PhD - International Relations / The thesis examines the design and implementation of African regional economic cooperation initiatives using the Lagos Plan of Action (LPA) and the New Partnership for Africa’s Development (NEPAD) as comparative case studies. With regards to design, it focuses on the international political economy of the shift from the LPA’s state-led, inward-looking, collective self-reliance model to NEPAD’s outward looking, market-friendly orientations. Pertaining to implementation, it examines the domestic political economy of institutionalising compliance with regionally agreed policy prescriptions in the absence of an overarching central authority. It focuses on the level of implementation of the LPA and the prospects of implementing NEPAD. The thesis pursues two main sets of arguments: First, it argues that African states’ common concerns about their vulnerability in the global economy have informed the design of a number of ambitious regional initiatives. Within this context, the shift from the LPA to the NEPAD has been dictated by changes in global realities and circumstances. Second, it argues that individual African governments’ concern with vulnerability nationally has been responsible for the low levels of implementation of regional economic initiatives. In this regard, the prospects for the sustained implementation of regional cooperation initiatives is structured by expectations of socio- economic benefits, the cost of compliance to states and the institutions to enforce compliance. The study employs neo-liberal and nationalist perspectives of international political economy to explain how global realities have dictated Africa’s economic cooperation options. To explain African governments’ attitude towards regional initiatives, the thesis uses insights from comparative political economy. The thesis meanwhile employs insights from institutional economics and rational choice institutionalism to highlight the difficulties of institutionalising compliance with regional policy prescriptions. To capture the differences in the contexts within which the LPA and the NEPAD were crafted and the variations in their orientations, the thesis uses a combination of ‘historical explanation’ and ‘structured focused comparison’ methodology that allows for two separate, but structurally linked accounts of the processes of design and implementation of the two initiatives.

Submitted by Andre Moraes Queiroz (andre.moraesqueiroz@ufpe.br) on 2015-04-14T13:40:30Z No. of bitstreams: 2 Dissertação Aleide Lima.pdf: 1775977 bytes, checksum: 02788df7796db55323f52a980da5d08a (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-04-14T13:40:30Z (GMT). No. of bitstreams: 2 Dissertação Aleide Lima.pdf: 1775977 bytes, checksum: 02788df7796db55323f52a980da5d08a (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2013 / Marcadores moleculares, como mutações nos genes FLT3 e NPM1, são ferramentas úteis para a avaliação prognóstica de pacientes com leucemia mieloide aguda (LMA) e, até o momento, não tinham sido estudadas em pacientes com LMA no Estado de Pernambuco. Dessa forma, esse trabalho teve como objetivo caracterizar pacientes adultos com LMA diagnosticados na Fundação HEMOPE de acordo com achados clínico-laboratoriais e as mutações nos genes FLT3 e NPM1. Foram incluídos 115 pacientes com LMA de novo (15 com leucemia promielocítica aguda (LPA) e 100 com outros subtipos LMA). As frequências das mutações FLT3/ITD, FLT3/TKD e NPM1 nos pacientes não-LPA foram de 22%, 2% e 24%, respectivamente. Nos pacientes com LPA, a frequência foi de 40% e 6,7% para as mutações FLT3/ITD e NPM1, respectivamente, não sendo diagnosticado nenhum caso com mutação FLT3/TKD. As mutações FLT3/ITD e no NPM1 foram relacionadas com alta contagem de leucócitos (p=0,021; p=0,012) e mutações no NPM1 foram mais frequentes em pacientes com mais de 60 anos (p=0,01) e no grupo de cariótipo normal (p=0,008). Não foi observada diferença nas sobrevidas global (SG) e livre de doença (SLD) e nas taxas de remissão completa (TRC) e de recaída (TR) entre os grupos com e sem mutação FLT3/ITD e no NPM1 quando avaliados os pacientes não-LPA; entretanto, pacientes LPA com mutação FLT3/ITD apresentaram menores TRC, SG e SLD. Os resultados comprovam o valor preditivo da mutação FLT3/ITD para um curso clínico desfavorável na LPA do adulto, enquanto que, para os pacientes não-LPA, as mutações FLT3/ITD e no NPM1, aparentemente, não apresentaram o mesmo impacto prognóstico.

