The aims of this thesis were to investigate the utility of in vitro drug sensitivity testing to optimize the use of cancer chemotherapy and to assess the properties of a new cancer drug in a phase I clinical trial. Tumour cells from patients were analysed with the short-term Fluorometric Microculture Cytotoxicity Assay (FMCA). In samples from a wide spectrum of tumour types, the effect of the drug combination FEC (5Fu-epirubicin-cyclophosphamide) was generally appropriately predicted from the effect of the best component drug. However, of samples intermediately sensitive to the best single drug, 45% converted to sensitive when testing the combination. Thus, combination testing may identify advantageous interactions and improve in vitro test performance. In tumour samples from peritoneal carcinomatosis, significant differences in drug sensitivity between diagnoses were observed, cross-resistance between most drugs was modest or absent, and the concentration-effect relationships for two drugs in individual samples varied considerably. Thus, for optimal selection of drugs for intraperitoneal chemotherapy, differences in drug sensitivity at the diagnosis and individual patient level should be considered. In samples from patients with ovarian carcinoma, drug sensitivity was related to tumour grade, histologic subtype and patient treatment status. In a homogeneous subset of patients, the FMCA predicted individual patient tumour response with high sensitivity and specificity. Thus, if carefully interpreted in the context of important clinical variables, in vitro testing could be of value for individualizing chemotherapy in ovarian cancer. Employing a once weekly dosing schedule in a phase I trial, the mechanistically new and preclinically promising NAD depleting drug CHS 828 produced dose limiting thrombocytopenia and gastrointestinal toxicity without clear evidence of anti-tumour efficacy. It is concluded that in vitro drug sensitivity testing could be a way to optimize the use of chemotherapy and that successful development of new cancer drugs needs improved strategies.

BackgroundAtrazine suppression of the LH surge slowly develops over time and peaks after 4 days; sensitivity to atrazine decreases after 8 or 14 days of dosing. Adaptation of the LH response was correlated with increased phase I and phase II liver enzyme activity/expression. MethodsThe effect of atrazine on the LH surge was evaluated in female Sprague-Dawley rats administered 100 mg/kg/day atrazine by gavage for 1, 2, 3, or 4 consecutive days or 6.5, 50, or 100 mg/kg/day atrazine for 4, 8, or 14 days. ResultsNo statistically significant effects of atrazine were seen on peak plasma LH or LH area under the curve (AUC) after one, two, or three doses of 100 mg/kg/day. Four daily doses of 50 or 100 mg/kg atrazine significantly reduced peak LH and LH AUCs, whereas 6.5 mg/kg/day had no effect. After 8 or 14 days of treatment, statistically significantly reduced peak LH and LH AUC were observed in the 100 mg/kg/day dose group, but not in the 6.5 or 50 mg/kg/day dose groups, although significantly reduced LH was observed in one sample 9 hr after lights-on in the 50 mg/kg/day dose group on day 14. The number of days of treatment required to achieve a significant suppression of the LH surge is consistent with the repeat-dose pharmacokinetics of the chlorotriazines. ConclusionThe apparent adaptation to the effect of atrazine on the LH surge after 8 or 14 days may be related to the induction of phase I or, more likely, phase II metabolism observed in this study after 8 days, or to a decreased sensitivity of the hypothalamic-pituitary-adrenal axis or an homeostatic adaption of the effect of atrazine on the LH surge mechanism. Birth Defects Research 110:246-258, 2018. (c) 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

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.

In this project we review the developments of several variations of the up-and-down design utilized in Phase I clinical trials to estimate the maximum tolerated dose (MTD) of a drug which corresponds to a fixed probability of response or the pre-specified toxicity rate in the target population. In these designs selection of dose levels is restricted to one level higher, one level lower or the same. Several methods of estimation of the MTD are investigated. Some comparison of the designs by Monte Carlo simulation are carried out by the quality of the estimator of the target dose using the isotonic estimator. The designs are investigated under the generalized logistic (for different values of the power) and the gamma distributions. The NR is found to perform best on the basis of the quality of estimator under these distributions. The BCD is found to perform best on the basis of the average proportion of toxicity for a pre-specified toxicity rate of 0.2 whereas the KROW performs best for a toxicity rate of 0.3. / Thesis / Master of Science (MS)

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.