Association de tau avec les membranes Golgiennes : nouvelles avenues dans la pathogenèse de tau

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

The MHC class I peptide repertoire is molded by the transcriptome

Under steady-state conditions, major histocompatibility complex (MHC) I molecules are associated with self-peptides that are collectively referred to as the MHC class I peptide (MIP) repertoire. Very little is known about the genesis and molecular composition of the MIP repertoire. We developed a novel high-throughput mass spectrometry approach that yields an accurate definition of the nature and relative abundance of unlabeled peptides presented by MHC I molecules. We identified 189 and 196 MHC I–associated peptides from normal and neoplastic mouse thymocytes, respectively. By integrating our peptidomic data with global profiling of the transcriptome, we reached two conclusions. The MIP repertoire of primary mouse thymocytes is biased toward peptides derived from highly abundant transcripts and is enriched in peptides derived from cyclins/cyclin-dependent kinases and helicases. Furthermore, we found that ∼25% of MHC I–associated peptides were differentially expressed on normal versus neoplastic thymocytes. Approximately half of those peptides are derived from molecules directly implicated in neoplastic transformation (e.g., components of the PI3K–AKT–mTOR pathway). In most cases, overexpression of MHC I peptides on cancer cells entailed posttranscriptional mechanisms. Our results show that high-throughput analysis and sequencing of MHC I–associated peptides yields unique insights into the genesis of the MIP repertoire in normal and neoplastic cells

A comprehensive map of the mTOR signaling network

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation. mTOR signaling is frequently dysregulated in oncogenic cells, and thus an attractive target for anticancer therapy. Using CellDesigner, a modeling support software for graphical notation, we present herein a comprehensive map of the mTOR signaling network, which includes 964 species connected by 777 reactions. The map complies with both the systems biology markup language (SBML) and graphical notation (SBGN) for computational analysis and graphical representation, respectively. As captured in the mTOR map, we review and discuss our current understanding of the mTOR signaling network and highlight the impact of mTOR feedback and crosstalk regulations on drug-based cancer therapy. This map is available on the Payao platform, a Web 2.0 based community-wide interactive process for creating more accurate and information-rich databases. Thus, this comprehensive map of the mTOR network will serve as a tool to facilitate systems-level study of up-to-date mTOR network components and signaling events toward the discovery of novel regulatory processes and therapeutic strategies for cancer

Strategies to reduce waiting times in outpatient rehabilitation services for adults with physical disabilities : a systematic literature review

Objective: Identifying effective strategies to reduce waiting times is a crucial issue in many areas of health services. Long waiting times for rehabilitation services have been associated with numerous adverse effects in people with disabilities. The main objective of this study was to conduct a systematic literature review to assess the effectiveness of service redesign strategies to reduce waiting times in outpatient rehabilitation services for adults with physical disabilities. Methods: We conducted a systematic review, searching three databases (MEDLINE, CINAHL and EMBASE) from their inception until May 2021. We identified studies with comparative data evaluating the effect of rehabilitation services redesign strategies on reducing waiting times. The Mixed Methods Appraisal Tool was used to assess the methodological quality of the studies. A narrative synthesis was conducted. Results: Nineteen articles including various settings and populations met the selection criteria. They covered physiotherapy (n = 11), occupational therapy (n = 2), prosthetics (n = 1), exercise physiology (n = 1) and multidisciplinary (n = 4) services. The methodological quality varied (n = 10 high quality, n = 6 medium, n = 3 low); common flaws being missing information on the pre-redesign setting and characteristics of the populations. Seven articles assessed access processes or referral management strategies (e.g. self-referral), four focused on extending/modifying the roles of service providers (e.g. to triage) and eight changed the model of care delivery (e.g. mode of intervention). The different redesign strategies had positive effects on waiting times in outpatient rehabilitation services. Conclusions: This review highlights the positive effects of many service redesign strategies. These findings suggest that there are several effective strategies to choose from to reduce waiting times and help better respond to the needs of persons experiencing physical disabilities

Primordial fluctuations and non-Gaussianities from multifield DBI Galileon inflation

We study a cosmological scenario in which the DBI action governing the motion of a D3-brane in a higher-dimensional spacetime is supplemented with an induced gravity term. The latter reduces to the quartic Galileon Lagrangian when the motion of the brane is non-relativistic and we show that it tends to violate the null energy condition and to render cosmological fluctuations ghosts. There nonetheless exists an interesting parameter space in which a stable phase of quasi-exponential expansion can be achieved while the induced gravity leaves non trivial imprints. We derive the exact second-order action governing the dynamics of linear perturbations and we show that it can be simply understood through a bimetric perspective. In the relativistic regime, we also calculate the dominant contribution to the primordial bispectrum and demonstrate that large non-Gaussianities of orthogonal shape can be generated, for the first time in a concrete model. More generally, we find that the sign and the shape of the bispectrum offer powerful diagnostics of the precise strength of the induced gravity.Comment: 34 pages including 9 figures, plus appendices and bibliography. Wordings changed and references added; matches version published in JCA

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m$^{-}$$^{2}$ once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485

Analysis of Blood Stem Cell Activity and Cystatin Gene Expression in a Mouse Model Presenting a Chromosomal Deletion Encompassing Csta and Stfa2l1

The cystatin protein superfamily is characterized by the presence of conserved sequences that display cysteine protease inhibitory activity (e.g., towards cathepsins). Type 1 and 2 cystatins are encoded by 25 genes of which 23 are grouped in 2 clusters localized on mouse chromosomes 16 and 2. The expression and essential roles of most of these genes in mouse development and hematopoiesis remain poorly characterized. In this study, we describe a set of quantitative real-time PCR assays and a global expression profile of cystatin genes in normal mouse tissues. Benefiting from our collection of DelES embryonic stem cell clones harboring large chromosomal deletions (to be reported elsewhere), we selected a clone in which a 95-kb region of chromosome 16 is missing (Del16qB3Δ/+). In this particular clone, 2 cystatin genes, namely Csta and Stfa2l1 are absent along with 2 other genes (Fam162a, Ccdc58) and associated intergenic regions. From this line, we established a new homozygous mutant mouse model (Del16qB3Δ/16qB3Δ) to assess the in vivo biological functions of the 2 deleted cystatins. Stfa2l1 gene expression is high in wild-type fetal liver, bone marrow, and spleen, while Csta is ubiquitously expressed. Homozygous Del16qB3Δ/16qB3Δ animals are phenotypically normal, fertile, and not overtly susceptible to spontaneous or irradiation-induced tumor formation. The hematopoietic stem and progenitor cell activity in these mutant mice are also normal. Interestingly, quantitative real-time PCR expression profiling reveals a marked increase in the expression levels of Stfa2l1/Csta phylogenetically-related genes (Stfa1, Stfa2, and Stfa3) in Del16qB3Δ/16qB3Δ hematopoietic tissues, suggesting that these candidate genes might be contributing to compensatory mechanisms. Overall, this study presents an optimized approach to globally monitor cystatin gene expression as well as a new mouse model deficient in Stfa2l1/Csta genes, expanding the available tools to dissect cystatin roles under normal and pathological conditions

Role for miR-204 in human pulmonary arterial hypertension

Reduced miR-204 expression facilitates the excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells characteristic of human pulmonary arterial hypertension