Tumor metastasis is a fundamental property of malignant cancer cells and the major cause of death in cancer patients. Recent studies indicate that tumor cell invasion and metastasis may be initiated by the formation of the actin-rich cell protrusions with ECM degradation activity, invadopodia. However, despite extensive research on the biology of invadopodia, very little is known about their specific inducers during tumor progression. Autotaxin (ATX) is a secreted lysophospholipase whose expression levels within tumors correlates strongly with their aggressiveness and invasiveness. ATX produces lyosophosphatidic acid (LPA), a phospholipid with known tumor promoting functions that acts through the G-protein coupled receptors, LPA[subscript 1-6] . Recently, overexpression of ATX and LPA receptors (LPA[subscript 1-3]) has been linked to increased tumor invasion and metastasis in vivo , however, the role of other LPA receptors (LPA[subscript 4-6]) as well as the exact mechanisms by which ATX induces tumor metastasis remain poorly characterized. In order to determine the involvement of ATX and LPA in invadopodia production, we used the fibrosarcoma HT-1080 cells stably transfected with ATX or shRNA targeting ATX in fluorescent matrix degradation assays. Our results demonstrate that ATX is implicated in the production of invadopodia resulting in an increase in both their formation and function. Using LPC or LPA, the substrate and product of ATX, we further show that invadopodia production is dependent on the production of LPA from LPC. Among the LPA receptors, LPA 4 has the highest expression in HT1080 cells. Using LPA[subscript 4] shRNA as well as agonists and inhibitors of the cAMP pathway, we provide evidence that LPA[subscript 4] signaling through the cAMP-EPAC-Rap1 axis, regulates invadopodia formation downstream of ATX. Furthermore, inhibition of Rac1, a known effector of Rap1 and invadopodia formation, abolished EPAC-induced invadopodia production, suggesting downstream participation of Rac1. Finally, results using LPA[subscript 4] shRNA support the requirement of this receptor for in vitro cell invasion and in vivo metastasis formation. Our results suggest that ATX through LPA[subscript 4] is a strong inducer of invadopodia formation that correlates with the ability of the cells to invade and metastasize. This study also revealed an unexpected signaling pathway for cell invasion involving LPA[subscript 4]-driven cAMP production and subsequent activation of the EPAC-Rap1-Rac1 axis.

Feeding plant-based feed in fish farming is one of the causes for increased phosphorus loading in water environment and consequent eutrophication of water. Phosphorus contained in plant components is deposited in the form of phytic acid, which is poorly digestible for cyprinids. The aim of this work was to monitor the influence of feeds with low phytate phosphorus content or the addition of enzyme for increasing the utilization of phosphorus on the production parameters and the fish exterior. In the first feed test, varieties of wheat Vánek and of barley Bojos were used for control groups. Lpa mutant lines of wheat JS-12/IDO 563 and of barley M955 were used for experimental diets. The feed test was conducted for 64 days in two repetitions. No statistically significant change occurred in the production parameters. In case of lpa barley a slight decrease in Fc occurred. In the second feed test, a feed mixture KP1 was used for the control group. Enzymatic phytase The Phyzyme XP 10.000 TPT was used in experimental diets. To feed mixtures F500 and F1000 was added only enzyme and to feed mixtures F500C3 and F1000C3 beside enzyme citric acid was added. The test lasted 72 days in two repetitions. Significant statistical difference in production parameters was recorded. FCR decreased in the groups F500C3 and F1000C3, whereas SGR increased in these groups. In groups F500C3 and F1000C3, the total length and body length also increased. According to the results, it can be concluded that lpa cereals have no effect on the reared fish. The use of the combination of phytase and citric acid has a positive influence on the production parameters without negative effects on the other parameters evaluated.

