixing systems and technologies. Dealing with the application in concrete and other substrates commercial chemical fixing systems show some disadvantages up to date. Especially the rather long curing time in order to realize the final bond strength, inhomogenities in the composite, the partial use of toxic substances and application limits of such systems in horizontal direction as well as hollow section materials has so far prevented the use of such composites for all-purpose applications. A new chemical fixing system, which consists of hexamethylene tetramine (hexa) cured novolac and inorganic filler, was developed for application in concrete. It is applied by a thermo-curing procedure. The uncatalyzed curable mixture has a high reactivity at temperature between 150-300 °C. Compared with commercial chemical fixing systems, the premixed curable mass has many benefits. First it has a unique storage stability and second, it is free of toxic and volatile substances. Another important aspect is, it is self-foaming. In this study was investigated the overall kinetics of the reaction during the curing process of these polymer composites. An appropriate method for this experiment proved to be the DSC in isothermal and non-isothermal mode and MDSC. This turned out to be a safe quality control technique for these systems. Parallel to the non-isothermal and isothermal DSC conductivity measurements have been performed to determine the end point of the curing reaction.

Le système immunitaire joue un double rôle dans le cancer : il peut non seulement supprimer la croissance tumorale en détruisant les cellules cancéreuses, mais aussi promouvoir la progression de la tumeur en sélectionnant les cellules tumorales ou en créant un microenvironnement tumoral immunosuppresseur. Notre idée principale est de développer des stratégies pour mieux comprendre l'immunologie du cancer colique.Au cours de ma thèse, je me suis tout d'abord intéressée à une population du système immunitaire : les MDSC (Myeloïd Derived Suppressor Cells). Nous avons exploré des stratégies pour réduire le nombre de ces cellules au cours de la croissance tumorale. Nous avons pu découvrir que de petites doses de 5 fluorouracil sont capables d'induire spécifiquement une mort par apoptose des cellules myéloïdes suppressives. Nous avons ainsi caractérisé un effet immunologique positif nouveau du 5-fluorouracil. Cet effet immunologique contribue à l'effet antitumoral du 5-fluorouracil chez la souris. Dans une deuxième partie nous avons étudié le rôle pronostic des infiltrats immunitaires dans une série de patients présentant un cancer du côlon avec des métastases hépatiques. Nous avons étudié le rôle pronostic des infiltrats en cellules CD8, CD45R0 et Foxp3. Nous avons mis en évidence que la présence d'un fort infiltrat en cellules CD45RO et Foxp3 est un facteur de bon pronostic. L'association des 2 marqueurs permet de définir 3 groupes pronostics et ainsi d'individualiser un groupe de mauvais pronostic ne bénéficiant probablement pas de la chirurgie hépatique.

Increasingly the role of epigenetic machinery as a bridge between underlying DNA sequence and cellular phenotype is being discovered. The establishment of a myriad of unique cellular types sharing identical gene sequences in a multicellular organism gives a broad sense for the inherent role of epigenetic influence on cell differentiation. Importantly, the epigenetic mechanisms involved in establishing cell identity unsurprisingly contribute to diseased states, including cancer. Recent research continues to elucidate contributory roles of epigenetic mechanisms, such as DNA methylation, histone modification, and microRNA regulation, in human cancers. Additionally, chromatin remodelers, such as the Nucleosome Remodeling Factor (NURF), have been identified as important regulators for normal cell biology. While much has been done to identify and characterize the role of NURF chromatin remodeling complex as a key regulator of development in a number of model organisms, little has been published on the implications of NURF in diseases such as cancer. Our preliminary data shows dysregulation of E-cadherins, N-cadherins, and MHC-I genes in Bptf (an essential subunit of NURF) knocked down murine breast cancer cell lines. These proteins have well documented roles in the development and metastatic progression of cancers. To study the effect of Bptf knockdown on the development and progression of cancer we injected Bptf knocked down mouse breast cancer cell lines, 4T1, 66cl4, and 67NR, into syngenic BALB/c mice. Our findings reveal decreased tumor growth in 66cl4 and 67NR as measured by tumor weight at 3-4 weeks post injection. Tumor growth did not appear to be significantly affected in 4T1 challenged mice. However, mice inoculated with Bptf knockdown 4T1 cell lines have decreased metastasis to lungs as compared to control while metastasis of 66cl4 tumors to the lungs appear unaffected. To assess the role of the immune system in decreasing tumor growth in BALB/c mice, we injected 66cl4 tumors into NOD-SCID-Gamma (NSG) immune deficient mice. The tumors from these mice show no difference in tumor growth between Bptf knockdown and control tumors, implicating a role for the immune system regulating the decreased tumor weight in BALB/c mice. To delineate which immune cell effector may impede breast cancer carcinogenesis, we performed an in vitro natural killer (NK) cell cytotoxicity assay against 66cl4 tumors and found greater susceptibility to NK killing in Bptf knockdown tumors.

