Oxidative stress is a documented factor in the pathogenesis of inflammation and cancer. Vitamin E with its antioxidant properties holds promise for use in clinical practice. There are two main forms of vitamin E, tocopherols and tocotrienols. Palm oil contains almost 70% of tocotrienols. Tocotrienols exerts its antiproliferative activity against malignant cells but not on normal cells. Tocotrienols play an important role in counteracting cellular inflammatory response secondary to oxidative stress, thus exerting an anticancer property. Tocotrienols mediate function of NF-kappa B, STAT3 (signal transduction and activators), and COX-2. In addition to its role as an antioxidant and anti-inflammatory agent, tocotrienols also mediate multiple cell cycle pathways. More work needs to be done on animal models and in genetic models of pancreatic cancer to gather more data to eventually consider phase III clinical trial in human subjects.

Indiana University-Purdue University Indianapolis (IUPUI) / Phase I clinical trials (P1Ts) are the first step in testing new medical therapies in humans, and are essential for developing new and innovative therapies for children with cancer. P1Ts are ethically controversial as they are not intended to directly benefit participants, but are particularly controversial for children with cancer who are only able to participate when there is no known curative therapy for their cancer. Benefits of pediatric oncology P1T participation may include improved quality of life (QOL) and hope. Risks may include fostering unrealistic hope, burdening children with additional medical procedures and toxicities, and limiting the opportunity for palliation. The goal of this dissertation was to investigate the P1T participation experience for children with cancer and their parents by: (1) assessing what is currently known about the participation experience, (2) exploring ways to understand and assess treatment burden and QOL during participation, and (3) interviewing parents about the experience of having a child participate in a P1T. Following a review of the literature, two studies were conducted: a longitudinal pilot study of 13 parent and child dyads who enrolled in a pediatric oncology early phase clinical trial at the recruiting institution, and a phenomenological study of 11 parents of children with cancer who participated in pediatric oncology P1Ts. Key findings included a dearth of research on the experiences of children and parents in pediatric oncology P1Ts. Instead, existing research has focused on consent processes. The longitudinal pilot study provided some insight into experiences of children and parents during trial participation, including that there may be time points when parents’ and children’s perceptions of the child’s quality of life substantively differ. Interviews with parents confirmed some of the anticipated benefits and risks of participation in P1Ts, and highlighted parents’ sense of running out of time to find an effective treatment and needing to use time they have with their child well. Specific challenges in conducting this research were participant attrition due to disease progression and the need for multi-site research to obtain an adequate sample.

In dieser Arbeit soll daher die anatomische, histologische und physiologische Funktion der Leber und des ihr zugehörigen Gallengangsystems näher dargestellt, die für die Biotransformation der Phase I wichtigsten Enzyme und ihre chemischen Reaktionsprozesse angesprochen und die jeweiligen Reaktionen im Einzelnen erklärt werden, um als Vorlage für grafische Darstellungen und Animationen in einem derzeit zu erstellenden „Toxnetz-Explorer“ zu dienen. Das Lernprogramm „Toxnetz-Explorer“ soll in Zukunft zur interaktiven Weiterbildung im Rahmen des Postgradual-Studienganges (PGS) „Toxikologie und Umweltschutz“ dienen. Für die toxikologische Ausbildung wichtige Aspekte der Körperfunktionen und organspezifische toxikologische Vorgänge sollen in diesem Programm anhand von Grafiken und Animationen dargestellt werden, welche durch zugehörige Lehrtexte vervollständigt werden.