Proton sources driven by high-power lasers are a promising addition to the portfolio of conventional proton accelerators. Regarding particle cancer therapy, where tumours are irradiated with protons or ions, the novel accelerator technology can be particularly beneficial for translational research - the research branch in which results of basic research are transferred to new approaches for the prevention, diagnosis and treatment of cancer. The overarching aim in the thesis at hand was a translational pilot study to irradiate tumours on mice’s ears with laser-accelerated protons while achieving the quality level of conventional proton accelerators. This is the only way to compare the radiobiological data of the novel accelerator technology with those of the established ones. To enable such experiments a predetermined dose distribution according to the radiobiological model’s requirements must be delivered to a sample volume. Ergo, the laser-driven protons have to be transported and shaped after their initial acceleration. Intense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. This work demonstrates the successful implementation of a highly efficient and tuneable pulsed dual solenoid setup to generate a homogeneous (laterally and in depth) volumetric dose distribution using only a single dose pulse from the broad laser-driven proton spectrum. The experiments using the ALBUS-2S beamline were conducted at the titanium:sapphire high-power laser Draco PW at the Helmholtz-Zentrum Dresden–Rossendorf. The beamline and its model were characterised and verified via independent methods, leading to first experimental studies providing volumetrically homogeneous dose distributions to detector targets as well as tumour and normal tissue in proof-of-concept studies. To perform the mouse pilot study, a new solenoid with cooling capacities was designed, characterised and implemented in the course of this thesis. The combination of the new solenoid and an overall performance improvement of the laser-proton accelerator, enabled the successful conduction of the mouse model study. The results show that laser-accelerated protons induce a comparable tumour growth delay as protons from conventional accelerators. This outcome and the demonstration of the flawless interaction between laser-proton accelerator, beam transport, dosimetry and biology qualify the laser-based accelerator technology for complex studies in translational cancer research. Looking into the future, their unique extremely high intensity renders them of particular interest for the investigation into the ultra-high dose rate regime. There, the so-called FLASH effect shows fewer side effects in normal tissue while maintaining the same effect in the tumour when the target dose is administered in milliseconds rather than minutes, as currently common. The ALBUS-2S setup at Draco PW already provides all necessary conditions to realise irradiation times of around ten nanoseconds in preclinical studies. This significantly expands the parameter space for investigating the FLASH effect and is presented as a proof-of-concept in this thesis.

Les métastases sont des conséquences dramatiques lors de la progression des cancers. Malgré les traitements actuels la médiane de survie de patients atteints de métastases osseuses n’est que de 24 mois. Donc l’identification de nouvelles cibles thérapeutiques dans le traitement ou la prévention des métastases revêt un caractère crucial. L’objectif de ce travail de thèse est d’étudier le rôle de l’acide lysophosphatidique (LPA) et de l’autotaxine (ATX) dans la dissémination métastatique des cancers du sein. Notre laboratoire a montré que le LPA contrôle la croissance tumorale et la progression des métastases osseuses dans le contexte des cancers du sein. On sait depuis peu qu’en raison de son activité lysophospholipase D, ATX produit du LPA à partir de la lysophosphatidylcholine et contrôle les niveaux de LPA dans la circulation sanguine. ATX est une protéine sécrétée présentant des propriétés métastatiques. Les travaux présentés dans cette thèse montrent que l'expression d'ATX par les cellules tumorales contrôle les événements précoces de la dissémination métastatique des cancers du sein ainsi que le processus plus tardif de formation et de progression des métastases osseuses en agissant sur la fonction ostéoclastique. Il existe un grand nombre de récepteurs capables de transmettre l’activation cellulaire par le LPA (LPA1-6). Ce travail de thèse montre également que le niveau d’expression du récepteur LPA1 au niveau de la tumeur primaire est un facteur prédictif de la rechute métastatique chez les patientes ayant un cancer du sein. D’autre part dans un modèle animal préclinique, nous avons observé que le ciblage thérapeutique précoce de LPA1 par le DEBIO-0719 bloque efficacement la dissémination métastatique des cellules de cancer du sein. En conclusion, nos résultats montrent que le ciblage de l’axe ATX/LPA/LPA1 présente un haut potentiel thérapeutique chez des patientes atteintes d’un cancer du sein à fort risque métastatique / Metastases consist of poor disease progression for patients with cancers. Bone metastases are frequently found in multiple cancers. Despite the improvement of current therapies, the survival