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Polymeric materials are increasingly being used in diverse, very demanding applications. Either pre- or post- application environments may require exposures to conditions hostile to the polymer's integrity. Frequently, these demanding conditions result in degradation of the polymer and subsequent decreases in desirable properties. Clearly then, a methodology to predict important properties, such as Tg, molecular weight, and tensile strength, from knowledge of the environmental history of a polymeric-based specimen is beneficial. The current study focuses on bisphenol A polycarbonate and tracks changes in the properties of this material as a function of the degree of degradation, t. For the purposes of the present research, the environmental effects have been limited to those associated with elevated temperature, although the methodology is general. This t parameter is a product of the kinetic rate constant, k, found from isothermal kinetics, and the time of degradation, t. Elucidation of t has been linked to measurement of the molecular weight distribution which in turn can be related to various properties to yield predictive relationships for these properties. Only the thermal history of the polymer and its initial properties are required for the model. This technique is not limited to a specific polymer or even to thermal degradation. As long as the kinetics of the process can be mathematically modeled, this approach should apply to a host of other situations, providing property prediction simply from knowledge of the material history. The research seeks to better understand the thermal degradation of polycarbonate. Kinetics of the process was explored, and the chemical mechanisms were examined. A key part of the project was the determination of the molecular weights and molecular weight distributions at each level of degradation. Furthermore, mechanical stress-strain properties, glass transition temperatures, and melt viscosities were also measured. This information, together with the kinetic expressions, facilitated prediction of these types of material properties for a known thermal history. Ph. D.

Au XXe siecle, le Japon aura laisse sur le monde une marque indelebile. Mais au-dela des coups d'eclat culturels, militaires et economiques, le pays du soleil levant est le lieu d'une pensee ou la modernite est a la fois l'enjeu et l'acteur de profonds debats. Cet ouvrage rassemble des articles de chercheurs provenant de six pays, incluant le Canada, les Etats-Unis, le Japon et la France. Leurs contributions sont autant d'incursions dans ce riche territoire qu'est la modernite japonaise. De l'histoire de l'art du debut du siecle au systeme d'esclavage sexuel, de la citoyennete des femmes a l'epoque imperiale aux positions totalitaires de Watsuji Tetsuro, proches de celles de Heidegger, l'histoire du Japon moderne est ici reexaminee dans ce qu'elle a de plus fondamental.Ce qui unifie ces articles malgre la diversite de leurs approches et methodologies (philosophie, litterature, sciences naturelles, geographie, entre autres), c'est une volonte constante de repenser le nationalisme culturel et son role dans la construction de la modernite japonaise, ainsi qu'un questionnement serieux des paradigmes memes de l'histoire des idees.Livia Monnet est professeur au Departement de litterature comparee et au Centre d'etudes de l'Asie de l'Est de l'Universite de Montreal. Elle est l'auteur de plusieurs livres et de nombreux articles sur la litterature et le cinema japonais contemporains.

Abstract 741 We have previously shown that a costimulation blockade-containing regimen could provide effective protection against acute GvHD (aGvHD) in a non-human primate model. We therefore designed a first-in-disease trial of in vivo CD28:CD80/86-directed costimulation blockade with CTLA4-Ig (abatacept) to prevent aGvHD after unrelated-donor HSCT for patients > 12y. (Clinical Trials.Org #NCT01012492). In this trial, 10mg/kg abatacept was administered IV on day −1, +5, +14, +28 in addition to standard prophylaxis with cyclosporine + MTX. Enrollment of all patients is complete, and the study is evaluable for feasibility, toxicity, engraftment, and the primary immunologic outcome: the incidence of Grade III-IV aGvHD by d+100. Patient Characteristics and Survival: 10 patients, with a median age of 44.5 y (17–74) were enrolled and treated. 6 patients received HLA-mismatched grafts (matched at 7/8 alleles) and 4 received 8/8 HLA-matched URD grafts. 8 received PBSCs and 2 received BM. All received high-intensity conditioning (Bu/Cy, TBI/Cy or Flu/Mel). With a median follow-up of 367 days (262–680), 7 patients are alive and in remission. 2 patients died of relapse (Day +121 and Day +147). One patient died, in remission, of multi-organ failure on day +453 post-transplant. Feasibility, Pharmacokinetics and Pharmacodynamics of Abatacept in HSCT: All 10 patients received all 4 scheduled abatacept doses, without infusion reactions. The average peak (230.9 +/− 7.4 mg/ml) and trough (45.9 +/− 2.8 mg/ml) abatacept levels, as well as the terminal T1/2 (19.6 +/− 1.9 days) were similar to that observed previously. Importantly, as has been previously established in vitro, patients receiving abatacept demonstrated significant inhibition of post-transplant CD4+ T cell proliferation (with >80% reduction in the accumulation of Ki-67+ proliferating CD4+ T cells at d+14 and +28 compared to a control cohort who received cyclosporine + methotrexate without abatacept, Figure 1). This data establishes, for the first time, the feasibility of giving abatacept to this new patient population, and that the PK and PD parameters in HSCT closely mirror those previously shown to effectively control immune-mediated diseases. Engraftment: All patients achieved neutrophil engraftment (median d+16.5) and donor engraftment (100% CD33 chimerism at d+30). Lymphocyte recovery was rapid: Day +100 mean peripheral blood counts showed ALC = 1053 +/− 259 cells/ml, total T cells = 741 +/− 208 cells/ml, and CD8+ T cells = 381 +/− 99 cells/ml. The Day +100 CD4+ T cells = 285 +/− 105 cells/ml, not significantly different from historical controls (n = 43) that received CNI/MTX aGvHD prophylaxis without abatacept (262 +/−26 cells/ml). GvHD: Patients receiving the abatacept-containing regimen had encouragingly low rates of early severe aGvHD: Two patients developed aGvHD before day +100, with one of these patients (Gr II) progressing to steroid-dependent cGvHD of the liver and one patient (Gr III) with complete resolution of aGvHD (and currently off steroids). The cumulative incidence of grade II-IV and III-IV aGvHD by day 100 was thus 20% and 10%, respectively (Figure 2). Importantly, there was no Gr IV aGvHD, no patient received salvage therapy for aGvHD, and there were no deaths from aGvHD. After day +100, one patient developed late acute GvHD (currently off all immunosuppression), and two patients developed overlap syndrome. Both had responsive disease and are currently either weaning or off corticosteroids. No other patient developed late aGvHD, and no other patient has developed moderate or severe cGvHD. Infection: No life-threatening infections occurred. 5 patients developed CMV reactivation, all responsive to antivirals. No patient developed CMV disease. No EBV viremia >1000 copies/ml occurred. One patient developed EBV+ plasmacytic hyperplasia of the tongue, which resolved without intervention. No other EBV-related disease occurred. Conclusions: This trial demonstrates, for the first time, the feasibility of adding in vivo T cell costimulation blockade with abatacept for aGvHD prevention. The decreased CD4+ T cell proliferation post-transplant and the encouragingly low rates of early, severe aGvHD suggest that costimulation blockade may be an effective agent for aGvHD prophylaxis and support the conduct of a larger, randomized phase 2 study. Disclosures: Off Label Use: Abatacept was used in this trial. It is a costimulation blockade agent which was tested for its ability to prevent aGvHD.

Objective: To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS). Methods: We long-listed licensed drugs with evidence of human safety, blood–brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review. Results: From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine. Conclusions: We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.

OBJECTIVE: To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS). METHODS: We long-listed licensed drugs with evidence of human safety, blood-brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review. RESULTS: From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine. CONCLUSIONS: We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.