Étude de la voie HOX-Flt3 dans les leucémies de type pré-B induites par E2A-Pbx1

Introduction: Notre laboratoire a précédemment établi que Hoxa9 accélérait l’apparition de leucémie de type B induite par E2A-PBX1. Une analyse par qRT-PCR a montré que les niveaux d’ARN de Flt3, une cible de Hoxa9, étaient 32 fois plus élevés dans les leucémies Hoxa9/E2A-PBX1 par rapport que dans les leucémies E2A-PBX1. Il est important de noter que l’expression aberrante de Flt3 est retrouvée dans les leucémies ALL de type B et les AML. De plus, l’activation constitutive de Flt3 est associée à un faible pronostic. Nous avons posé l’hypothèse que la maintenance/ré-initiation des leucémies de type pré-B induites par E2A-Pbx1 est associée à la présence du récepteur Flt3. Méthodes et Résultats: Premièrement, nous avons analysé par FACS la présence de Flt3 et mesuré l’expression de Flt3 par qRT-PCR des cellules E2A-PBX1 leucémiques pré-B. Nous avons montré que les cellules leucémiques E2A-PBX1 expriment l’ARNm du gène Flt3. Cependant, le récepteur n’était détectable à la surface cellulaire que dans des proportions variant de 0.3 à 28%. Deuxièmement, nous avons évalué le potentiel leucémique des fractions positive et négative pour Flt3. Toutes deux ont été capables de ré-initier la leucémie environ 20 jours après transplantation. Des analyses par FACS ont montré qu’une proportion de cellules leucémiques exprimaient Flt3, incluant même celles provenant de la fraction Flt3-. Troisièmement, une stratégie de perte de fonction de Flt3 par shARN a été mise en œuvre afin d’examiner le rôle de la voie de signalisation de Flt3 dans les cellules leucémiques E2A-PBX1. Pour ce faire, des cellules primaires leucémiques ont été infectées, soit par le shARN anti-Flt3 soit shARN contrôle, et transplantées dans des souris receveuses. Les cellules leucémiques contenant le shARN ont été capables de régénérer la leucémie. Cependant, une proportion des cellules exprimaient toujours Flt3, ce qui indique que l’efficacité des shARn n’était pas suffisante. Conclusion et Perspectives: Nos shARN ne sont pas suffisamment efficaces sur les cellules leucémiques choisies. De ce fait, nous proposons d’utiliser des cellules leucémiques moins agressives tout en réalisant le même set-up expérimental. Des transplantations dans des receveurs KO Flt3-/- seraient également requises afin de réellement étudier l’impact de la voie de signalisation Flt3 dans la ré-initiation leucémique.Introduction: Previous work in the laboratory have established that Hoxa9 accelerated the onset of E2A-PBX1 induced B cell leukaemia. qRT-PCR analysis showed that RNA levels of HOXA9 target Flt3 was 32-fold increased in Hoxa9/E2A-PBX1 compared to E2A-PBX1 leukaemia. It is important to note that aberrant expression of Flt3 is found in both B-ALL and AML. Moreover, constitutive activation of Flt3 is associated with a poor prognosis. We hypothesized that the acceleration of E2A-PBX1 B-ALL by Hoxa9 is caused through increased Flt3 signalling. Methods and Results: First, to evaluate whether Flt3 signalling is functionally relevant for E2A-PBX1 induced leukaemia, Flt3 expression was analysed by FACS and qRT-PCR. So far, we showed that E2A-PBX1 B-ALL express FLT3 but the receptor was detected on a variable proportion of the cells, ranging from 0.3-28 %. Secondly, we evaluated the leukemic potential of Flt3 positive and negative fractions. Both reinitiate leukaemia around 20 days post-transplantation. Thirdly, a shRNA mediated knockdown strategy for Flt3 has been applied to test the relevance of Flt3 signalling on E2A-PBX1 leukemic cells. To test this, primary leukaemic cells were infected, either with the shRNA anti-Flt3 or the shRNA control, and transplanted into recipient mice. Unexpectedly, no difference was observed between the two groups of mice. Conclusion and Relevance: Our shFLT3 is not efficient enough on the chosen leukemic cells. Therefore, we propose to apply the same set-up to a less aggressive leukaemia. Moreover, transplanting cells in Flt3-/- KO mice is required to really assess the impact of Flt3 signalling

