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La leucémie aiguë lymphoblastique (LAL) est une maladie complexe à l’étiologie multifactorielle. Elle représente la forme la plus commune de cancer pédiatrique et malgré une augmentation significative du taux de survie des patients, près de 15% d’entre eux ne répondent pas aux traitements classiques et plus de 2/3 subissent les effets du traitement à long terme. Réduire ces chiffres passe par une meilleure compréhension des causes sous-jacentes de la LAL. À travers l’analyse des données de séquençage de nouvelle génération (SNG) de la cohorte QcALL du CHU Sainte-Justine, je me suis intéressé aux déterminants génomiques contribuant aux différents aspects de la LAL (prédispositions, développement/progression et rechutes). Dans un premier temps, j’ai développé un outil d’analyse (SNooPer) basé sur un algorithme d’apprentissage intégrant les données SNG normales et tumorales des patients, permettant d’identifier les mutations somatiques au sein de données à faible couverture (low-pass). Cet outil, couplé aux analyses prédictives in silico et aux validations fonctionnelles adéquates, nous a permis de caractériser les événements rares ou récurrents impliqués dans le processus leucémogène. En analysant les données de LALs pré-B, j’ai pu mettre en évidence une série de mutations drivers rares au niveau de gènes (ACD, DOT1L, HCFC1) qui n’avaient jamais été associés à la LAL. L’étude fonctionnelle de la mutation identifiée au niveau d’ACD, membre du complexe shelterin, a démontré qu’elle conduit à une réduction de l’apoptose et une augmentation de la taille des télomères. Outre l’intérêt de la découverte de ces nouveaux drivers, je souhaitais démontrer l’importance des mutations somatiques rares afin d'établir la spécificité interindividuelle, généralement sous-estimée, et d’identifier l’ensemble des fonctions cellulaires impliquées. Au cours de ces travaux, j'ai également mis en évidence de nouveaux évènements récurrents de la LAL à cellules T (LAL-T), en particulier au niveau de patients présentant un phénotype immature encore mal caractérisé. J'ai démontré l’influence d'une mutation dans le gène codant pour U2AF1, membre de la machinerie d’épissage (spliceosome), sur l’épissage de gènes d’intérêt et ainsi confirmer l’importance du dysfonctionnement de l’épissage dans le développement de la leucémie. J'ai également identifié deux suppresseurs de tumeurs portés par le chromosome X, MED12 et USP9X, qui n’avaient jamais été associés à la LAL-T auparavant et qui représentent un intérêt particulier étant donné le débalancement de l'incidence en fonction du sexe (ratio garçon:fille =1.22). Enfin, grâce à l’étude longitudinale de patients LAL-B ayant subi une ou plusieurs rechutes, j'ai analysé l'architecture et l'évolution clonales des tumeurs. J’ai ainsi identifié 2 profils évolutifs distincts gouvernant les rechutes précoces et tardives: d'un côté, une dynamique élevée alimentée par un dysfonctionnement des mécanismes de réparation de l'ADN et conduisant à l'émergence rapide de clones mieux adaptés – de l'autre, une dynamique réduite, quasi-inerte, suggérant l'échappement de cellules en dormance épargnée par la chimiothérapie. De manière générale, cette thèse a permis de contribuer à la caractérisation des déterminants génomiques qui constituent la variabilité inter- et intra-tumorale, participent au processus leucémogène et/ou aux mécanismes de résistance au traitement. Ces nouvelles connaissances contribueront à un raffinement de la stratification des patients et leur prise en charge personnalisée. / Acute lymphoblastic leukemia (ALL) is a complex disease with a multi-factorial etiology. It represents the most frequent pediatric cancer and despite a significant increase of survival rate, about 15% of the patients still do not respond to current treatment protocols and over 2/3 of survivors experience long-term treatment related side effects. To reduce these numbers, a better understanding of the underlying causes of ALL is needed. Through the analysis of next-generation sequencing (NGS) data obtained from the established Quebec cALL (QcALL) cohort of the Sainte-Justine hospital, I have been particularly concerned about the genomic determinants that contribute to different phases of ALL (predispositions, onset/progress and relapses). First, I developed an analysis tool (SNooPer) based on a machine learning algorithm integrating both normal and tumor NGS data of the patient to identify somatic mutations from low-pass sequencing. This tool, combined to in silico predictive analysis and to adequate functional validations, allowed us to characterize rare or recurrent events involved in the leukemogenesis process. Through the analysis of pre-B ALLs, I have been able to identify several rare driver genes which had never been associated to ALL before (ACD, DOT1L, HCFC1). The functional study of the identified mutation in ACD, a member of the shelterin complex, showed a concomitant lengthening of the telomeres and decreased apoptosis levels in leukemia cells. Besides the interest aroused by the discovery of these new drivers, I wanted to demonstrate the importance of low-frequency somatic events to establish the generally underestimated interindividual specificity and identify all cellular functions involved. During this work, I also identified new recurrent driver events in T-cell ALL (T-ALL), particularly among poorly characterized immature T-ALL patients. For example, I demonstrated the impact of a recurrent mutation in U2AF1, member of the spliceosome, on alternative splicing of cancer-relevant genes, further suggesting the importance of aberrant splicing in leukemogenesis. I also identified two new X-linked tumor suppressors, MED12 and USP9X, never associated to T-ALL before and obtained results supporting a potential role for these genes in the male-biased sex ratio observed in T-ALL (ratio male:female =1.22). Finally, through the longitudinal study of pre-B cALLs who suffered one or multiple relapses, I analyzed the clonal architecture and evolution of the tumors. I identified two distinct evolution patterns governing either early or late relapses: on one hand a highly dynamic pattern, sustained by a defect of DNA repair processes, illustrating the quick emergence of fitter clones - and on the other hand, a quasi-inert evolution pattern suggesting the escape from dormancy of neoplastic stem cells likely spared from initial cytoreductive therapy. Overall, this thesis contributed to the characterization of genomic determinants that constitute the inter- and intra-tumor variability, participate in leukemogenesis and/or in resistance mechanisms. This new knowledge will contribute to refine patient stratification and treatment.