Yes / Introduction: Skin ageing involves senescent fibroblast accumulation, disturbance in extracellular matrix (ECM) homeostasis, and decreased collagen synthesis. Objective: to assess a cell therapy product for aged skin (RCS-01; verum) consisting of ~25 × 106 cultured, autologous cells derived from anagen hair follicle non-bulbar dermal sheath (NBDS). Methods: For each subject in the verum group, 4 areas of buttock skin were injected intradermally 1 or 3 times at monthly intervals with RCS-01, cryomedium, or needle penetration without injection; in the placebo group RCS-01 was replaced by cryomedium. The primary endpoint was assessment of local adverse event profiles. As secondary endpoints, expression of genes related to ECM homeostasis was assessed in biopsies from randomly selected volunteers in the RCS-01 group taken 4 weeks after the last injection. ­Results: Injections were well tolerated with no severe adverse events reported 1 year after the first injection. When compared with placebo-treated skin, a single treatment with RCS-01 resulted in a significant upregulation of TGFβ1, CTGF, COL1A1, COL1A2, COL3A1, and lumican mRNA expression. Limitations: The cohort size was insufficient for dose ­ranging evaluation and subgroup analyses of efficacy. Conclusions: RCS-01 therapy is well tolerated and associated with a gene expression response consistent with an improvement of ECM homeostasis. / Replicel Life Sciences Inc, Vancouver, Canada.

No description available.

The Liquid Argon calorimeter of the ATLAS detector at CERN near Geneva is equipped with improved readout and trigger electronics for the operation at higher luminosity LHC in the frame of several upgrades (Phase-0, I, and II). Special attention is given to an early digitisation of detector raw data and their following digital data transmission and processing via FPGAs already for the Level-1 trigger. The upgrades additionally foresee to provide higher spatial granularity information for the Level-1 trigger in order to improve its performance for low momentum single particles at increased collision rates. The first part of this dissertation contains the development and implementation of a modular detector simulation framework, AREUS, which allows to analyse different filter algorithms for the energy reconstruction as well as their performance with respect to the expected digitised detector raw data. In this detector simulation framework the detailed algorithmic functionality of the FPGAs has been taken into account. Various filter algorithms, especially the Optimal Filter and a Wiener Filter with Forward Correction, are discussed with regard to their performance in energy reconstruction of the future Liquid Argon calorimeter trigger system. In the second part of this thesis, the high-speed data transfer for the acquisition of the trigger data is being developed. For this purpose, a generic 10 Gigabit Ethernet UDP stack is designed in VHDL, that is currently applied in an ALTERA® Stratix-IV FPGA as part of the readout electronics of a demonstrator setup in the context of the Phase-0 Upgrade. After implementation in a prototype electronics board, data transfer from the detector front-end is realised. A successful test in the demonstrator setup installed in the ATLAS detector verifying the correct transmission of the Liquid Argon calorimeter trigger signals concludes this work. / Das Flüssig-Argon-Kalorimeter des ATLAS-Detektors am CERN bei Genf wird für den Betrieb am LHC mit erhöhter Luminosität im Rahmen mehrerer Upgrades (Phase-0, I und II) mit verbesserter Auslese- und Triggerelektronik ausgestattet. Ein besonderes Augenmerk liegt hierbei auf der frühzeitigen Digitalisierung der Detektorrohdaten und deren folgende digitale Übertragung sowie Verarbeitung mittels FPGAs bereits für den Level-1 Trigger. Die Upgrades sehen zusätzlich vor, dem Level-1 Trigger eine höhere Ortsauflösung bereitzustellen um seine Leistungsfähigkeit der Energierekonstruktion von niedrigenergetischen Teilchen bei erhöhter Kollisionsrate zu verbessern. Der erste Teil dieser Dissertation beinhaltet die Entwicklung und Umsetzung einer modularen Detektorsimulationsumgebung, AREUS, mit der verschiedene Filteralgorithmen zur Energierekonstruktion sowie deren Performanz in Abhängigkeit der erwarteten digitalisierten Detektorrohdaten analysiert werden können. Dabei wurde in der Simulationsumgebung die Funktionalität der Rechenarithmetik der später verwendeten FPGAs berücksichtigt. Verschiedener Filteralgorithmen, im Besonderen der Optimal Filter und ein Wiener Filter mit Korrekturglied, werden im Hinblick auf ihre Performanz der Energierekonstruktion für das zukünftige Triggersystem des Flüssig-Argon-Kalorimeters diskutiert. Der zweite Teil dieser Arbeit beschäftigt sich mit der Hochgeschwindigkeitsdatenübertragung zur Erfassung von Triggerdaten. Zu diesem Zweck wird ein generischer 10 Gigabit Ethernet UDP Stack in VHDL entworfen, der als Teil der Ausleseelektronik eines Demonstrator-Testaufbaus im Rahmen des Phase-0 Upgrades in einem ALTERA® Stratix-IV FPGA aktuell zum Einsatz kommt. Nach Implementierung in einem Prototypen einer Auslesekarte konnte ein Transfer von Detektordaten realisiert werden. Eine Überprüfung am Demonstrator-Testaufbau, welcher im ATLAS Detektor installiert ist, schließt diese Dissertation ab. Sie hat eine korrekte Übertragung von Triggersignalen des Flüssig-Argon-Kalorimeters erfolgreich bestätitgt.

