In the context of an intensive upgrade plan for the Large Hadron Collider (LHC) in order to provide proton beams of increased luminosity, a revision of the data readout electronics of the Liquid-Argon-Calorimeter of the ATLAS detector is scheduled. This is required to retain the efficiency of the trigger at increased event rates despite its fixed bandwidth. The focus lies on the early digitization and finer segmentation of the data provided to the trigger. Furthermore, there is the possibility to implement new energy reconstruction algorithms which are adapted to the specific requirements of the trigger. In order to constitute crucial design decisions, such as the digitization scale or the choice of digital signal processing algorithms, comprehensive simulations are required. High trigger efficiencies are decisive at it for the successful continuation of the measurements of rare StandardModel processes as well as for a high sensitivity to new physics beyond the established theories. It can be shown that a significantly improved resolution of the missing transverse energy calculated by the trigger is achievable due to the revised segmentation of the data. Various energy reconstruction algorithms are investigated in detail. It can be concluded that these will facilitate reliable trigger decisions for all expected working conditions and for the whole possible energy range.

No description available.

In the context of an intensive upgrade plan for the Large Hadron Collider (LHC) in order to provide proton beams of increased luminosity, a revision of the data readout electronics of the Liquid-Argon-Calorimeter of the ATLAS detector is scheduled. This is required to retain the efficiency of the trigger at increased event rates despite its fixed bandwidth. The focus lies on the early digitization and finer segmentation of the data provided to the trigger. Furthermore, there is the possibility to implement new energy reconstruction algorithms which are adapted to the specific requirements of the trigger. In order to constitute crucial design decisions, such as the digitization scale or the choice of digital signal processing algorithms, comprehensive simulations are required. High trigger efficiencies are decisive at it for the successful continuation of the measurements of rare StandardModel processes as well as for a high sensitivity to new physics beyond the established theories. It can be shown that a significantly improved resolution of the missing transverse energy calculated by the trigger is achievable due to the revised segmentation of the data. Various energy reconstruction algorithms are investigated in detail. It can be concluded that these will facilitate reliable trigger decisions for all expected working conditions and for the whole possible energy range.

This thesis presents an electrical model of two pairs of interconnects of the ATLAS Phase-1 Upgrade Hadronic Endcap Front End Crate prototype baseplane. Stripline transmission lines of the baseplane are modeled using Keysight Technologies' Electromagnetic Professional's (EMPro) 3D electromagnetic simulation (Finite Element Method) and the connectors are modeled using built-in models in Keysight Technologies' Advanced Design System (ADS). The model is compared in both the time and frequency domain to measured Time Domain Reflectometer (TDR) traces and S-parameters. The S-parameters of the model are found to be within 5% of the measured S-parameters for transmission and reflection, and range from 25% below to 100% above for forward and backward crosstalk. To make comparisons with measurements, the cables used to connect the prototype HEC baseplane to the measurement system had to be included in the model. Plots of the S-parameters of a model without these cables are presented for one pair of interconnects for which the crosstalk is expected to be the higher than most other interconnects of the baseplane. / Graduate / 0605 / 0798 / rdporter@uvic.ca

PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.

No / PURPOSE: C-1311 is a member of the novel imidazoacridinone family of anticancer agents. This phase 1 trial was designed to investigate the safety, tolerability and preliminary anti-tumour activity of C-1311. PATIENTS AND METHODS: This was a phase 1, inter-subject dose escalating and pharmacokinetic study of intravenous (IV) C-1311, administered weekly during 3consecutive weeks followed by 1week rest (constituting 1 cycle) in subjects with advanced solid tumours. RESULTS: Twenty-two (22) patients were treated with C-1311, the highest dose given was 640mg/m(2). All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1-2, except for the blood and lymphatic system disorders, which were primarily of grades 3-4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3weeks every 4weeks is 480mg/m(2), with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7days. Treatment at this dose offers a predictable safety profile and excellent tolerability. CONCLUSION: The safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound.

The overall aim of this thesis was to study participants' understanding of clinical cancer trials, and their motivation for participation. Of particular interest was the question of whether the patients hoped for a cure resulting from the trial. The thesis was based on four studies and used three methods: interviews, a questionnaire, and empirical bioethics. The results of Study I indicated that the participants in phase 1 trials understood most of the information provided, but were unaware of both the very small potential for treatment benefit, and the risk of harm. Patients in phase 3 trials had a good understanding of the trial, except regarding side effects and their right to withdraw. Some found it hard to ask questions and felt they needed more information (Study III). The participants in phase 1 trials were strongly motivated by the generally unrealistic hope for therapeutic benefit (Study I). When the chances of a cure are minuscule, as for participants with end-stage cancer in phase 1 trials, hope can play an important, positive role and offer meaning to one’s remaining life. However, hope for an unrealistic outcome could also deprive patients of an opportunity to spend their remaining lives, as they would otherwise choose (Study II). The participants in phase 3 trials indicated that their motivation for participation was multifaceted; the most common motivations included hope of therapeutic benefit, altruism, access to extra clinical examinations or better care, and a wish to repay society for the help they had received (Study III). After stratifying and analysing the motivation data by gender, age, education and previous experience of trial participation, males and those aged ≥65 years were significantly more motivated to participate out of a desire to reciprocate the help they had received, either because of a sense of duty or because their families or friends considered that they should attend (Study IV). In conclusion, the informed consent process seems to work relatively well, with good results within most subgroups. However, patients with end-stage cancer who are participating in phase 1 trials are a vulnerable group as they have very little potential for treatment benefit coupled with a tangible risk of harm.

