NCube/papyrus huggingface dataset:
Expansion des mégacaryocytes par HoxB4 pour accélérer la reconstitution plaquettaire

Haematopoietic stem cell (HSC) transplantation is the most efficient treatment against a number of cancers or other disorders of the hematologic system. Prior to HSC transplantation, patients are exposed to high doses of radiotherapy and/or chemotherapy to eliminate malignant cells. However, these treatments result in a state of aplasia, particularly in thrombocytopenia, which is characterised by very low blood platelet counts. Platelets produced by megakaryocytes (MK) are essential components of the blood system and play a critical role in the prevention of bleeding. Thus a low platelet blood level is a major complication and contributes significantly to transplant related mortality. At present, regular infusion of platelets isolated from healthy donors is the treatment of choice for thrombocytopenia. However, this is cumbersome for patients as well as donors and, in many instances results in platelet refractoriness due to the generation of auto-antibodies against disparate HLA molecules expressed on donor platelets. Therefore, the development of strategies to accelerate MK production and thus platelet reconstitution post HSC transplant would represent a major advance. It has already been shown that HoxB4 expands HSC and multipotent progenitors (CFU-GEMM) that give rise to megakaryocytes (MK). Thus HoxB4 is a great candidate for in vitro MK progenitor expansion. However, the short half-life of HoxB4 protein prompted us to generate a second generation of HoxB4 proteins with greater intracellular stability. We therefore studied the capacity of wild type (WT) and HoxB4 with 3 substitutions (1423 (HoxB4L7A), 1426 (HoxB4Y23A) and 1427 (HoxB4Y28A) resulting in a longer protein half-life to expand HSC as well as MK progenitors. Retroviral-mediated expression of HoxB4Y23A and HoxB4Y28A proteins showed a greater expansion of murine MK progenitors, in comparison with HoxB4WT or HoxB4L7A proteins or GFP control. We also evaluated the ability of HSC expressing second generation HoxB4 to generate platelets in a murine model. Our results show that retroviral-mediated transduction of second generation HoxB4 in murine HSC does not provide a significant advantage over HoxB4WT in platelet reconstitution in mice. Interestingly, treatment of CD34+ cells derived from cord blood showed only marginal effect of HoxB4WT or second generation HoxB4 soluble recombinant proteins when cultured under conditions optimized for megakaryocyte differentiation. Unexpectedly, CD34+ cells derived from mobilized peripheral blood of myeloma patients showed a significant increase in MK progenitor differentiation in the presence of TAT-HoxB4WT when cultured in expansion medium for HSC. Thus, HoxB4 holds promise in autologous HSC transplantation for the treatment of thrombocytopenic patients.

Keyphrases: HoxB4, Expansion, CD34, Platelets, Hematopoietic stem cell (HSC), Megakaryocyte (MK), Cord blood, Thrombocytopenia
Étude de l’attribution de la responsabilité chez des adolescents auteurs d’agression sexuelle : facteurs explicatifs et prise en charge

This research is about blame attribution of 166 juvenile sex offenders between the age of 12 and 19. The first goal is to determine which psychological aspects (age, post-traumatic stress, cognitive distortions, self-esteem, alienation, immaturity) influence the 3 types of blame attribution (culpability, external attribution and internal attribution) as well as to determine the focus level of treatment. The results of the multiple regressions show two models. The model predicting culpability is only composed by post-traumatic stress. This model explains 26% (adjusted) of the culpability variance (R2=0,29, F(6,120)=8,35, p<0,01). The model predicting external attribution is composed by age and cognitive distortions. It explains 25% (adjusted) of variance (R2=0,28, F(6,122)=8,03, p<0,01). Internal attribution hasn’t shown a correlation with the studied variables. The second goal is to estimate the efficiency provided by different services to modify blame attribution according to the care environments, length of treatment and therapeutic approach in order to come up with the best set up. Thanks to ANOVAs, it was possible to find out that none of the modalities have an impact on blame attribution. This research has some limits, especially statistical power. For consideration of future studies, links between blame attribution and recidivism could be investigated.