Cette thèse est consacrée aux méthodes statistiques d’extrapolation dans les essais de recherche de dose en pédiatrie. Dans un premier temps, nous réalisons une revue systématique de la littérature sur le sujet. Elle met en évidence la nécessité de proposer de nouvelles méthodes pour la conception des études d’escalade de dose chez l’enfant. Nous apportons des réponses à cette problématique en exploitant l’information disponible chez l’adulte. Dans une première série de travaux, nous étudions l’intérêt de la prédiction des paramètres pharmacocinétiques (PK) en pédiatrie à l’aide de méthodes d’extrapolation : l’allométrie et la maturation. Cette évaluation est réalisée à partir de données PK chez l’adulte et l’enfant pour la méfloquine. Faisant appel aux paramètres prédits, nous développons une approche pour choisir les temps de prélèvements (design) d’une étude PK. Nous recommandons un design obtenu par optimisation grâce à la méthode de D-optimalité en utilisant le logiciel PFIM. Ce design est ensuite validé à l’aide de simulations sur différents modèles. Une seconde série de travaux nous amène à proposer des recommandations pour la planification d’un essai de recherche de dose. Nous avançons d’abord des techniques pour choisir les doses à tester grâce à l’utilisation des données adultes et de l’extrapolation. Nous proposons ensuite une méthode proche de la méta-analyse pour prédire les probabilités de toxicités pour chaque dose. Enfin, nous employons la méthode de l’Effective sample size afin de construire une loi a priori lors de l’utilisation d’une estimation bayésienne. Nous validons ces recommandations sur une étude de cas en utilisant une méthode d’escalade de dose, la méthode de réévaluation séquentielle bivariée, pour laquelle nous évaluons à la fois la toxicité et l’efficacité. A partir de l’exemple de la molécule erlotinib, nous effectuons une série de simulations sur plusieurs scénarios afin d’illustrer les performances de la planification. / This thesis addresses extrapolation techniques for statistical models for dose-finding studies in pediatrics. After a litterature review on these clinical trials, we observed the need of methodological propositions for the planification of dose- finding studies in pediatrics. We deal with this issue using information from the adult population. In a first research, the objectives are to design a pharmacokinetic (PK) study by using information from adults and evaluate the robustness of the recommended design through a case study of mefloquine. Pediatric PK parameters are predicted from adult PK using extrapolation functions such as allometry and maturation. A D-optimal design for children is obtained with PFIM by assuming the extrapolated design. The robustness of the recommended design is evaluated in a simulation study with four different models and is compared to the empirical design used for the pediatric data. In a second research, we propose a global approach to conduct a pediatric dose-finding clinical trial using extrapolation from adult information. First, we extrapolate the dose-range from adults using allometry and maturation. Then, using an approach to meta-analysis, we choose the initial probabilities of toxicity for each dose. Finally, we use the effective sample size method to choose the prior distribution of parameters in a Bayesian setting. We perform a simulation study based on the molecule erlotinib to evaluate the performances of this global approach.