of bone metastasis patients is only 24 months. The aim of this work consisted in understanding the role of lysophosphatidic acid (LPA), autotaxin (ATX) and the LPA receptor LPA1 in the metastatic dissemination of breast cancers. Our laboratory showed previously that LPA produced tumor growth and the progression of osteolytic bone metastases of breast cancer cells. Due to its lysophospholipase D activity, ATX generates LPA from lysophosphatidylcholine and controls LPA levels in the blood. ATX is a secreted protein with metastatic properties. In the present thesis, we first demonstrated that ATX expressed by tumors cells controls early events of metastatic dissemination of breast cancer cells and latter bone metastases formation and progression by acting on osteoclastic function. There is a large number of receptors mediating the cellular activation of LPA (LPA1-6). This work showed additionally that the LPA1 expression level at the primary tumor site is predictive for the metastatic relapse of breast cancers. On the other hand, in a preclinical animal model, we observed that targeting LPA1 at early stage of tumor development with the DEBIO-0719 decreased efficiently the metastatic dissemination of breast cancer cells. Altogether, these results indicate that targeting the ATX/LPA/LPA1 track has a high therapeutic potential against metastasis formation for patients with breast cancer

Cytosolic LPA acyltransferase in yeast An isooctane tolerant strain of S. cerevisiae KK-12 was reported to have increased saturated fatty acid content (Miura et. al., 2000). Amongst the various genes upregulated on isooctane treatment, ICT1 (Increased Copper Tolerance 1) was found to have maximal expression (Miura et. al., 2000; Matsui et. al., 2006). This gene in S. cerevisiae is encoded by YLR099C annotated as Ict1p. However, the physiological significance of Ict1p was not understood. Here we showed that an increase in the synthesis of phosphatidic acid (PA) is responsible for enhanced phospholipid synthesis, which confers organic solvent tolerance to S. cerevisiae. This increase in the PA formation is due to the upregulation of Ict1p, a soluble oleoyl-CoA dependent lysophosphatidic acid (LPA) specific acyltransferase. Analysis of Δict1 strain by in vivo [32P]orthophosphate labeling showed a drastic reduction in PA, suggesting the role of Ict1p in phospholipid biosynthesis. Overexpression of Ict1p in S. cerevisiae showed an increase in PA and the overall phospholipid content on organic solvent exposure. The purified recombinant enzyme was found to specifically acylate LPA. Specific activity of Ict1p was found to be higher for oleoyl-CoA as compared to palmitoyl-CoA and stearoyl-CoA. The study therefore, provides a mechanistic basis of solvent tolerance in S. cerevisiae.It is well known that phosphatidic acid (PA) is formed by the acylation of LPA by LPA acyltransferase. However, all the LPA acyltransferases characterized till date have distinct transmembrane domains and form a member of membrane bound biosynthetic machinery of phospholipid biosynthesis. They have a conserved signature motif, H(X)4D. Phosphatidic acid is an important precursor for the synthesis of glycerophospholipids and triacylglycerols. PA enters the biosynthetic pathway of phospholipids through a CTP-dependent activation catalyzed by CDPdiacylglycerol synthase. This enzyme forms CDP-diacylglycerol, which serves as a direct precursor for phosphatidylinositol, phosphatidylglycerol and cardiolipin. PA can also be dephosphorylated by phosphatidic acid phosphatase yielding diacylglycerol, which serves as a precursor for the formation of PE and PC through the CDP-ethanolamine and CDP-choline pathway or for the triacylglycerol synthesis through a dephosphorylation step followed by an acylation establishing it as a supreme molecule for the acylglycerol biosynthesis. Since, PA is an important intermediate and that there are mechanisms to synthesize PA, other than the conventional membrane bound pathways, we wanted to understand whether such a mechanism of PA biosynthesis is conserved across the plant and animal kingdom. Therefore, we resorted to analyze Ict1p like proteins in Arabidopsis and human whose complete genome sequence is available. Cytosolic LPA acyltransferase in Arabidopsis Homology search with ICT1 in Arabidopsis thaliana genome, led to the identification of At4g24160 as a close relative. In order to gain an insight into the significance of such proteins in plants we performed a genome wide survey of At4g24160 like proteins in Arabidopsis. We identified that A. thaliana genome encodes twenty four At4g24160 like proteins, most of which belong to the α/β- hydrolase family of proteins and possess a distinct lipase motif (GXS/NXG). Interestingly, amongst these twenty four, only At4g24160 has a conserved HX4D motif. Domain analysis of these proteins suggests a wide functional diversification during evolution. Gene expression studies revealed their importance during various abiotic stress. Bacterial expression of At4g24160 followed by its purification using Ni2+-NTA column chromatography and characterization revealed it to be a LPA acyltransferase. Expression analysis showed that it is highly expressed in the pollen grains followed by the root