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1
Bayet, Manon. "Modélisation de la leucémie aiguë lymphoblastique B induite par la mutation PAX5 P80R". Electronic Thesis or Diss., Université de Toulouse (2023-....), 2024. http://www.theses.fr/2024TLSES005.
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L'équipe s'intéresse aux altérations de facteurs de transcription impliquées dans les leucémies aiguës, dont PAX5 qui est essentiel pour le développement des cellules B. C'est pourquoi le modèle murin transgénique PAX5-ELN a été généré, qui exprime la protéine de fusion oncogénique durant le développement des lymphocytes B, et récapitule le processus multi-étapes des LAL-B (Jamrog L et al., PNAS, 2018). J'ai participé à l'identification des cellules à l'origine de la LAL-B et à la caractérisation de leur propriétés fonctionnelles et moléculaires. Nos travaux indiquent qu'au stade pré-leucémique, PAX5-ELN induit l'émergence d'une population aberrante de progéniteurs B avec une propriété anormale d'auto-renouvellement. Cette population est enrichie en cellules quiescentes résistantes aux agents de chimiothérapie, activent un programme moléculaire de cellule souche, et sont le support de l'initiation leucémique à long terme. Ce travail fait l'objet d'une publication récente que je signe en deuxième auteure (Fregona V, Bayet M et al., J Exp Med, in press). En parallèle, ma thèse s'est tournée vers la modélisation de l'initiation et de la transformation leucémique induite par la mutation PAX5P80R, une altération initiatrice fréquente chez les patients. J'ai donc utilisé des cellules de foie fœtal issus d'embryon de souris Pax5-/- pour sélectionner les progéniteurs lymphoïdes non engagés dans le lignage B. Après transduction avec des rétrovirus CTL, PAX5 Wt ou PAX5P80R, j'ai montré que PAX5P80R ne restaure pas efficacement l'engagement définitif des cellules vers le lignage B. Les études de transplantation ont permis de montrer que PAX5P80R induit un potentiel de prise de greffe aberrant suivi du développement de la LAL-B. Cette transformation leucémique est associée à la sélection de clones porteurs de mutations additionnelles affectant la voie JAK/STAT. Nos analyses ont permis d'identifier Hif2 comme un candidat potentiel dans la leucémogenèse. Enfin, un criblage pharmacologique d'inhibiteurs de Hif révèle l'Acriflavine comme un composé intéressant ciblant les cellules leucémiques. Ainsi, la modélisation de la LAL-B par la mutation PAX5P80R fournit à l'équipe un nouvel outil mimant le processus multi-étapes de la LAL-B, et permet de déchiffrer les mécanismes biologiques par lesquels la mutation mène à la transformation tumorale. Ce travail fait l'objet d'un manuscrit en préparation que je signe en première auteure (Bayet M, Fregona V, et al., in preparation). Les modèles PAX5-ELN et PAX5P80R permettent non seulement d'étudier les différentes étapes de la leucémogenèse B, mais servent aussi de support pour le développement de criblage de petites molécules sur cellules primaires. J'ai donc mis en place un protocole miniaturisé et robuste par FACS pour cribler des composés chimiques ciblant les cellules pré-leucémiques. Notre approche multiparamétrique permet d'évaluer simultanément l'effet des composés sur les cellules pré-leucémiques et les sous-populations B normales. J'ai donc criblé une banque de 1040 composés synthétiques et naturels (chimiothèque essentielle) reflétant la diversité chimique de la chimiothèque nationale française. Ce criblage, associé à des contre-criblages en dose-réponse, m'a permis d'identifier 5 molécules d'intérêt. Dans l'ensemble, mon travail montre la faisabilité d'un criblage de petites molécules sur une population enrichie en cellules initiatrice de la leucémie et prenant en compte la complexité intrinsèque des cellules primaires du lignage B. Enfin, j'ai procédé à la rédaction et la publication d'une revue dans le journal Cancers qui expose les concepts d'hétérogénéité tumorales des cellules leucémiques des patients, l'utilité des modèles de souris transgéniques pour explorer le compartiment des cellules initiatrices de la leucémie, et les efforts actuels visant à découvrir de nouvelles thérapies ciblées (Fregona V*, Bayet M* et al, Cancers (Basel), 2021), que je signe en co-première auteureThe team is interested in alterations in transcription factors involved in acute leukemia, including PAX5, which is essential for B-cell development. This is why the PAX5-ELN transgenic mouse model was generated, which expresses the oncogenic fusion protein during B-cell development, and