Ontario Neurodegenerative Disease Research Initiative (ONDRI): Structural MRI Methods and Outcome Measures

The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 years multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural MRI, from neurodegenerative patients with Alzheimer\u27s disease, mild cognitive impairment, Parkinson\u27s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. The purpose of this paper is to serve as a reference and conceptual overview of the comprehensive neuroimaging pipeline used to generate regional brain tissue volumes and neurovascular marker data that will be made publicly available online

Photodepletion differentially affects CD4(+) Tregs versus CD4(+) effector T cells from patients with chronic graft-versus-host disease

Even the most potent immunosuppressive drugs often fail to control graft-versus-host disease (GVHD), the most frequent and deleterious posttransplantation complication. We previously reported that photodepletion using dibromorhodamine (TH9402) eliminates T cells from healthy donors activated against major histocompatibility complex-incompatible cells and spares resting T cells. In the present study, we identified photodepletion conditions selectively eradicating endogenous proliferating T cells from chronic GVHD patients, with the concomittant sparing and expansion of CD4(+) CD25(+) forkhead box protein 3-positive T cells. The regulatory T-cell (Treg) nature and function of these photodepletion-resistant cells was demonstrated in coculture and depletion/repletion experiments. The mechanism by which Tregs escape photodepletion involves active P-glycoprotein-mediated drug efflux. This Treg-inhibitory activity is attributable to interleukin-10 secretion, requires cell-cell contact, and implies binding with cytotoxic T-lymphocyte antigen 4 (CTLA-4). Preventing CTLA-4 ligation abrogated the in vitro generation of Tregs, thus identifying CTLA-4-mediated cell-cell contact as a crucial priming event for Treg function. Moreover, the frequency of circulating Tregs increased in chronic GVHD patients treated with TH9402 photodepleted cells. In conclusion, these results identify a novel approach to both preserve and expand Tregs while selectively eliminating CD4(+) effector T cells. They also uncover effector pathways that could be used advantageously for the treatment of patients with refractory GVHD. (Blood. 2010;116(23):4859-4869)Transplantation and immunomodulatio

Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-ALL

The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL. SIGNIFICANCE: Phf6 controls HSC homeostasis, leukemia initiation, and T-ALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of T-ALL

Estabelecimento de ciclo de cura de pré-impregnados aeronáuticos Establishment of cure cycle of aeronautic prepregs

Os compósitos poliméricos podem ser produzidos via moldagem em autoclave, onde as condições de processamento podem ser otimizadas a partir do conhecimento físico-químico da matriz polimérica. A evolução da cinética da reação de cura ocorre simultaneamente com as modificações no comportamento reológico do sistema polimérico, sendo comum denominar o fenômeno de comportamento reo-cinético. O presente trabalho tem como objetivo conhecer os parâmetros de cura, cinéticos e reológicos, de três diferentes sistemas de pré-impregnados de resina epóxi (cura a 177 &deg;C), conhecidos como F161, F584 e 8552, hoje usados na indústria aeronáutica brasileira. Este estudo foi realizado com o auxílio das técnicas de DSC e reologia, utilizando-se análises dinâmicas e isotérmicas. Com isso, foi possível estabelecer a ordem de reação e a cinética de cura dos sistemas estudados. Neste estudo, foram utilizados como modelos matemáticos o de ordem n e o autocatalítico com ordem total de aproximadamente 2. A temperatura de gel foi de ~100 &deg;C, e o tempo de gel correspondente foi de 135 segundos. A partir do conhecimento da cinética de cura e dos parâmetros reológicos dos sistemas de pré-impregnados foi possível estabelecer um ciclo de cura destinado à consolidação das peças aeronáuticas via moldagem em autoclave.<br>Autoclave molding produces polymer composites, where the processing conditions can be optimized with physicochemical knowledge of the polymeric matrix. The cure reaction evolves simultaneously with changes in rheology, which is normally refered to as rheo-kinetic behavior. With the knowledge of the appropriate cure cycle one can identify the steps in which pressure should be applied and when to raise the temperature. This paper is aimed at investigating the cure, kinetics and rheological parameters of three prepreg epoxy systems, namely F161, F584 and 8552, which are currently used in the Brazilian aeronautic industry. Differential scanning calorimetry (DSC) and rheological techniques have been used, both in the isothermal and dynamic modes. Kinetics data were obtained from dynamic and isothermal DSC, with rheological measurements being carried out during the cure. The mathematical models used were the nth order reaction model and the autocatalytic model with order of 2. The gel temperature was ~100 &deg;C, and the corresponding gelification time was 135 s. With the determination of the kinetics for the cure and of the rheological parameters of the prepreg systems, a cure cycle should be established that led to high-performance composites using the autoclave molding