L’immunothérapie en agissant au niveau de la tumeur primitive et en empêchant le développement des métastases constitue une des stratégies du traitement des patients atteints de cancer. Afin d’améliorer l’efficacité de celle-ci, il est nécessaire de comprendre comment est induit la mort des cellules tumorales. Dans le laboratoire, il a été observé la guérison de rats BDIX porteurs de tumeurs PROb par un triacyl lipide A. Il a été montré que cet effet impliquait le système immunitaire en mettant en jeu des interactions avec les TLR présents sur de nombreuses cellules tumorales et de l’immunité innée comme les neutrophiles.Dans ce travail, nous avons étudié l’implication éventuelle des neutrophiles dans l’activité anti tumorale du triacyl lipide A chez l’homme.Dans une étude de phase 1 chez des patients porteurs de tumeurs solides réfractaires, nous avons montré que le triacyl lipide A était bien toléré et qu’il induisait la sécrétion de cytokines impliquées dans la réponse immunitaire et notamment dans le recrutement des neutrophiles. Nous avons ensuite, dans un second temps démontré l’implication éventuelle des neutrophiles dans cette réponse immunitaire en vérifiant leur présence dans des tumeurs coliques humaines et en analysant leur proximité avec les cellules tumorales, ces deux facteurs déterminant leur cytotoxicité vis-à-vis des cellules tumorales. Nous avons ensuite fait une analyse comparative par rapport au tissu sain pour rechercher si ces neutrophiles étaient activés et comparer l’expression de chimio attractants. / Immunotherapy acting at the primary tumor site and preventing the development of metastases is one of the strategies for treatment of patients with cancer. To improve the efficiency of the latter, it is necessary to understand how it induces tumor cell death. In the laboratory, it was observed the cure of PROb tumors in rats BDIX by the triacyl lipid A. It has been shown that this effect involved the immune system involving interactions with TLRs present in many tumor cells and innate immunity cells such as neutrophils.In this work, we investigated the possible involvement of neutrophils in the antitumor activity of triacyl lipid A in humans.In a Phase 1 study in patients with refractory solid tumors, we showed that the triacyl lipid A was well tolerated and induced the secretion of cytokines involved in the immune response, particularly in the recruitment of neutrophils. Then, in a second part, we demonstrated the prospective involvement of neutrophils in the immune response by checking their presence in human colon cancers and analyzing their proximity to tumor cells, these two factors determining their cytotoxicity to cells tumor. Then we made a comparative analysis with healthy tissue to research whether these neutrophils were activated and compare the expression of chemo attractors.

L'immunothérapie en agissant au niveau de la tumeur primitive et en empêchant le développement des métastases constitue une des stratégies du traitement des patients atteints de cancer. Afin d'améliorer l'efficacité de celle-ci, il est nécessaire de comprendre comment est induit la mort des cellules tumorales. Dans le laboratoire, il a été observé la guérison de rats BDIX porteurs de tumeurs PROb par un triacyl lipide A. Il a été montré que cet effet impliquait le système immunitaire en mettant en jeu des interactions avec les TLR présents sur de nombreuses cellules tumorales et de l'immunité innée comme les neutrophiles.Dans ce travail, nous avons étudié l'implication éventuelle des neutrophiles dans l'activité anti tumorale du triacyl lipide A chez l'homme.Dans une étude de phase 1 chez des patients porteurs de tumeurs solides réfractaires, nous avons montré que le triacyl lipide A était bien toléré et qu'il induisait la sécrétion de cytokines impliquées dans la réponse immunitaire et notamment dans le recrutement des neutrophiles. Nous avons ensuite, dans un second temps démontré l'implication éventuelle des neutrophiles dans cette réponse immunitaire en vérifiant leur présence dans des tumeurs coliques humaines et en analysant leur proximité avec les cellules tumorales, ces deux facteurs déterminant leur cytotoxicité vis-à-vis des cellules tumorales. Nous avons ensuite fait une analyse comparative par rapport au tissu sain pour rechercher si ces neutrophiles étaient activés et comparer l'expression de chimio attractants.

No description available.