Keyphrases: Blame attribution, Juvenile, Sex offense, Treatment, Psychological factors
How Could Emergency Modify our Normal Ethics Standards? A Brief Review of Selected Chapters in Emergency Ethics

This review is about Emergency Ethics, the first in the four-volume series Emergency Ethics, Law and Policy. It analyses chapters addressing the question: How could emergency modify our normal ethics standards? The chapters offer three angles on the question: conceptual analysis, empirical analysis and case study.

Keyphrases: vide moral, emergency, ethics, moral black hole, natural disaster, ethics theories
Les potentielles sources d’erreurs au niveau des preuves d’ordre scientifique

Several causes can be listed to explain a miscarriage of justice. The present work focuses on the mistakes made in the scientific expertise admitted in court. For the literature review, we present an overview of the various errors that can occur throughout the legal process; from of the crime scene to the presentation of scientific evidence in court. Secondly, the analysis is based on actual cases where several convicts were acquitted following the discovery of errors made by a forensic pathologist. The latter made serious mistakes during the autopsy, in his analyzes and his testimony. We focus on how medical expertise is presented by the expert, on the way the value of the scientific evidence is ruled and also how the lawyers deal with this scientific expertise. We find that many errors could have been avoided by using a probabilistic approach. Some responsibility also goes to criminal justice system players who must be vigilant towards the scientific evidence and not see it as an absolute truth.

Keyphrases: Témoignage expert, Miscarriage of justice, Scientific expertise, Expert testimony, Forensic science, Forensic evidence
But the Pain Remains: A Response to Verpaelst

People who experience chronic pain often refrain from expressing their pain overtly due to fear of stigmatization. Health professionals working with these persons may also find it challenging to face the persistent nature of their clients’ pain. Through his painting, Verpaelst helps to overcome these difficulties.

Keyphrases: chronic pain, stigmatization, pain management, professional-patient relationship, limitations of therapy
The Gandarela Mountain Range and the “resistance space” against iron ore mining threat: a focus on the contrapositions

Analyzing a clipping of Lefebvre's space theory and its dialogue with the doxa from Pierre Bourdieu as the theoretical basis, this research aims to build the concept of the “resistance space”. This is a qualitative study characterized as a metaphilosophy by which the knowledge is linked to the practice. This analysis on empirical object is based on the environmental conflict in the Gandarela Mountain Range, located in Brazil, in the state of Minas Gerais. Brazil is a giant supplier of iron ore exports for the world economy, and the state of Minas Gerais is where Vale – a very large transnational mining company - started its operation in the 1940s. Gandarela is the last mountain range environmentally well protected in the heart of Minas Gerais, holding a huge aquifer, but it has iron ore underground. An environmental-social movement has arisen to protect the place. For more than two years, participant observation was carried out and also in-depth interviews were applied to people belonging to the Movement for the Preservation of the Gandarela Mountain Range, who fights to block an iron ore mining activity proposed by “Vale”. The resistance movement proposed the creation of a National Park as an instrumental strategy, and the movement goes beyond conservationism, it opposes the actual social metabolism of the world economy and believes in a different society. Inspired by Lefebvre’s space theory I developed a spacial analysis of the Gandarela case. My hypothesis is that the “resistance space” transits between the abstract space and the differential space. The notion of the “resistance space” contributes for understanding the dimensions from the resistance struggles, their thoughts, and glimpses which guide their actions in the name of territories and communities. This research reached three dialectic representations of the resistance space: the “instruments”, the “contrapositions”, and the “utopia”. The focus of the paper is on the “contrapositions” of the resistance space, the arguments against mining and the current pattern of economic development, thoughts that go beyond development and economic valuation.