L’objectif des essais de phase I en oncologie est d’identifier la dose maximale tolérée (DMT). Le schéma « 3+3 » nécessite d’interrompre les inclusions en attendant l’évaluation d’une cohorte de trois patients pour définir la dose à attribuer aux patients suivants. Les investigateurs d’oncologie pédiatrique ont proposé l’adaptation Rolling 6 pour éviter cette suspension temporaire des inclusions. Dans une étude de simulation, nous avons montré qu’un schéma adaptatif avec attribution des doses basées sur un modèle statistique permettait de pallier ce problème, et identifiait plus fréquemment la DMT. Néanmoins ces trois schémas restent limités pour identifier la DMT, notamment du fait que le critère de jugement est un critère binaire, la survenue de toxicité dose-limitante sur un cycle de traitement. Nous avons proposé un nouveau schéma adaptatif utilisant les données ordinales répétées de toxicité sur l’ensemble des cycles de traitement. La dose à identifier est celle associée au taux de toxicité grave maximal par cycle que l’on juge tolérable. Le grade maximal de toxicité par cycle de traitement, en 3 catégories (grave / modéré / nul), a été modélisé par le modèle mixte à cotes proportionnelles. Le modèle est performant à la fois pour détecter un effet cumulé dans le temps et améliore l’identification de la dose cible, sans risque majoré de toxicité, et sans rallonger la durée des essais. Nous avons aussi étudié l’intérêt de ce modèle ordinal par rapport à un modèle logistique mixte plus parcimonieux. Ces modèles pour données longitudinales devraient être plus souvent utilisés pour l’analyse des essais de phase I étant donné leur pertinence et la faisabilité de leur implémentation. / Phase I dose-finding trials aim at identifying the maximum tolerated dose (MTD). The “3+3” design requires an interruption of enrolment while the evaluation of the previous three patients is pending. In pediatric oncology, investigators proposed the Rolling 6 design to allow for a more continuous enrollment. In a simulation study, we showed that an adaptive dose-finding design, with dose allocation guided by a statistical model not only minimizes accrual suspension as with the rolling 6, and but also led to identify more frequently the MTD. However, the performance of these designs in terms of correct identification of the MTD is limited by the binomial variability of the main outcome: the occurrence of dose-limiting toxicity over the first cycle of treatment. We have then proposed a new adaptive design using repeated ordinal data of toxicities experienced during all the cycles of treatment. We aim at identifying the dose associated with a specified tolerable probability of severe toxicity per cycle. The outcome was expressed as the worst toxicity experienced, in three categories (severe / moderate / no toxicity), repeated at each treatment cycle. It was modeled through a proportional odds mixed model. This model enables to seek for cumulated toxicity with time, and to increase the ability to identify the targeted dose, with no increased risk of toxicity, and without delaying study completion. We also compared this ordinal model to a more parsimonious logistic mixed model.Because of their applicability and efficiency, those models for longitudinal data should be more often used in phase I dose-finding trials.