Hoxa9 collaborates with E2A-PBX1 in mouse B cell leukemia in association with Flt3 activation and decrease of B cell gene expression

Background: The fusion protein E2A-PBX1 induces pediatric B cell leukemia in human. Previously, we reported oncogenic interactions between homeobox (Hox) genes and E2A-PBX1 in murine T cell leukemia. A proviral insertional mutagenesis screen with our E2A-PBX1 B cell leukemia mouse model identified Hoxa genes as potential collaborators to E2A-PBX1. Here we studied whether Hoxa9 could enhance E2A-PBX1 leukemogenesis. Results: We show that Hoxa9 confers a proliferative advantage to E2A-PBX1 B cells. Transplantation experiments with E2A-PBX1 transgenic B cells overexpressing Hoxa9 isolated from bone marrow chimeras showed that Hoxa9 accelerates the generation of E2A-PBX1 B cell leukemia, but Hoxa9 is unable to transform B cells alone. Quantitative-reverse transcriptase polymerase chain reaction analysis demonstrated a strong repression of B cell specific genes in these E2A-PBX1/Hoxa9 leukemias in addition to Flt3 activation, indicating inhibition of B cell differentiation in combination with enhanced proliferation. Overexpression of Hoxa9 in established E2A-PBX1 mouse leukemic B cells resulted in a growth advantage in vitro, which was also characterized by an enhanced expression of Flt3. Conclusions: we show for the first time that Hoxa9 collaborates with E2A-PBX1 in the oncogenic transformation of B cells in a mouse model that involves Flt3 signaling, which is potentially relevant to human disease

Clarifying values: an updated and expanded systematic review and meta-analysis

Background Patient decision aids should help people make evidence-informed decisions aligned with their values. There is limited guidance about how to achieve such alignment. Purpose To describe the range of values clarification methods available to patient decision aid developers, synthesize evidence regarding their relative merits, and foster collection of evidence by offering researchers a proposed set of outcomes to report when evaluating the effects of values clarification methods. Data Sources MEDLINE, EMBASE, PubMed, Web of Science, the Cochrane Library, and CINAHL. Study Selection We included articles that described randomized trials of 1 or more explicit values clarification methods. From 30,648 records screened, we identified 33 articles describing trials of 43 values clarification methods. Data Extraction Two independent reviewers extracted details about each values clarification method and its evaluation. Data Synthesis Compared to control conditions or to implicit values clarification methods, explicit values clarification methods decreased the frequency of values-incongruent choices (risk difference, –0.04; 95% confidence interval [CI], –0.06 to –0.02; P < 0.001) and decisional conflict (standardized mean difference, –0.20; 95% CI, –0.29 to –0.11; P < 0.001). Multicriteria decision analysis led to more values-congruent decisions than other values clarification methods (χ2 = 9.25, P = 0.01). There were no differences between different values clarification methods regarding decisional conflict (χ2 = 6.08, P = 0.05). Limitations Some meta-analyses had high heterogeneity. We grouped values clarification methods into broad categories. Conclusions Current evidence suggests patient decision aids should include an explicit values clarification method. Developers may wish to specifically consider multicriteria decision analysis. Future evaluations of values clarification methods should report their effects on decisional conflict, decisions made, values congruence, and decisional regret

Le kantisme et l’éducation de la volonté

Vaisson J. Le kantisme et l’éducation de la volonté. In: La revue pédagogique, tome 71, Juillet-Décembre 1917. pp. 213-225

Le kantisme et l’éducation de la volonté

Vaisson J. Le kantisme et l’éducation de la volonté. In: La revue pédagogique, tome 71, Juillet-Décembre 1917. pp. 213-225

Le congrès olympique

Vaisson . Le congrès olympique . In: Revue internationale de l'enseignement, tome 34, Juillet-Décembre 1897. pp. 299-301

Le congrès olympique

Vaisson . Le congrès olympique . In: Revue internationale de l'enseignement, tome 34, Juillet-Décembre 1897. pp. 299-301

Avoid the quasi-equilibrium assumption when evaluating the electrocatalytic oxygen evolution reaction mechanism by Tafel slope analysis

