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Les glioblastomes (GB) sont des tumeurs cérébrales invasives, résistantes et qui récidivent systématiquement malgré un traitement associant chirurgie, radio- et chimiothérapie. Ces tumeurs de très mauvais pronostic, se caractérisent par une survie médiane de 15 mois. L'agressivité des GB est notamment due à la présence d'une sous-population de cellules souches (GSC). Les GSC sont caractérisées par leurs capacités d'auto-renouvellement, d'expression de différents marqueurs souches, de multipotence et de tumorigenèse. Elles sont fortement impliquées dans la résistance et la récidive tumorale et leur ciblage pourrait améliorer le traitement des GB. Au vu de la littérature et de résultats obtenus au laboratoire, l'intégrine ß8 est apparue comme une nouvelle cible potentielle de ces GSC. Cette intégrine est décrite comme possédant un rôle majeur dans la survie et l'auto-renouvellement des cellules progénitrices neurales saines et sa surexpression est associée à une diminution de la survie des patients. Nous avons alors émis l'hypothèse que l'intégrine ß8 pourrait être impliquée dans le maintien de l'état souche des GSC. J'ai démontré au cours de ma thèse que cette intégrine est surexprimée dans des primocultures de GSC issues de résections de GB ainsi que dans des coupes de tumeurs de patients. De plus, j'ai mis en évidence que ß8 est associée à l'état souche et à des fonctionnalités propres à ces cellules, notamment leur auto-renouvellement, leur viabilité, leur migration et leur radiorésistance. En inhibant sélectivement ß8 dans nos primocultures de GSC par si/shRNA, j'ai en effet observé in vitro une diminution de la formation de neurosphères et de la migration cellulaire ainsi qu'une augmentation de la différentiation et de la mort cellulaire, cette dernière étant potentialisée après irradiation. Enfin, in vivo, j'ai mis en évidence que l'inhibition de ß8 se traduit par une diminution de la tumorigenèse et une augmentation de la survie des souris. En conclusion, mes résultats de thèse permettent d'identifier l'intégrine ß8 comme une protéine membranaire nécessaire au maintien de l'état souche dans les GSC mais surtout comme une potentielle cible thérapeutique radiosensibilisante dans les GB. / Glioblastomas (GB) are invasive, resistant and recurrent brain tumors (median overall survival of 15 months) despite standard treatment including surgical resection, radio- and chemotherapy. This tumor aggressiveness could partly be explained by the presence into the tumor of Glioblastoma-Stem like Cells (GSC), characterized by their ability to self-renew, their higher expression of specific GSC markers, their multipotent aptitude and their high tumorigenic potential. They are strongly involved in tumor resistance and recurrence and their targeting could improve GB treatment. Regarding current literature but also transcriptomic results obtained in our lab, a specific ß8 integrin emerged as a potential selective target in GSC. We then hypothesized that ß8 integrin could be involved in stemness maintenance of GSC. I first demonstrated, during my doctoral thesis, that ß8 is overexpressed in primocultures of GSC isolated from patients resections and also in human GB samples. Moreover, I showed that this integrin could be associated with stemness and features unique to these cells, including self-renewal ability, viability, migration and radioresistance. Indeed, the selective inhibition of ß8 in GSC by si/shRNA resulted in vitro in a decrease of neurosphere formation and migration, associated with an increase of differentiation patterns and cell death, this one being potentiated after irradiation. Finally, in vivo, I showed that ß8 inhibition decreased tumorigenesis and increased mice survival. In conclusion, my doctoral results allow to identify ß8 integrin as a membrane protein essential for stemness maintenance of GSC but mostly as a new potential radiosensitizing therapeutic target for GB.