Keyphrases: philosophy, ethics, iron mining, Lefebvre’s space theory, resistance, contrapositions., philosophy, ethics, economics, contrapositions
Le corps ambivalent dans l'exposition «En imparfaite santé : la médicalisation de l'architecture» (2011-2012)

Scientific and technological progress is not without fault – the unforeseen consequences of its implementation may cause new problems. This is the underlying Machiavellian observation of the project Imperfect Health: the Medicalization of Architecture by the Canadian Centre for Architecture (2011-2012), presented as an exhibition and a catalogue. This dissertation studies how both platforms, the first being experiential, and the second theoretical, put forward a critique of today's medicalization process that has entered the field of contemporary architecture. The exhibition is approached as a discourse as well as an installation of objects for the public. A special focus is directed towards the scenography and the path of the visitor through it. Another aspect considered is the role of the graphic design, which serves as an instrument supporting the leitmotif of confrontation. In the study of the catalogue, the emphasis is put on the introductory essay, in which the fundamentally ambivalent concept of the pharmakon, while never stated, continually runs through it as an implicit theme. The peritext, which designates the physical framing of the catalogue’s main content, is also examined. A comparative analysis follows and concludes that each platform communicates a different message, proposing that this strategy has been made possible by the ambivalence of the concept of the body, understood literally and metaphorically. The conclusion of the dissertation presents a brief opening towards a contextualisation of this dual interpretation and of the questioning of the authority held by technical and scientific discourse. Even if Imperfect Health directs its critique towards the modernist vision of architecture that still prevails, we infer that the project is as much, if not more, about today's omnipresence of the digital. The latter, like modern architecture, does not only impact the understanding of the human and architectural body, it also reinforces a positivist belief in technology that is not always counterbalanced by critical thought.

Keyphrases: architecture, exhibition, architecture, body, medicalization, Canadian Centre for Architecture
Where there's smoke, there's fire : the brain reactivity of chronic smokers to anti-smoking stimuli

Background: Studies have shown that appetitive smoking-related stimuli trigger important cravings in smokers which promote the maintenance of smoking behavior. Neuroimaging studies have been valuable in elucidating the mechanisms underlying this clinical feature. However, another important but under-explored feature of tobacco dependence is the inability for aversive smoking-related stimuli, such as anti-smoking campaigns, to influence this craving and smoking response. Using functional magnetic resonance imaging, the goal of this study was three-fold: to examine the neurobiological response of chronic smokers when processing aversive smoking-related cues; to further characterize this response using control conditions (i.e., aversive nonsmoking-related, appetitive smoking-related cues); to examine the pattern of functional connectivity during this task between executive and affective systems that may interact in ways that promote or hinder the impact of aversive events. Methods: Thirty chronic smokers passively viewed aversive smoking-related, aversive nonsmoking-related, appetitive smoking-related and neutral images presented in a block design while being scanned. Results: Aversive smoking-related stimuli elicited significantly greater activation in the medial prefrontal cortex, amygdala, inferior frontal gyrus and lateral orbitofrontal cortex than neutral stimuli. Aversive smoking-related stimuli elicited lower activation in medial/subcortical structures compared to the processing of aversive nonsmoking-related and appetitive smoking cues. Executive and affective systems are negatively associated when aversive cues are smoking-related, but not when nonsmoking-related. Conclusion: The brain activation pattern observed suggests that chronic smokers experience an aversive response when processing aversive smoking related stimuli, however we argue that the latter triggers a weaker negative emotional and driving response than the aversive nonsmoking-related and appetitive smoking-related cues respectively. Executive systems, activated during aversive smoking-related processing, may act to down-regulate activity in regions key to an affective and persuasive response; a mechanism that may reduce the extent to which “feeling bad” affects a change in behavior.