cap. In addition, the gene was found to be upregulated under salt stress conditions. Direct correlation between salt stress and phospholipid biosynthesis is well known in the literature. We envisage that At4g24160 might be one of the gene products involved in membrane repair when exposed to such a stressCytosolic LPA acyltransferase in human Homology search with Ict1p revealed another interesting candidate protein in Homo sapiens known as Comparative Gene Identification–58 (cgi-58). Mutations in CGI- 58 are known to be the causative reason for a rare autosomal recessive genetic disorder known as Chanarin-Dorfman syndrome characterized by the excessive TG accumulation and defective membrane phospholipid regulation in several tissues. It is known to be a coactivator of adipose triglyceride lipase (ATGL), promoting lipolysis of TG (Lass et. al., 2006). However, the exact biochemical role remains unknown. To understand the biochemical function of cgi-58, the gene was overexpressed in E. coli and the purified, recombinant protein was found to specifically acylate lysophosphatidic acid in an acyl-CoA dependent manner. Overexpression of CGI-58 in Δict1 rescued the metabolic defect of the strain. Heterologous overexpression of CGI-58 in S. cerevisiae followed by metabolic labeling with [32P]orthophosphate showed an increased biosynthesis of membrane phospholipids. Analysis of neutral lipid biosynthesis by [14C]acetate labeling showed an increase in DG and free fatty acids. However, marked decrease in the TG biosynthesis was seen. Decrease in TG was confirmed by ESI-MS. In addition, physiological significance of cgi-58 in the mice white adipose tissue is reported in this thesis. We found soluble lysophosphatidic acid acyltransferase activity in the mice white adipose tissue. Immunoblot with anti-Ict1p antibodies followed by MALDI-TOF analysis of the cross reacting protein in lipid droplets revealed its identity as cgi-58. These observations suggest the existence of an alternate cytosolic phosphatidic acid biosynthetic pathway in the white adipose tissue. Collectively, our observations suggest a possible involvement of cgi-58 in the phospholipid biosynthesis of adipocytes and its probable role in maintaining the TG homeostasis. In conclusion, the study reveals the significance of cytosolic lipid metabolic enzymes having conserved biochemical function, in maintaining homeostasis in living organisms across phylogeny.

Theory and research suggest that at least two subgroups of individuals with psychopathicpersonality that can be differentiated based on their levels of anxiety. What we know so far ofthe distinction between these subgroups is based predominantly on relatively small samples ofmales in institutionalized populations. The present study is the first to use a large andrandomly selected sample of the general population to try to identify subgroups of individualswith psychopathic personality separately for males and females (n=2500; 52.6% females;M=22.15; SD=1.38). Latent profile analysis suggested a two-group solution; where bothsubgroups were high on psychopathic traits, but low respectively high on a measure ofanxiety. The identified subgroups differed across theoretically and empirically relevantconstructs in that the high anxious group reported significantly more maltreatment history,aggression, symptoms of ADHD and post-traumatic stress, and treatment involvement.Generally, the differences between the high anxious and the low anxious subgroups were thesame for males and females, but an important difference was that the female high anxioussubgroup reported being significantly more involved in treatment. In conclusion, the gainedsubgroups are in several ways, but not in all, in line with theories of primary and secondary psychopathy.

No description available.

Proton sources driven by high-power lasers are a promising addition to the portfolio of conventional proton accelerators. Regarding particle cancer therapy, where tumours are irradiated with protons or ions, the novel accelerator technology can be particularly beneficial for translational research - the research branch in which results of basic research are transferred to new approaches for the prevention, diagnosis and treatment of cancer. The overarching aim in the thesis at hand was a translational pilot study to irradiate tumours on mice’s ears with laser-accelerated protons while achieving the quality level of conventional proton accelerators. This is the only way to compare the radiobiological data of the novel accelerator technology with those of the established ones. To enable such experiments a predetermined dose distribution according to the radiobiological model’s requirements must be delivered to a sample volume. Ergo, the laser-driven protons have to be transported and shaped after their initial acceleration. Intense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. This work demonstrates the successful implementation of a highly efficient and tuneable pulsed dual solenoid setup to generate a homogeneous (laterally and in depth) volumetric dose distribution using only a single dose pulse from the broad laser-driven proton spectrum. The experiments using the ALBUS-2S beamline were conducted at the titanium:sapphire high-power