History has shown that assassination could be wielded as an effective weapon in the pursuit of interest, security and power. As the feudal age neared its end in Europe, nation states emerged. Despite its pragmatic usefulness, assassination was considered unfit for this new form of governance. States no longer sought to destroy one another as predicted by Thomas Hobbes, but adhered to John Locke's proposed values, which believed that states could mutually exist as rivals. In this system which favored negotiation and settlements, it was difficult for assassination to have a place. Yet at the start of the 21st century, assassination once again saw employment. As of today, it is preferably referred to as targeted killing by its employers and has become somewhat of a 'new normal.' Clearly, there must be certain permissive catalysts that allowed this to happen. This master's thesis firstly explores the ways the United States, Israel and Russia conduct their assassination/targeted killing operations to present the unique ways these states eliminate their enemies, and secondly pinpoints the permissive causes that allowed these three super and great powers of assassination to transform the international norm against assassination and turn a dishonest, immoral practice into something more acceptable and fit...

5 Abstract In this thesis the anticancer drug vandetanib was studied. Vandetanib is a tyrosine kinase inhibitor affecting signalling of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) or RET protooncogene (REarranged during Transfection). It is primarily used for the treatment of advanced tumors of the thyroid gland. Unfortunately, the usage of vandetanib in the cancer treatment is significantly limited by its toxicity and cardiotoxicity (one of the adverse effects is connected with long QT interval). One way, how to minimize these side effects, is binding a drug into a suitable transporter. Apoferritin and liposomes were used as a transport nanoparticles in this study. The aim of this thesis was to study the stability of the complex of nanoparticle apoferritin with vandetanib molecules (ApoVan) and to study the effect of pH on the release of inhibitor from the ApoVan form. Experiments have shown that ApoVan complex is relatively stable after its storage at 4 řC and - 20 řC for up to 8 weeks. Unfortunately after monitoring the effect of pH on the release of vandetanib from ApoVan, it was found that vandetanib is gradually released from its ApoVan form into the neutral environment at pH 7,4 as well as into the acidic environment at pH 6,5 and the way ApoVan is...

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L’hypoxie est l’une des principales causes de résistance aux traitements dans les glioblastomes. Des stratégies permettant de lever l’hypoxie ou de limiter ses effets sont de ce fait nécessaires. Ces travaux de thèse s’intéressent à deux stratégies de vectorisation ciblée agissant contre l’hypoxie. La première stratégie vise à lutter contre les effets de l’hypoxie par une approche combinée de vectorisation cellulaire et moléculaire ciblant une protéine à action pro-tumorale : l’érythropoïétine. Des macrophages ont ainsi été modifiés génétiquement pour leur permettre de surexprimer une forme tronquée de récepteur à l’érythropoïétine conduisant à un ralentissement de la croissance d’un modèle de glioblastome. Les constructions moléculaires ont ensuite été modifiées pour rendre la surexpression inductible par l’hypoxie. La deuxième stratégie vise à réoxygéner spécifiquement la tumeur en se basant sur des nanozéolithes vectrices de gaz hyperoxiques. Les résultats montrent que ces nanoparticules microporeuses ne présentent pas d’effets toxiques majeurs in vitro et in vivo. L’incorporation de fer dans les zéolithes augmente significativement la capacité de transport d’O2 et le gadolinium permet leur utilisation comme agent de contraste en imagerie par résonance magnétique. D’autre part, les nanozéolithes vectrices de CO2/O2 s’accumulent spécifiquement dans le tissu tumoral et augmentent localement le volume sanguin et la quantité d’oxygène. Ainsi, les deux approches développées au cours de cette thèse démontrent le potentiel des stratégies ciblées dirigées contre l’hypoxie dans les glioblastomes. / Hypoxia is one of the main causes of resistance to treatments in glioblastoma, the worst primary brain tumor in term of survival. Two targeted vectorization strategies directed against hypoxia are presented in this thesis work. The first strategy was designed to inhibit hypoxia-induced erythropoietin through the use of macrophages. Macrophages were genetically engineered to overexpress a truncated form of the erythropoietin receptor resulting in a decrease in the tumor volume in a hypoxic model of glioblastoma in vivo. Hypoxia-inducible constructs were then developed. The second strategy aimed to use nanozeolites carrying hyperoxic gases as a tool to specifically reoxygenate the tumor. Results show that these microporous nanoparticles have no adverse effects in vitro and in vivo. The incorporation of iron in the zeolites significantly increases their oxygen transport capacity and the gadolinium allows their use as a contrast agent for magnetic resonance imaging. In addition, nanozeolites carrying CO2/O2 accumulate specifically in the tumor tissue and locally increase the blood volume/oxygenation. Thus, the two strategies developed during this thesis demonstrate the potential to fight against hypoxia specifically in glioblastoma.

