Étude de la modulation de la cascade de l'interféron suite à l'infection par le VIH

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

Optimal human papillomavirus vaccination strategies to prevent cervical cancer in low-income and middle-income countries in the context of limited resources: a mathematical modelling analysis

Introduction of human papillomavirus (HPV) vaccination has been slow in low-income and middle-income countries (LMICs) because of resource constraints and worldwide shortage of vaccine supplies. To help inform WHO recommendations, we modelled various HPV vaccination strategies to examine the optimal use of limited vaccine supplies and best allocation of scarce resources in LMICs in the context of the WHO global call to eliminate cervical cancer as a public health problem. Methods In this mathematical modelling analysis, we developed HPV-ADVISE LMIC, a transmission-dynamic model of HPV infection and diseases calibrated to four LMICs: India, Vietnam, Uganda, and Nigeria. For different vaccination strategies that encompassed use of a nine-valent vaccine (or a two-valent or four-valent vaccine assuming high cross-protection), we estimated three outcomes: reduction in the age-standardised rate of cervical cancer, number of doses needed to prevent one case of cervical cancer (NNV; as a measure of efficiency), and the incremental cost-effectiveness ratio (ICER; in 2017 international $per disability-adjusted life-year [DALY] averted). We examined different vaccination strategies by varying the ages of routine HPV vaccination and number of age cohorts vaccinated, the population targeted, and the number of doses used. In our base case, we assumed 100 Findings We predicted that HPV vaccination could lead to cervical cancer elimination in Vietnam, India, and Nigeria, but not in Uganda. Compared with no vaccination, strategies that involved vaccinating girls aged 9-14 years with two doses were predicted to be the most efficient and cost-effective in all four LMICs. NNV ranged from 78 to 381 and ICER ranged from$28 per DALY averted to $1406 per DALY averted depending on the country. The most efficient and cost-effective strategies were routine vaccination of girls aged 14 years, with or without a later switch to routine vaccination of girls aged 9 years, and routine vaccination of girls aged 9 years with a 5-year extended interval between doses and a catch-up programme at age 14 years. Vaccinating boys (aged 9-14 years) or women aged 18 years or older resulted in substantially higher NNVs and ICERs. Interpretation We identified two strategies that could maximise efforts to prevent cervical cancer in LMICs given constraints on vaccine supplies and costs and that would allow a maximum of LMICs to introduce HPV vaccination. Funding World Health Organization, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, PATH, and The Bill & Melinda Gates Foundation. Translations For the French and Spanish translations of the abstract see Supplementary Materials section

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033

The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4. Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.This work was supported by the Swiss Bridge Award 2011, the Swiss Cancer League (KFS-29-02-2012 to MEH) and the Swiss National Science Foundation (3100A-163297, to MEH and MD)

Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries.