The research programme studied the cure reaction of a phenolic novolak resin and the effects of various additives and fillers on the reaction. The programme utilised the recently developed thermal analysis technique of temperature-modulated differential scanning calorimetry (TMDSC) performed in conjunction with other available thermal analysis techniques. TMDSC enables the signal for the heat of reaction to be separated from the underlying specific heat change in the resin. This meant that the reaction could be studied without interference from any physical changes in the resin. The manufacture of composite brake materials required the use of numerous additives and fillers to produce the desired properties. The influence of such additives on the cure rate and final properties of the resin was known to occur but had not previously been measured due to the difficulties presented by the presence of opaque additives. Some additives also underwent thermally induced physical changes in the temperature range of the cure. The final properties and the processing of new brake materials undergoing development often required trial and error adjustments to compensate for changes in cure rate. An understanding of the influence of additives would enable more rapid commercial development of brake materials through an improvement in the ability to predict both the properties of the product and the optimal processing parameters. Processing efficiency could also be improved through detailed knowledge of the kinetics. Moulding cycle times and post-baking times and temperatures were longer than necessary in order to ensure adequate cure at the end of each stage because of the lack of kinetic data. The cure of phenolic resin has been shown to be highly complicated with numerous alternate and competing reactions. For the manufacture of composite materials, knowledge of the kinetic parameters of individual reactions is not considered to be important; rather the overall kinetic parameters are required for prediction. Therefore the kinetic model parameters that best described the observed behaviour were chosen even though the model had no basis in the molecular interaction theory of reaction. Rather it served as a convenient tool for predictions. Characterisation of the resin proved to be difficult due to the presence of overlapping peaks, and volatile reaction products. TMDSC was successfully used to determine the reaction kinetics of the pure resin and the influence of certain additives on the reaction kinetics. The determination of the kinetic parameters using TMDSC agreed well with the traditional Differential Scanning Calorimetry isothermal and non-isothermal techniques. Both the Perkin-Elmer and TA Instruments were utilised for the research and were found to provide reasonably good agreement with each other. The capabilities and limitations of the individual instruments were critically examined, frequently beyond the manufacturers' specifications. TMDSC suffers from a limitation in the heating rate of the sample compared to DSC. However, it was observed that valuable information could still be obtained from TMDSC despite using heating rates that were higher than specified by manufacturers. Hot Stage Microscopy and thermogravimetry were additional experimental techniques used to aid in the characterisation of the resin. Some inhomogeneity of the resin was identified as well as differences in the behaviour of the cure between open (constant pressure) and closed (constant volume) environments were observed. A novel method of determining the orders of the cure reactions and their kinetic parameters was utilised. Reaction models for the overall cure reactions were postulated and tested by fitment to sections of experimental data in temperature regions which appeared to be free of interference from overlapping peaks. Once an individual peak was reasonably well modelled, adjacent overlapping peaks were able to be modelled both individually and in combinations by fitment to experimental data. The Solver function in Microsoft Excel was utilised to find the best fitting model parameters for the experimental data. The model parameters were able to be refined as overlapping peaks were progressively incorporated into the calculations. This method produced results that agreed well with the traditional method of analysing reaction peak temperatures at multiple scanning rates. Model fitment was shown to be of benefit where overlapping reactions occur. Various model scenarios could be tested and optimised to particular sections of experimental data. This enabled the researcher to easily identify areas of possible anomalies and postulate alternative scenarios. The accuracy of the postulated model was able to be determined by its successful fitment to experimental data from experiments run under different conditions.