Tafel slope analysis is a powerful tool in comparing experimental data to a proposed reaction mechanism. Typically, in order to simplify the analysis, the non-rate-determining steps in the reaction mechanism are assumed to be in quasi-equilibrium. Here, Tafel analysis of the oxygen evolution reaction following the electrochemical oxide mechanism is performed using a full kinetic model. It is shown that this model (which uses the steady-state assumption) predicts a larger number of Tafel slopes than if the quasi-equilibrium assumption is used and provides and predicts the surface coverages which underpin these Tafel slopes. Importantly, this model predicts Tafel slopes of 30, 40, 60, and 120 mV, all of which are experimentally found on IrO2 and RuO2 anodes. Models using the quasi-equilibrium assumption fail to predict some Tafel regions, as these can occur when a non-rate-determining step is not at quasi-equilibrium. Keywords: Oxygen evolution reaction, Tafel slope, Reaction mechanism, Quasi-equilibrium, Electrocatalysi

Harmonizing evidence-based practice, implementation context, and implementation strategies with user-centered design: a case example in young adult cancer care

BackgroundAttempting to implement evidence-based practices in contexts for which they are not well suited may compromise their fidelity and effectiveness or burden users (e.g., patients, providers, healthcare organizations) with elaborate strategies intended to force implementation. To improve the fit between evidence-based practices and contexts, implementation science experts have called for methods for adapting evidence-based practices and contexts and tailoring implementation strategies; yet, methods for considering the dynamic interplay among evidence-based practices, contexts, and implementation strategies remain lacking. We argue that harmonizing the three can be facilitated by user-centered design, an iterative and highly stakeholder-engaged set of principles and methods.MethodsThis paper presents a case example in which we used a three-phase user-centered design process to design and plan to implement a care coordination intervention for young adults with cancer. Specifically, we used usability testing to redesign and augment an existing patient-reported outcome measure that served as the basis for our intervention to optimize its usability and usefulness, ethnographic contextual inquiry to prepare the context (i.e., a comprehensive cancer center) to promote receptivity to implementation, and iterative prototyping workshops with a multidisciplinary design team to design the care coordination intervention and anticipate implementation strategies needed to enhance contextual fit.ResultsOur user-centered design process resulted in the Young Adult Needs Assessment and Service Bridge (NA-SB), including a patient-reported outcome measure and a collection of referral pathways that are triggered by the needs young adults report, as well as implementation guidance. By ensuring NA-SB directly responded to features of users and context, we designed NA-SB for implementation, potentially minimizing the strategies needed to address misalignment that may have otherwise existed. Furthermore, we designed NA-SB for scale-up; by engaging users from other cancer programs across the country to identify points of contextual variation which would require flexibility in delivery, we created a tool intended to accommodate diverse contexts.ConclusionsUser-centered design can help maximize usability and usefulness when designing evidence-based practices, preparing contexts, and informing implementation strategies-in effect, harmonizing evidence-based practices, contexts, and implementation strategies to promote implementation and effectiveness

Testing E-mail Content to Encourage Physicians to Access an Audit and Feedback Tool: A Factorial Randomized Experiment

Background: In Ontario, an online audit and feedback tool that provides primary care physicians with detailed information about patients who are overdue for cancer screening is underused. In the present study, we aimed to examine the effect of messages operationalizing 3 behaviour change techniques on access to the audit and feedback tool and on cancer screening rates. Methods: During May–September 2017, a pragmatic 2×2×2 factorial experiment tested 3 behaviour change techniques: anticipated regret, material incentive, and problem-solving. Outcomes were assessed using routinely collected administrative data. A qualitative process evaluation explored how and why the e-mail messages did or did not support Screening Activity Report access. Results: Of 5449 primary care physicians randomly allocated to 1 of 8 e-mail messages, fewer than half opened the messages and fewer than 1 in 10 clicked through the messages. Messages with problem-solving content were associated with a 12.9% relative reduction in access to the tool (risk ratio: 0.871; 95% confidence interval: 0.791 to 0.958; p = 0.005), but a 0.3% increase in cervical cancer screening (rate ratio: 1.003; 95% confidence interval: 1.001 to 1.006; p = 0.003). If true, that association would represent 7568 more patients being screened. No other significant effects were observed. Conclusions: For audit and feedback to work, recipients must engage with the data; for e-mail messages to prompt activity, recipients must open and review the message content. This large factorial experiment demonstrated that small changes in the content of such e-mail messages might influence clinical behaviour. Future research should focus on strategies to make cancer screening more user-centred