Keyphrases: addiction, tobacco, craving, anti-smoking, neuroimaging, connectivity, toxicomanie
Identification de déterminants impliqués dans la différenciation des cellules souches embryonnaires

Stem cells have captured public’s attention in the last years, thanks to their involvement in cancer therapies and also their huge theoretical potential in the regenerative medicine field. In order to translate this new technology to the clinic, a better understanding of their regulatory mechanisms is still needed. It is well established that mouse embryonic stem cell (ESC) fate is highly regulated by core pluripotency factors. However, it is conceivable that novel self-renewal or differentiation regulators are not yet described. To investigate this possibility, we used a viral-based approach to generate a collection of ESC with nested chromosomal deletions called DelES (Deletion in ES cells). This library contains more than a thousand independent ESC clones highly enriched in chromosomal deletions which together cover ~25% of the mouse genome. Using this resource, we conducted an embryoid body (EB) differentiation screen and showed that several clones were having an abnormal EB formation phenotype. Complementation studies later identified Rps14-a ribosomal protein (RP) coding gene- as a novel haploinsufficient gene in EB formation from undifferentiated ESC. Further analyses of our screen results showed a strong bias for a subset of small subunit ribosomal protein genes which are critical for ESC differentiation but not for their self-renewal activity. Interestingly, the most severe differentiation phenotypes were found with ribosomal proteins associated to the ribosome’s mRNA exit site, namely Rps5, Rps14 and Rps28. While RP gene imbalance often leads to a p53 response that can be corrected by p53 suppression, ESC clones with decreased expression of mRNA exit site RP genes were surprisingly insensitive to p53 reduction, but were rescued by BAC or cDNA complementation, thus confirming the causative nature of these genes in the ESC phenotype. Finally, polysomal profiling and RNA-Seq studies showed that Rps5 deleted ESC exhibit an abnormal mesodermal gene signature. Together, our work presents a highly valuable resource for functional genomic studies in ESC and also highlights a novel p53-independent role linked to RP gene imbalance. Our results shed light on the relevance of these subunits for the developmental transition of ESC from a pluripotent to a differentiated state.

Keyphrases: Embryonic stem cells, Ribosomal proteins
Analyse de la logique d’intervention d’une adaptation québécoise d’un modèle de soins centré sur le patient appuyé par un dossier médical personnel dans les suivis pédiatriques au sein d’un groupe de médecine de famille

In order to improve the performance of primary care services, a project in Quebec to develop an adaptation of a patient-centered care model supported by a personal health record (PHR) has been implemented in a urban family medicine group (FMG). Thus, this thesis is a comparative analysis between the logic of intervention as it is described in the literature on patient centered model and integrated PHR, and the empirical results obtained in the FMG of the project. More specifically, the analysis takes place during the pre-deployment phase of the intervention. Furthermore, it is an organizational analysis. The main results revealed that the logic of intervention applied in the project is relatively far from what is known as the «best» models in the literature on patient-centered care and integrated PHR. This is in part explainable by the resistance to change of the different stakeholders (eg. doctors, nurses, etc.) concerned by the project, which is coherent with what we found on the subject in the literature. Otherwise, the main effects expected by the actors involved in the project are the improvement of informational continuity, service efficiency, comprehensiveness and overall productivity. Furthermore, in the current structural context of Quebec's health care system, the implementation of a patient-centered model supported by a PHR would involve important structural changes such as a revision of the health care professionals remuneration model and the legislative framework (eg. medical liability), otherwise, significant effects on performance dimensions such as accessibility, quality, continuity, comprehensiveness, efficiency, effectiveness and responsiveness could be significantly limited. These structural arrangements should promote, among others, interprofessional collaboration, systems interconnectivity, improved multi-directional communication between the patient and the health care professionals and a culture in which the patient actively participates in the management of his health and where the health care professional gives him the necessary support (eg. education, prevention, transparency).