Wildfires have caused concern as they have increased in severity and intensity over the last few decades. Land managers have sought management actions to mitigate the risk of wildfire by reducing fuel loads, thus decreasing wildfire intensity. Camp Williams is a National Guard camp near Bluffdale, Utah, where small arms and artillery training occurs. Managers at Camp Williams have created fuel breaks by implementing targeted sheep and goat grazing to remove fine fuel and thin brush. Management objectives set utilization of fine fuels (herbaceous) at 80% by weight. Questions arose regarding the ecological impact of the prescribed grazing rates in these fuel breaks. This study evaluated three fuel breaks and quantified the impacts of targeted sheep and goat grazing at 80% utilization. During the summer of 2015, herbaceous cover, shrub cover, shrub density, and bunch grass density was collected along eight paired (inside fuel break and outside fuel breaks) transects. Results indicate that the current management grazing plan could lead to an increase of invasive annual grasses, which may be counterproductive in fuel breaks. Often fine fuel treatments rely on high levels of grazing utilization (> 80%). However, high levels of utilization can lead to ecological degradation by reducing or eliminating native bunchgrasses. The objectives of the second study conducted were to determine how different levels of grazing utilization (30%, 50%, and 80%) relate to fuel characteristics and subsequent fire behavior. Results suggest that moderating grazing utilization levels (50%) may allow for more sustainable fuel reduction treatments while still reducing wildfire risks.

Indiana University-Purdue University Indianapolis (IUPUI) / Glioblastoma (GBM) is a deadly, malignant brain tumor with a poor long-term prognosis. The current median survival is approximately fifteen to seventeen months with the standard of care therapy which includes surgery, radiation, and chemotherapy. An important factor contributing to recurrence of GBM is high resistance of GBM cancer stem cells (CSCs), for which a systemically delivered single drug approach will be unlikely to produce a viable cure. Therefore, multi-drug therapies are needed. Currently, only temozolomide (TMZ), which is a DNA alkylator, affects overall survival in GBM patients. CSCs regenerate rapidly and over-express a methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to drug resistance. Idasanutlin (RG7388, R05503781) is a potent, selective MDM2 antagonist that additively kills GBM CSCs when combined with TMZ. By harnessing the strengths of nanotechnology, therapy can be combined with diagnostics in a truly theranostic manner for enhancing personalized medicine against GBM. The goal of this thesis was to develop a multi-drug therapy using multi-functional nanoparticles (NPs) that preferentially target the GBM CSC subpopulation and provide in vivo preclinical imaging capability. Polymer-micellar NPs composed of poly(styrene-b-ethylene oxide) (PS-b-PEO) and poly(lactic-co-glycolic) acid (PLGA) were developed investigating both single and double emulsion fabrication techniques as well as combinations of TMZ and RG7388. The NPs were covalently bound to a 15 base-pair CD133 aptamer in order to target a specific epitope on the CD133 antigen expressed on the surface of GBM CSC subpopulation. For theranostic functionality, the NPs were also labelled with a positron emission tomography (PET) radiotracer, zirconium-89 (89Zr). The NPs maintained a small size of less than 100 nm, a relatively neutral charge and exhibited the ability to produce a cytotoxic effect on CSCs. There was a slight increase in killing with the aptamer-bound NPs compared to those without a targeting agent. This work has provided a potentially therapeutic option for GBM specific for CSC targeting and future in vivo biodistribution studies.

京都大学 / 0048 / 新制・論文博士 / 博士(農学) / 乙第12879号 / 論農博第2806号 / 新制||農||1028(附属図書館) / 学位論文||H26||N4878(農学部図書室) / 31597 / (主査)教授 植田 和光, 教授 植田 充美, 教授 矢﨑 一史 / 学位規則第4条第2項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

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