BACKGROUND: The WHO Director-General has issued a call for action to eliminate cervical cancer as a public health problem. To help inform global efforts, we modelled potential human papillomavirus (HPV) vaccination and cervical screening scenarios in low-income and lower-middle-income countries (LMICs) to examine the feasibility and timing of elimination at different thresholds, and to estimate the number of cervical cancer cases averted on the path to elimination. METHODS: The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC), which consists of three independent transmission-dynamic models identified by WHO according to predefined criteria, projected reductions in cervical cancer incidence over time in 78 LMICs for three standardised base-case scenarios: girls-only vaccination; girls-only vaccination and once-lifetime screening; and girls-only vaccination and twice-lifetime screening. Girls were vaccinated at age 9 years (with a catch-up to age 14 years), assuming 90% coverage and 100% lifetime protection against HPV types 16, 18, 31, 33, 45, 52, and 58. Cervical screening involved HPV testing once or twice per lifetime at ages 35 years and 45 years, with uptake increasing from 45% (2023) to 90% (2045 onwards). The elimination thresholds examined were an average age-standardised cervical cancer incidence of four or fewer cases per 100 000 women-years and ten or fewer cases per 100 000 women-years, and an 85% or greater reduction in incidence. Sensitivity analyses were done, varying vaccination and screening strategies and assumptions. We summarised results using the median (range) of model predictions. FINDINGS: Girls-only HPV vaccination was predicted to reduce the median age-standardised cervical cancer incidence in LMICs from 19·8 (range 19·4-19·8) to 2·1 (2·0-2·6) cases per 100 000 women-years over the next century (89·4% [86·2-90·1] reduction), and to avert 61·0 million (60·5-63·0) cases during this period. Adding twice-lifetime screening reduced the incidence to 0·7 (0·6-1·6) cases per 100 000 women-years (96·7% [91·3-96·7] reduction) and averted an extra 12·1 million (9·5-13·7) cases. Girls-only vaccination was predicted to result in elimination in 60% (58-65) of LMICs based on the threshold of four or fewer cases per 100 000 women-years, in 99% (89-100) of LMICs based on the threshold of ten or fewer cases per 100 000 women-years, and in 87% (37-99) of LMICs based on the 85% or greater reduction threshold. When adding twice-lifetime screening, 100% (71-100) of LMICs reached elimination for all three thresholds. In regions in which all countries can achieve cervical cancer elimination with girls-only vaccination, elimination could occur between 2059 and 2102, depending on the threshold and region. Introducing twice-lifetime screening accelerated elimination by 11-31 years. Long-term vaccine protection was required for elimination. INTERPRETATION: Predictions were consistent across our three models and suggest that high HPV vaccination coverage of girls can lead to cervical cancer elimination in most LMICs by the end of the century. Screening with high uptake will expedite reductions and will be necessary to eliminate cervical cancer in countries with the highest burden. FUNDING: WHO, UNDP, UN Population Fund, UNICEF-WHO-World Bank Special Program of Research, Development and Research Training in Human Reproduction, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, National Health and Medical Research Council Australia Centre for Research Excellence in Cervical Cancer Control

Modulation de l'anisotropie dans le ferrite de cobalt en couches minces pour des applications en électronique de spin

The field of magnetic storage is in constant progress to constantly push further the storage capacity of the device. A promising approach is the perpendicular magnetic recording of datas. The material presented in this manuscript is cobalt ferrite. It is an excellent candidate for the realization of perpendicular storage device due to its properties. The present work deals with the modification of the magnetic anisotropy by doping the ferrite cobalt thin films with rare earth elements. We have demonstrated the possibility to modulate the easy magnetization axis of undoped cobalt ferrite by changing the partial pressure of O2/N2 during the elaboration of the thin films. We have also highlighted the insertion of rare earth elements into the structure of the cobalt ferrite although their important ionic radii. The impact of the rare earth anisotropy on the magnetic properties of the ferrite cobalt has also been observed.Le domaine de l’enregistrement magnétique est en constante évolution pour repousser davantage les limites de stockage de l’information, une approche prometteuse étant l’enregistrement perpendiculaire. Le matériau faisant l’objet de ce manuscrit est le ferrite de cobalt CoFe2O4 (= CFO). Ses propriétés font de lui un candidat prometteur pour la réalisation de dispositif à enregistrement perpendiculaire, cela passant par le contrôle de sa direction de facile aimantation.Ce travail de thèse traite ainsi de la modification de l’anisotropie magnétocristalline du CFO en couche mince par dopage aux éléments de terres rares. Nous avons démontré la possibilité de moduler la direction de facile aimantation du CFO non dopé, en modifiant la pression partielle en O2/N2 lors de l’élaboration. Nous avons également mis en évidence l’insertion des éléments lanthanides dans la structure du CFO ainsi que l’impact de l’anisotropie de la terre rare sur les propriétés magnétiques du matériau

Modulation of the anisotropy of cobalt ferrite thin films for spintronic applications