This diploma thesis explores the phenomenon of formation and development of alcohol dependence. In the first series focuses on the historical description, which demonstrates considerable anchored in the life of our ancestors already. It also defines the concept of addiction, its causes and consequences, whether psychological, medical or social. Its objective is to describe the possibilities of social work in this phenomenon. defines therefore primarily targets and understanding of social work and consequently specifics of client alcoholism. An important element is the role of the social worker in the client's motivation to change, which uses Nešpor's model of spontaneous changes in motivation. Then, on the basis of available social services selects several most suitable, which can help to improve the client's situation. Has an essential role in this issue also primary prevention, ie it discusses the methodology, target groups, focusing on adolescents and the focus is on the firm role of the family. Finally contains some official documents on primary prevention, which are discussed current issues of primary prevention practice and subsequent survey, mapping aspect of social workers on the incidence risk of alcohol dependence among adolescents attending social facilities.

Text in English / Against the background of high prevalence of substance abuse in the globe generally and South Africa in particular, research has shown an association between substance abuse and other mental disorders or vice-versa. With most rehabilitation centres offering separate diagnosis and treatment for the two disorders, the problem of relapse has been significant. The purpose of this study is to explore the perceived effectiveness of CBT as a treatment model for substance use disorders with co-occurring disorders. Subsequently, the research will add to the already existing research evidence. The study was conducted in five rehabilitation centres in Gauteng Province. The qualitative descriptive research approach was used to conduct the study. Both purposive and snowball sampling were used to recruit participants in this study. The sample consisted of CBT specialist participants from diverse race, gender, ethnicity, and age ranging from 30 to 65 years, with at least a minimum of five years’ experience. A pilot study with two specialist participants was conducted, and this enhanced trustworthiness and authenticity of the study. The primary method of qualitative data collection employed in this study was semi-structured individual interviews for specialist participants. Grounded theory analysis was employed to analyse data. The findings of the study emphasised a need to not separate treatment of substance use disorders and psychiatric pathologies. More importantly, the effectiveness of CBT in treating both disorders was established by the study. The study further encourages more time in therapy as the way to increase effective results accompanied by less relapse rate. Accordingly, the findings of this study encourage more research and use of CBT treatment for substance use disorders with co-occurring disorders in South Africa. This study found that the most used substances are both legal and illegal, and they are further classified as depressants, stimulants, opioids, and new psychoactive substances. A vulnerable population to abuse substances includes adolescent and young adults, individuals with co-occurring disorders, and low socio-economic status. The disorders that normally co-exist with substance use disorder ranges from depression, bipolar disorder, schizophrenia, sleeping disorder, impulsivity, antisocial behaviour, borderline disorder, paranoia, panic disorder, and suicide behaviour. The study found that genetic predisposition, depression, parental neglect and financial problems, experimentation with substances for relaxation, peer group pressure, and co-occurring disorders are high risk causes for substance abuse. The experience of participants in treating substance use disorder with co-occurring disorders involves which disorders get treated first, and the mental state of patients for effective treatment. The various substance abuse treatment models includes person centred approach, bio-psychosocial approach, holistic approach, eclectic therapy, integrated approach, resilient approach, rational emotive behavioural therapy, family therapy, motivational interviewing, 12-step programme, and cognitive behavioural therapy. The participants’ experience with CBT entails its usability in both individual and group therapy, the use of CBT skills after therapy, and CBT effectiveness in relapse prevention. Accessibility and affordability of CBT treatment is influenced by access to rehabilitation centres and cost of rehabilitation centres. Lastly, individual factors, family factors, and environmental factors are part of the contributing factors towards high relapse rates. / Psychology / M.A. (Psychology)