laser Draco PW at the Helmholtz-Zentrum Dresden–Rossendorf. The beamline and its model were characterised and verified via independent methods, leading to first experimental studies providing volumetrically homogeneous dose distributions to detector targets as well as tumour and normal tissue in proof-of-concept studies. To perform the mouse pilot study, a new solenoid with cooling capacities was designed, characterised and implemented in the course of this thesis. The combination of the new solenoid and an overall performance improvement of the laser-proton accelerator, enabled the successful conduction of the mouse model study. The results show that laser-accelerated protons induce a comparable tumour growth delay as protons from conventional accelerators. This outcome and the demonstration of the flawless interaction between laser-proton accelerator, beam transport, dosimetry and biology qualify the laser-based accelerator technology for complex studies in translational cancer research. Looking into the future, their unique extremely high intensity renders them of particular interest for the investigation into the ultra-high dose rate regime. There, the so-called FLASH effect shows fewer side effects in normal tissue while maintaining the same effect in the tumour when the target dose is administered in milliseconds rather than minutes, as currently common. The ALBUS-2S setup at Draco PW already provides all necessary conditions to realise irradiation times of around ten nanoseconds in preclinical studies. This significantly expands the parameter space for investigating the FLASH effect and is presented as a proof-of-concept in this thesis. / Protonenquellen, die von Hochleistungslasern getrieben werden, sind eine vielversprechende Ergänzung zu herkömmlichen Protonenbeschleunigern. Im Hinblick auf die Partikeltherapie von Krebserkrankungen, bei der Tumoren mit Protonen oder Ionen bestrahlt werden, kann die neuartige Beschleunigertechnologie vor allem der translationalen Forschung von Nutzen sein, in der die Ergebnisse der Grundlagenforschung in neue Ansätze zur Vorsorge, Diagnose und Behandlung von Krebserkrankungen übertragen werden. Übergeordnetes Ziel der vorliegenden Arbeit war eine translationale Pilotstudie zur Bestrahlung von Tumoren an Mäuseohren mit laserbeschleunigten Protonen bei gleichzeitiger Erfüllung des Qualitätsniveaus konventioneller Protonenbeschleuniger. Mit den Ergebnissen ist ein Vergleich der strahlenbiologischen Daten der neuen und der etablierten Beschleunigertechnologie möglich. Um dieses Experiment zu realisieren, muss eine vorher festgelegte Strahlendosis, die den Anforderungen des radiobiologischen Modells entspricht, an ein Probenvolumen abgegeben werden. Die lasergetriebenen Protonenpulse müssen dafür nach ihrer Beschleunigung transportiert und geformt werden. Intensive lasergetriebene Protonenpulse sind von Natur aus breitbandig und stark divergent. Sie stellen eine Herausforderung für etablierte Beamline-Konzepte auf dem Weg zu einer anwendungsangepassten Bestrahlungsfeldbildung dar, insbesondere bei einer räumlichen Anwendung. Diese Arbeit zeigt die erfolgreiche Implementierung eines hocheffizienten und abstimmbaren gepulsten Zwei-Solenoid-Aufbaus zur Erzeugung einer homogenen (lateral und in der Tiefe) volumetrischen Dosisverteilung mit einem einzigen Dosispuls aus dem breiten lasergetriebenen Protonenspektrum. Die Experimente an der ALBUS-2S3 Beamline wurden am Titan:Saphir-Hochleistungslaser Draco4 PW am Helmholtz-Zentrum Dresden– Rossendorf durchgeführt. Die Beamline und ihr Modell wurden experimentell charakterisiert und mit unabhängigen Methoden verifiziert. Es konnten erste experimentelle Studien durchgeführt werden, bei denen volumetrisch homogene Dosisverteilungen auf Detektorziele sowie Tumor- und Normalgewebe in Proof-of-Concept Studien appliziert wurden. Für die Durchführung der Maus-Pilotstudie wurde im Rahmen dieser Arbeit ein neuer kühlbarer Solenoid entworfen, charakterisiert und implementiert. Zusammen mit einer allgemeinen Leistungsverbesserung des Laser-Protonen Beschleunigers wurde die Pilotstudie erfolgreich abgeschlossen. Sie zeigt, dass laserbeschleunigte Protonen eine vergleichbare Verzögerung des Tumorwachstums bewirken wie Protonen aus konventionellen Beschleunigern. Dieses Ergebnis und der Nachweis des einwandfreien Zusammenspiels von Laser- Protonen-Beschleuniger, Strahltransport, Dosimetrie und Biologie qualifizieren die laserbasierte Beschleunigertechnologie für komplexe Studien in der translationalen Krebsforschung. Mit Blick auf die Zukunft sind sie aufgrund ihrer einzigartigen, extrem hohen Intensität besonders interessant für die Untersuchung im Bereich ultrahoher Dosisleistungen. Dort zeigt der so genannte FLASH-Effekt weniger Nebenwirkungen im gesunden Normalgewebe bei gleicher Wirkung im Tumor. Die Zieldosis wird dabei innerhalb von Millisekunden verabreicht und nicht, wie derzeit üblich, innerhalb von Minuten. Der ALBUS-2S-Aufbau bei Draco PW bietet bereits alle notwendigen Voraussetzungen, um in präklinischen Studien Bestrahlungszeiten von etwa zehn Nanosekunden zu realisieren. Dies erweitert den Parameterraum für die Untersuchung des FLASH-Effekts erheblich und wird in dieser Arbeit auch als Proof-of-Concept vorgestellt.