Le domaine de l’enregistrement magnétique est en constante évolution pour repousser davantage les limites de stockage de l’information, une approche prometteuse étant l’enregistrement perpendiculaire. Le matériau faisant l’objet de ce manuscrit est le ferrite de cobalt CoFe2O4 (= CFO). Ses propriétés font de lui un candidat prometteur pour la réalisation de dispositif à enregistrement perpendiculaire, cela passant par le contrôle de sa direction de facile aimantation.Ce travail de thèse traite ainsi de la modification de l’anisotropie magnétocristalline du CFO en couche mince par dopage aux éléments de terres rares. Nous avons démontré la possibilité de moduler la direction de facile aimantation du CFO non dopé, en modifiant la pression partielle en O2/N2 lors de l’élaboration. Nous avons également mis en évidence l’insertion des éléments lanthanides dans la structure du CFO ainsi que l’impact de l’anisotropie de la terre rare sur les propriétés magnétiques du matériau.The field of magnetic storage is in constant progress to constantly push further the storage capacity of the device. A promising approach is the perpendicular magnetic recording of datas. The material presented in this manuscript is cobalt ferrite. It is an excellent candidate for the realization of perpendicular storage device due to its properties. The present work deals with the modification of the magnetic anisotropy by doping the ferrite cobalt thin films with rare earth elements. We have demonstrated the possibility to modulate the easy magnetization axis of undoped cobalt ferrite by changing the partial pressure of O2/N2 during the elaboration of the thin films. We have also highlighted the insertion of rare earth elements into the structure of the cobalt ferrite although their important ionic radii. The impact of the rare earth anisotropy on the magnetic properties of the ferrite cobalt has also been observed

Modulation of the anisotropy of cobalt ferrite thin films for spintronic applications

Le domaine de l’enregistrement magnétique est en constante évolution pour repousser davantage les limites de stockage de l’information, une approche prometteuse étant l’enregistrement perpendiculaire. Le matériau faisant l’objet de ce manuscrit est le ferrite de cobalt CoFe2O4 (= CFO). Ses propriétés font de lui un candidat prometteur pour la réalisation de dispositif à enregistrement perpendiculaire, cela passant par le contrôle de sa direction de facile aimantation.Ce travail de thèse traite ainsi de la modification de l’anisotropie magnétocristalline du CFO en couche mince par dopage aux éléments de terres rares. Nous avons démontré la possibilité de moduler la direction de facile aimantation du CFO non dopé, en modifiant la pression partielle en O2/N2 lors de l’élaboration. Nous avons également mis en évidence l’insertion des éléments lanthanides dans la structure du CFO ainsi que l’impact de l’anisotropie de la terre rare sur les propriétés magnétiques du matériau.The field of magnetic storage is in constant progress to constantly push further the storage capacity of the device. A promising approach is the perpendicular magnetic recording of datas. The material presented in this manuscript is cobalt ferrite. It is an excellent candidate for the realization of perpendicular storage device due to its properties. The present work deals with the modification of the magnetic anisotropy by doping the ferrite cobalt thin films with rare earth elements. We have demonstrated the possibility to modulate the easy magnetization axis of undoped cobalt ferrite by changing the partial pressure of O2/N2 during the elaboration of the thin films. We have also highlighted the insertion of rare earth elements into the structure of the cobalt ferrite although their important ionic radii. The impact of the rare earth anisotropy on the magnetic properties of the ferrite cobalt has also been observed

Efficacité antivirale des différents types d'interférons sur la multiplication du virus BK