L'objectif de cette thèse est de proposer de nouveaux algorithmes pour surmonter les limitations actuelles et de relever les défis ouverts dans le traitement de l'imagerie spectroscopique par résonance magnétique (ISRM). L'ISRM est une modalité non invasive capable de fournir la distribution spatiale des composés biochimiques (métabolites) utilisés comme biomarqueurs de la maladie. Les informations fournies par l'ISRM peuvent être utilisées pour le diagnostic, le traitement et le suivi de plusieurs maladies telles que le cancer ou des troubles neurologiques. Cette modalité se montre utile en routine clinique notamment lorsqu'il est possible d'en extraire des informations précises et fiables. Malgré les nombreuses publications sur le sujet, l'interprétation des données d'ISRM est toujours un problème difficile en raison de différents facteurs tels que le faible rapport signal sur bruit des signaux, le chevauchement des raies spectrales ou la présence de signaux de nuisance. Cette thèse aborde le problème de l'interprétation des données d'ISRM et la caractérisation de la rechute des patients souffrant de tumeurs cérébrales. Ces objectifs sont abordés à travers une approche méthodologique intégrant des connaissances a priori sur les données d'ISRM avec une régularisation spatio-spectrale. Concernant le cadre applicatif, cette thèse contribue à l'intégration de l'ISRM dans le workflow de traitement en radiothérapie dans le cadre du projet européen SUMMER (Software for the Use of Multi-Modality images in External Radiotherapy) financé par la Commission européenne (FP7-PEOPLE-ITN). / The aim of this thesis is to propose new algorithms to overcome the current limitations and to address the open challenges in the processing of magnetic resonance spectroscopic imaging (MRSI) data. MRSI is a non-invasive modality able to provide the spatial distribution of relevant biochemical compounds (metabolites) commonly used as biomarkers of disease. Information provided by MRSI can be used as a valuable insight for the diagnosis, treatment and follow-up of several diseases such as cancer or neurological disorders. Obtaining accurate and reliable information from in vivo MRSI signals is a crucial requirement for the clinical utility of this technique. Despite the numerous publications on the topic, the interpretation of MRSI data is still a challenging problem due to different factors such as the low signal-to-noise ratio (SNR) of the signals, the overlap of spectral lines or the presence of nuisance components. This thesis addresses the problem of interpreting MRSI data and characterizing recurrence in tumor brain patients. These objectives are addressed through a methodological approach based on novel processing methods that incorporate prior knowledge on the MRSI data using a spatio-spectral regularization. As an application, the thesis addresses the integration of MRSI into the radiotherapy treatment workflow within the context of the European project SUMMER (Software for the Use of Multi-Modality images in External Radiotherapy) founded by the European Commission (FP7-PEOPLE-ITN framework).

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Le pemphigus est une maladie bulleuse auto-immune sévère causée par des auto- anticorps (Ac) ciblant la desmogléine (Dsg) 1 et/ou 3, principalement de la sous-classe IgG4. Certains Ac non spécifiques à la Dsg ont été décrits, comme la desmocolline 3 (Dsc3), mais leur pertinence est peu connue. Suite à l’étude RITUX3 en 2017, le traitement de première intention du pemphigus est le rituximab (RTX). Ce projet comprend trois volets qui s’inscrivent dans la caractérisation immunologique des patients inclus dans l’étude RITUX3, visant à mieux comprendre la pathogénèse et la prise en charge du pemphigus. Nous avons d’abord étudié la diversité isotypique des Ac anti-Dsg3. Nous avons démontré qu’un nombre d’isotypes plus élevé mène à un risque de rechute, particulièrement l’IgG3 anti-Dsg3 qui était détecté chez 71% des rechuteurs, comparativement à 12% des patients en rémission complète. Ensuite, nous avons étudié la prévalence et la pathogénicité in vitro des Ac anti-Dsc3. Ils étaient détectés chez 21% des patients, soit significativement plus qu’une population de donneurs sains. L’isotype principal était l’IgA, et leur pathogénicité in vitro a été démontrée à partir de sérums de patients et de souris immunisées. La présence de ces Ac permettait d’expliquer une bonne proportion des cas de discordance entre le profil sérologique d’anti-Dsg et le phénotype clinique des patients. Finalement, nous avons étudié la prévalence d’Ac anti-rituximab (ARA) chez les patients traités par RTX. Ils étaient détectés chez 31% des patients, mais n’affectaient pas l’atteinte d’une rémission complète et ne seraient pas une contre-indication à des perfusions subséquentes. Par contre, un petit groupe de patients qui présentaient des ARA fonctionnels étaient à risque de rechute. / Pemphigus is a severe auto-immune blistering disease caused by auto-antibodies (Abs) targeting desmoglein (Dsg) 1 and/or 3, mainly of the IgG4 subclass. Several Abs non-specific to the Dsg have been described, including desmocollin (Dsc) 3, but their relevance is not well known. Since the RITUX3 clinical trial in 2017, rituximab (RTX) is recommended as the first-line treatment for moderate-to-severe pemphigus. This project consists of three parts with the main goal of immunologically characterizing patients who were included in the RITUX3 trial, to allow a better understanding of the pathogenesis and treatment of pemphigus. First, we studied the diversity of IgG anti-Dsg3 subclasses. A higher number of subclasses was associated with a significant risk of relapse, especially with IgG3 anti-Dsg3 detected in 71% of relapsing patients, compared to 12% of patients in complete remission. Then, we studied the prevalence and pathogenicity of anti-Dsc3 Abs. They were detected in 21% of patients, significantly more than healthy donors. The main isotype was IgA, and their in vitro pathogenicity was demonstrated with sera from patients and immunized mice. Their presence explained a good proportion of cases who presented discrepancies between the clinical phenotype and the serological profile of anti-Dsg Abs. Finally, we studied the prevalence of anti-RTX Abs (ARA) in patients treated with RTX. They were detected in 31% of patients but did not affect the rate of complete remission and are not a contra-indication to receive subsequent perfusions. However, a small group of patients who presented functional ARA were at risk of relapse.

Introduction: Allogeneic hematopoietic cell transplantation (HCT) during chemotherapy-induced aplasia may offer long-term survival in acute myeloid leukemia (AML) with otherwise poor prognosis including ELN adverse risk, relapsed or refractory disease. However, the value of residual morphologic disease prior HCT in this context has not been conclusively settled until yet. Therefore, we aimed to investigate variables predicting outcome in this unique setting of sequential conditioning therapy, with a focus on pretreatment morphologic blast count. In contrast to the most popular FLAMSA-RIC protocol, we used a melphalan-based conditioning regimen during aplasia. Methods: We retrospectively analyzed data from 173 AML patients who underwent a sequential melphalan-based conditioning therapy between 2003 and 2015 at our centre. All patients participated either in the prospective Phase 2 BRIDGE trial (NCT01295307), the Phase 3 AML2003 study (NCT00180102) or were treated according to this protocol and underwent allogeneic HCT after melphalan-based conditioning in treatment-induced aplasia. Results: Median bone marrow blast count prior to conditioning was 10% (range, 0–96%). Four year probabilities of EFS and OS were 34% (95% CI, 28–43%) and 43% (95% CI, 36–52%), respectively. In multivariate analysis, blast count >20% was associated with worse EFS (HR = 1.93; p = 0.009) and OS (HR = 1.80; p = 0.026). This effect was not significant anymore for HCT during 1st line therapy. Conclusion: Allogeneic HCT in aplasia with a melphalan-based conditioning regimen has the potential to cure a subset of adverse risk AML patients, even with persistent morphological disease prior HCT. However, a high pre-transplant blast count still indicates patients with a dismal prognosis, especially in the relapsed patient group, for whom post-transplant strategies should be considered to further optimize post HCT outcome.

Substance abuse is a significant challenge facing the World and in particular South Africa. In this study, various Western and African traditional perspectives were considered to gain an understanding of the substance abuse problem among adolescents. The study was conducted in one of the rural villages of the Ramotshere Moiloa Local Municipality in the North West Province of South Africa. Participants included 24 African male and female adolescents between 13 and 19 years of age, as well as 2 parents and 9 professionals. The 9 professionals are educators, a social worker, a clinical psychologist, a mental health worker, a traditional leader and a traditional healer, between 37 to 53 years of age. A qualitative, explorative research design was employed. Data sources included individual face-to-face interviews, focus group discussions, and a document review. Thematic analysis was employed to analyse data. The findings were based on the perceptions of participants and revealed that adolescents are socially entrapped to substances such as alcohol, tobacco, cannabis, cocaine, glue, nyaope, and segonyamahlo. Reasons for their use of substances included individual, family, and environmental factors. The findings revealed the severe impact of substance abuse on adolescents and their families. There was evidence of primary, secondary, and tertiary levels of substance abuse prevention programmes targeting adolescents and other community members. In addition, stakeholders such as parents, peers, professionals, traditional leaders, traditional healers, government, and non-government organisations were recommended to implement substance abuse prevention programmes to address the substance abuse problem among adolescents. Furthermore, the study highlighted efforts made to reflect on the implemented substance abuse prevention programmes. / Psychology / D. Phil. (Psychology)