Keyphrases: Personal health record (PHR), Patient-centered medical home, Primary care, Patient centered care model, Health care performance, Interconnectivity PHR-EHR, Family medicine group, Accessibility, Quality, Continuity, Efficiency
Study of nuclear receptor dynamics by BRET

Nuclear receptors (NRs) are ligand-dependent transcription factors that control a wide variety of biological processes in human physiology, which has made them preferred pharmacological targets for many diseases. One such receptor, the estrogen receptor alpha (ERα), can activate cell proliferation in some sections of the mammary epithelium while another, the retinoic acid receptor alpha (RARα), can cause growth arrest and cellular differentiation. Signalling by these receptors can be altered in breast cancer, contributing to tumorigenesis. ERα can be blocked by antiestrogens (AEs) in the clinical setting to inhibit tumor cell proliferation. However, attempts to activate the RARα pathway with retinoids have not proven beneficial in clinical trials. This may result from the lack of specificity of the tested ligands for RARa and/or from their activity only in a subset of breast tumors.  Since nuclear receptors form homo- and heterodimers, we sought to develop novel pharmacological assays to study the activity of specific receptor-dimer complexes, their dynamics and quaternary structure. We report here a new FRET technique dubbed BRET with fluorescence enhanced by combined transfers (BRETFect) that can detect the formation of ternary nuclear receptor complexes. BRETFect can monitor the activation of ERα-ERβ heterodimers and highlights an allosteric mechanism of activation that each receptor exerts on its dimer partner. Use of BRETFect in combination with PCA-BRET has allowed us to observe the formation of functional ERα multimers in live cells for the first time. The formation of multimers is favored by AEs which induce receptor degradation, and may underlie their specific properties. These assays are a net improvement over the classical luciferase-reporter experiment as they deliver real-time receptor specific information with no interference by other process such as transcription and translation. Using these BRET assays we developed a new class of NR hybrid ligands that can modulate ER or RAR activity and inhibit HDACs. This has allowed for the development of promising new bifunctional molecules such as the RAR-agonist/HDACi hybrid molecule TTNN-HA. In conclusion, the work presented here brings new insight in NR dynamics and quaternary structure and offers novel tools to study their mechanism of action or design new modulators of NR activity such as hybrid AE-HDACis and Retinoid-HDACis.

Keyphrases: FRET, BRET, Nuclear receptors, Pharmacology, estrogen, Retinoic acid
Nouvelle approche immunothérapeutique afin de traiter le neuroblastome réfractaire chez l’enfant

Despite aggressive treatment by chemotherapy followed by transplantation and treatment with anti-tumor cell disialoganglioside (GD2) monoclonal antibody, IL-2, GM-CSF and retinoic acid, 40% of patients with high-risk neuroblastoma (NB) still undergo disease progression or relapse. Furthermore, tumor-initiating cells (TIC) expressing the CD133 marker are present in NB tumors and are more resistant to chemotherapy. To evaluate a new immunotherapeutic approach, we took advantage of the anti-tumor effect of Natural Killer (NK) cells. We hypothesized that activated NK cells would be a potent therapeutic strategy to eliminate TIC and reduce relapse of NB. We aimed to establish the best strategy to increase the NK cell mediated cytotoxicity against NB. NK cell cytotoxic activity is increased by cytokines, chemokines and activated plasmacytoid dendritic cells (pDC) which produce high amounts of interferon-alpha (IFN-α) upon Toll-like receptor stimulation. We investigated NK-cell lytic properties against NB cell lines following activation by IFN-α or activated pDC. Our results reveal an increased cytolytic activity of NK cells against NB cell lines after stimulation by activated pDC, CD133+ (TIC) as well as anti-GD2 resistant NB cells are sensitive to NK cell mediated cytotoxicity following stimulation by activated pDC. We also examined the cellular mechanisms involved in NK cell-mediated lysis of NB cell lines. The increased cytotoxicity is partially mediated by TRAIL induced apoptosis and as well as by the release of cytolytic granules. In conclusion, we propose a new immunotherapeutic approach that can be used in combination with the anti-GD2 therapy for the treatment of high-risk NB patients.

Keyphrases: Cellule Natural Killer, TRAIL, Neuroblastoma, Immunotherapy, Natural Killer cell, Plasmacytoid dendritic cell, Tumor-initiating cell, TRAIL, Degranulation