Le polyomavirus humain BK (virus BK) établit une infection persistante asymptomatique dans les voies rénales de 80% de la population humaine. Chez les patients transplantés, la réactivation du virus BK est à l'origine de néphropathies et de cystites hémorragiques. L'augmentation des pathologies associées au virus BK en même temps que l'utilisation de traitements immunosuppresseurs de plus en plus puissants souligne un lien étroit entre la réponse immunitaire de l'hôte et la réactivation virale. Cependant la réponse immune à l'infection par le virus BK, en particulier le rôle des cytokines antivirales dans le contrôle de l'infection est peu documentée. Ici, nous avons étudié l'efficacité antivirale des interférons (IFN) sur la multiplication du virus BK. Nous avons testé les IFN-alpha, lambda et gamma sur la souche Dunlop du virus BK dans les cellules Véro et MRC 5. L'IFN-gamma inhibe de façon dose-dépendante la transcription virale de la région précoce et de la région tardive ainsi que l'expression de la protéine virale VP1. Un moindre effet antiviral a été observé avec l'IFN-alpha et l'IFN lambda. Ces résultats sont associés à une phosphorylation prolongée de STAT 1 avec l'IFN-gamma, non retrouvée avec l'IFN-alpha et lambda. La différence d'efficacité entre ces trois types d'IFN suggère que certaines protéines induites seulement par l'IFN-gamma ont un effet antiviral dans l'infection par le virus BK. L'analyse transcriptionnelle révèle neuf protéines qui pourraient être impliquées dans cet effet antiviral spécifique. Parmi elles, nous avons étudié l'effet antiviral de l'indoleamine 2,3-dioxygénase (IDO) et les protéines de liaison au guanylate (GBP ou guanylate binding protéines), GBP1 et GBP2, sur le virus BK. Nos résultats montrent que GBP1 et GBP2 mais pas IDO contribuent à l'activité antivirale de l'IFN-gamma sur le virus BK. Trouver le mécanisme d'action de ces protéines antivirales induites par l'IFN pourrait nous aider à développer une stratégie thérapeutiqueThe human polyomavirus BK (BK virus) establishes an asymptomatic persistent infection in the urinary tract of 80% of the human population. In transplant recipients, reactivation of the BK virus infection is the cause of nephropathy and hemorrhagic cystitis. Diseases associated with BK virus infections are increasing at the same time as potent immunosuppressive therapies are developing. This highlights the importance of components of the immune system in controlling viral reactivation. However, the immune response to the BK virus, particularly the role of antiviral cytokines in infection control, is poorly documented. Here, we investigated the antiviral efficacy of interferons (IFN) on the BK virus multiplication. We tested IFN-alpha, lambda and gamma on the Dunlop strain of BK virus in Vero cells and MRC 5 cells. Treatment with IFN-gamma inhibited the expression of the viral protein VP1 in a dose dependent manner and decreased the expression of the early and late viral transcripts. A weaker antiviral effect was observed with IFN-alpha and IFN-lambda. These results are associated with a prolonged STAT1 phosphorylation with IFN-gamma but not with IFN-alpha and lambda. The difference of efficacy between these three types of interferon suggests that some interferon induced proteins only produced by IFN-gamma had an antiviral effect on BK virus infection. Transcriptomic analysis reveals that nine proteins could be involved in this specific antiviral effect. Among them, we selected and investigated the antiviral effect of indoleamine 2,3-dioxygenase (IDO) and guanylate binding protein 1 and 2 (GBP1 and GBP2) on the BK virus. Our results suggest that GBP1 and GBP2 but not IDO contribute to the antiviral activity of IFN-gamma on the BK virus. Finding the action mechanism of these IFN gamma induced antiviral proteins could help to develop a therapeutic strateg

Travail de recherche sur les approches plurielles et les didactiques du plurilinguisme en lycée professionnel : s'ouvrir aux autres et prendre la parole

Ce travail de recherche en lycée professionnel a questionné le sujet des approches plurielles, du plurilinguisme, et leurs bénéfices induits sur l'apprentissage de la langue vivante. Comment les approches plurielles vont-elles permettre à tous les élèves d'éveiller la conscience de diversité linguistique et culturelle? Peuvent-elles favoriser l'apprentissage de la langue espagnole comme langue vivante en lycée professionnel, et ce pour tous les élèves? Divers appuis théoriques ont ancré notre étude, tels que les travaux de Malika Pedley (Pedley, 2017,) qui a su démontrer que le concours MTOT déclenchait chez les élèves une accélération dans le processus d'apprentissage de l'écriture de la langue étrangère. Les approches plurielles expérimentées au lycée Condorcet d'Arcachon et ce auprès de 87 élèves ont développé la conscientisation des langues en présence dans l'environnement scolaire et/ou familial. Elles ont favorisé la prise de la parole en classe d'espagnol et ont amélioré la compréhension de l'écrit des élèves. Cette interculturalité essentielle au vivre ensemble dans nos sociétés modernes doit être valorisée, et peut l'être par le prisme du plurilinguisme lequel a toute sa place à travers les approches plurielles dans nos cours de langue vivante, et/ou de français