The Liquid Argon calorimeter of the ATLAS detector at CERN near Geneva is equipped with improved readout and trigger electronics for the operation at higher luminosity LHC in the frame of several upgrades (Phase-0, I, and II). Special attention is given to an early digitisation of detector raw data and their following digital data transmission and processing via FPGAs already for the Level-1 trigger. The upgrades additionally foresee to provide higher spatial granularity information for the Level-1 trigger in order to improve its performance for low momentum single particles at increased collision rates. The first part of this dissertation contains the development and implementation of a modular detector simulation framework, AREUS, which allows to analyse different filter algorithms for the energy reconstruction as well as their performance with respect to the expected digitised detector raw data. In this detector simulation framework the detailed algorithmic functionality of the FPGAs has been taken into account. Various filter algorithms, especially the Optimal Filter and a Wiener Filter with Forward Correction, are discussed with regard to their performance in energy reconstruction of the future Liquid Argon calorimeter trigger system. In the second part of this thesis, the high-speed data transfer for the acquisition of the trigger data is being developed. For this purpose, a generic 10 Gigabit Ethernet UDP stack is designed in VHDL, that is currently applied in an ALTERA® Stratix-IV FPGA as part of the readout electronics of a demonstrator setup in the context of the Phase-0 Upgrade. After implementation in a prototype electronics board, data transfer from the detector front-end is realised. A successful test in the demonstrator setup installed in the ATLAS detector verifying the correct transmission of the Liquid Argon calorimeter trigger signals concludes this work. / Das Flüssig-Argon-Kalorimeter des ATLAS-Detektors am CERN bei Genf wird für den Betrieb am LHC mit erhöhter Luminosität im Rahmen mehrerer Upgrades (Phase-0, I und II) mit verbesserter Auslese- und Triggerelektronik ausgestattet. Ein besonderes Augenmerk liegt hierbei auf der frühzeitigen Digitalisierung der Detektorrohdaten und deren folgende digitale Übertragung sowie Verarbeitung mittels FPGAs bereits für den Level-1 Trigger. Die Upgrades sehen zusätzlich vor, dem Level-1 Trigger eine höhere Ortsauflösung bereitzustellen um seine Leistungsfähigkeit der Energierekonstruktion von niedrigenergetischen Teilchen bei erhöhter Kollisionsrate zu verbessern. Der erste Teil dieser Dissertation beinhaltet die Entwicklung und Umsetzung einer modularen Detektorsimulationsumgebung, AREUS, mit der verschiedene Filteralgorithmen zur Energierekonstruktion sowie deren Performanz in Abhängigkeit der erwarteten digitalisierten Detektorrohdaten analysiert werden können. Dabei wurde in der Simulationsumgebung die Funktionalität der Rechenarithmetik der später verwendeten FPGAs berücksichtigt. Verschiedener Filteralgorithmen, im Besonderen der Optimal Filter und ein Wiener Filter mit Korrekturglied, werden im Hinblick auf ihre Performanz der Energierekonstruktion für das zukünftige Triggersystem des Flüssig-Argon-Kalorimeters diskutiert. Der zweite Teil dieser Arbeit beschäftigt sich mit der Hochgeschwindigkeitsdatenübertragung zur Erfassung von Triggerdaten. Zu diesem Zweck wird ein generischer 10 Gigabit Ethernet UDP Stack in VHDL entworfen, der als Teil der Ausleseelektronik eines Demonstrator-Testaufbaus im Rahmen des Phase-0 Upgrades in einem ALTERA® Stratix-IV FPGA aktuell zum Einsatz kommt. Nach Implementierung in einem Prototypen einer Auslesekarte konnte ein Transfer von Detektordaten realisiert werden. Eine Überprüfung am Demonstrator-Testaufbau, welcher im ATLAS Detektor installiert ist, schließt diese Dissertation ab. Sie hat eine korrekte Übertragung von Triggersignalen des Flüssig-Argon-Kalorimeters erfolgreich bestätitgt.