recapitulates the multi-step process of B-ALL (Jamrog L et al., PNAS, 2018). I was involved in identifying the cells at the origin of-B-ALL and characterizing their functional and molecular properties. Our work indicates that at pre-leukemic stage, PAX5-ELN induces the emergence of an aberrant population of B-progenitors with an abnormal self-renewal property. This population is enriched in quiescent cells resistant to chemotherapeutic agents, activating a molecular stem cell program and supporting long-term leukemic initiation. This work is the subject of a recent publication signed by myself as second author (Fregona V, Bayet M et al., J Exp Med, in press). In parallel, my thesis focused on modeling the initiation and leukemic transformation induced by the PAX5P80R mutation, a frequent initiating alteration in patients. I used fetal liver cells derived from Pax5-/- mouse embryos to select lymphoid progenitors not committed to the B lineage. After transduction with CTL, PAX5 Wt or PAX5P80R retroviruses, I showed that PAX5P80R does not restore efficiently definitive commitment of cells to the B lineage. Transplantation experiments have shown that PAX5P80R induces aberrant engraftment potential followed by the development of B-ALL. This leukemic transformation is associated with the selection of clones carrying additional mutations affecting the JAK/STAT signaling pathway. Our analyses identified Hif2 as a potential candidate for leukemogenesis. Finally, pharmalogical screening of Hif inhibitors revealed Acriflavine as an interesting compound targeting leukemic cells. Thus, the modeling of B-ALL by the PAX5P80R mutation provides the team with a new tool to mimic the multi-step process of B-ALL, and to decipher the biological mechanisms by which the mutation leads to tumor transformation. This work is the subject of a manuscript in preparation which I have signed as first author (Bayet M, Fregona V, et al., in preparation). The PAX5-ELN and PAX5P80R models not only make it possible to study the various stages of B leukemogeneis, but also serve as a basis for the development of small molecule screening on primary cells. I therefore set up a miniaturized and robust protocol by FACS to screen chemical compounds targeting pre-leukemic cells. Our multiparametric approach enables us to simultaneously assess the effect of compounds on pre-leukeic cells and normal B subpopulations. I screened a bank of 1040 synthetic and natural compounds (essential chemical library) reflecting the chemical diversity of the French national chemical library. This screening, combined with dose-response counter-screening, enabled me to identify 5 molecules of interest. Overall, my work demonstrates the feasibility of small-molecule screening on a population enriched in leukemia-initiating cells, taking into account the intrinsic complexity of primary B-cells. Finally, I edited and published a review in the journal Cancers outlining the concepts of tumor heterogeneity in patients' leukemic cells, the utility of transgenic mouse models to explore the leukemia initiating cell compartment, and current efforts to discover new targeted therapies (Fregona V*, Bayet M* et al, Cancers (Basel), 2021), wich I co-authored
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Kline, Dana L. "Contextualizing Transformation| Initiation Dreams of Depth Psychotherapists-in-Training". Thesis, Pacifica Graduate Institute, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=1692045.
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This thesis explores how the depth psychotherapist can experience a sacred passage of initiation in the context of archetypal dreams. It examines the intersections of meaning making in alchemical and mythological dream imagery and the numinous experience of initiation. It explores C. G. Jung’s individuation process and whether identifying dream images as archetypal wounds can deepen the psychotherapist–client therapeutic relationship. Using hermeneutic and heuristic methodology, this research uses a comparative analytical lens and the author’s personal process of tracking two archetypal dreams that coincide with the author’s answer to the soul’s calling to depth psychology and the first phase of seeing psychotherapy clients in graduate training. Honoring the unconscious as a map for psychological complexes, emotional states, unexpressed narratives, and symbols of both the personal and collective, the author expands upon an ancient way of honoring the death and rebirth of an individual in a transformative state of growth.