A nefrolitíase é uma doença comum e recorrente com prevalência mundial variando de 5 a 20%, com pico de incidência entre a 3ª e 4ª década de vida e com maior prevalência em homens (3:1), frequentemente associado a atendimento de urgência. O tratamento da litíase ocorre em duas fases. Inicialmente, no episódio agudo de dor pela passagem do cálculo pelas vias urinárias, cujo objetivo terapêutico é o alívio da dor e a expulsão do cálculo. Para aqueles doentes com cálculos de repetição, o objetivo terapêutico será o de reduzir a formação de novos cálculos. Para ambos os objetivos, o arsenal terapêutico disponível é limitado. Estudos pré-clínicos com o Extrato Padronizado de C. langsdorffi - EPC-AF® (Apis-Flora, Ribeirão Preto, Brasil), um composto vegetal extraído da bioflora nacional, mostraram perfil de segurança e eficácia deste composto como potencial medicamento para o tratamento da litíase renal. Desta forma, o objetivo deste estudo foi o de avaliar o perfil de segurança em humanos e eficácia preliminar do EPC-AF®. Foi realizado um estudo clínico fase I/IIa, randomizado, duplo-cego, comparado com placebo, de dose única de forma ascendente. As doses utilizadas foram de 175 mg, 350 mg,700 mg, 1,4 g e 2,8 g administradas por via oral em dose única após jejum de 12h. Foram estudados grupos de 6 voluntários sadios por dose. Em cada grupo, 4 voluntários receberam de forma randomizada e cega o EPC-AF® e 2 voluntários placebo. O escalonamento para doses mais altas foi feito após a comprovação de que não houve eventos adversos com a dose previamente usada. No total, 30 voluntários sadios foram estudados na Unidade de Pesquisa Clínica do HCFMRP-USP. Foram coletados dados clínicos e laboratoriais para segurança, com destaque para toxicidade renal, onde foram estudados variação das concentrações urinárias de NGAL (neutrophil gelatinaseassociated lipocalin), NAG (N-acetyl-beta-D-glucosaminidase), KIM-1 (Kidney injury molecule-1) e alfa-1-microglobulina, além da dosagem sérica de cistatina C, um marcador da taxa de filtração glomerular. Os dados de eficácia preliminar foramcentrados na análise do perfil bioquímico urinário (pH, cálcio, citrato, oxalato, ácido úrico, magnésio e fosforo) em amostras de urina de 24h, coletadas antes e imediatamente após o uso de EPC-AF® ou placebo. Os resultados obtidos mostraram que o EPC-AF® é seguro nas doses de 175 a 2,8 g por via oral. Não foi observada variações significativas das concentrações de 24h dos principais componentes facilitadores ou inibidores da formação de cálculos urinários / Nephrolithiasis is a common and recurrent disease with a worldwide prevalence varying from 5 to 20%, with a incidence peak between the 3rd and 4th decade of life and with a higher prevalence in men than women (3: 1), often associated with urgent care. The treatment of lithiasis occurs in two phases. Firstly, in the acute episode of pain by the passage of the calculus through the urinary tract, whose therapeutic objective is to relieve pain and expel the stone. For those patients with recurrent stones the therapeutic goal will be reducing the formation of new stones. For both objectives, the available therapeutic arsenal is limited. Preclinical studies with C. langsdorffi standard extract (EPC-AF®, Apis-Flora, Ribeirão Preto, Brazil), an herbal compound extracted from a Brazilian native plant, showed a safety and efficacy profile of this compound as a potential drug for the treatment of renal lithiasis. Thus, the objective of this study was to evaluate the safety profile and the preliminary efficacy of EPC-AF® in healthy volunteers. A phase I/IIa clinical trial, randomized, double-blinded, placebocontrolled single-ascending dose was conducted. The doses used were 175 mg, 350 mg, 700 mg, 1.4 g and 2.8 g administered orally in a single dose after 12 h fasting. Groups of 6 healthy volunteers per dose were studied. In each group, 4 volunteers randomly and blindly received EPC-AF® and 2 volunteers received placebo. The escalation to higher doses was done after the confirmation that there were no adverse events with the dose previously used. In total, 30 healthy volunteers were studied on the General Clinical Research Centre of local teaching Hospital. Clinical and laboratory data were collected for safety, with emphasis on renal toxicity, where urinary concentrations of NGAL (neutrophil gelatinase-associated lipocalin), NAG (N-acetylbeta-D-glucosaminidase), KIM-1 (Kidney injury molecule-1) and alpha-1-microglobulin were measured, in addition to serum cystatin C, a marker of the glomerular filtration rate. Preliminary efficacy data were centered on urinary biochemical profile analysis (pH, calcium, citrate, oxalate, uric acid, magnesium and phosphorus) in 24-hour urinesamples collected before and immediately after use of EPC-AF® or placebo. The results showed that EPC-AF® is safe in doses of 175 to 2.8 g orally. No significant variations in 24-h concentrations of the major components facilitating or inhibiting the formation of urinary stones were observed