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Mishra, Shrikant. "Mechanism of TNF-α cytotoxicity in a leukemia virus transformation model". Diss., Virginia Tech, 1991. http://hdl.handle.net/10919/39214.
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Mishra, Shrikant. "Mechanism of TNF-[alpha] cytotoxicity in a leukemia virus transformation model /". This resource online, 1991. http://scholar.lib.vt.edu/theses/available/etd-08232007-112933/.
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Voronin, Yegor A. "Investigation of initiation of reverse transcription in retroviruses using vectors with two primer-binding sites". Morgantown, W. Va. : [West Virginia University Libraries], 2003. http://etd.wvu.edu/templates/showETD.cfm?recnum=3136.
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Jenkins, Catherine Elfi Sarah. "Mechanisms of acute leukemia disease initiation and maintenance through manipulation of IGF1R and RUNX family members". Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61331.
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Characterization of new pathways in Acute Myeloid Leukemia and T-cell Acute Lymphoblastic Leukemia which contribute to oncogenesis is necessary to relieve dependence on conventional chemotherapy for treatment of these diseases. In this dissertation, I characterized the role of signaling molecules (IGF1R) and transcription factors (RUNX1, RUNX3, NOTCH1) in regulating mechanisms of leukemia initiation and maintenance. I discovered that committed myeloid progenitor cells with genetically reduced levels of IGF1R were less susceptible to myelogenous leukemogenic transformation due, at least in part, to a cell-autonomous defect in clonogenic activity. Genetic deletion of IGF1R by inducible Cre recombinase however had no effect on growth/survival of established leukemia cells. I raise the possibility that IGF1R inhibitors in clinical development may be acting through alternate/related pathways. Second, in a retroviral insertional mutagenesis study, I cloned retroviral integration sites from hNOTCH1ΔE mouse leukemias to find genes which collaborate with Notch signaling in T-ALL initiation. Common integration sites include the previously identified Ikzf1, and a novel potentially Notch-collaborating gene, Runx3. Using a multicistronic lentiviral system, I show that RUNX1A, RUNX1B and RUNX3 were able to collaborate with the ΔEΔL allele of NOTCH1 to initiate leukemia. Finally, I sought to understand how RUNX1 and RUNX3 contribute to the biology of established T-cell leukemias. I found that both RUNX1 and RUNX3 contribute to T-ALL cell proliferation and survival. Although RUNX3 can induce cell proliferation, RUNX1 expression is finely tuned with overexpression and knockdown resulting in negative growth phenotypes. This may be in part to regulation of MYC, IL7R, IGF1R, and CDKN1B as well as affecting genome-wide H3K27Ac. I found that RUNX1 expression was targeted by the CDK7 inhibitor, THZ1. RUNX1 and RUNX3 are mediators of Notch-directed regulation of PKCθ, and as such are indirect regulators of LIC-activity. Finally, I showed that RUNX1 and Notch signaling provide complimentary, additive signals for growth of T-ALL cells. These experiments provide insight into the role of RUNX1 mutations in T-cell leukemia and point to a complementary role in supporting the Notch pathway.Medicine, Faculty of
Graduate
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Chakraborty, Pritam. "WAVELET TRANSFORMATION BASED MULTI-TIME SCALE METHOD FOR FATIGUE CRACK INITIATION IN POLYCRYSTALLINE ALLOYS". The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1325091714.
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Seok, Daniel y Grant Skrepnek. "Inpatient Charges and Mortality of Richter’s Transformation of Chronic Lymphocytic Leukemia in the United States". The University of Arizona, 2012. http://hdl.handle.net/10150/614535.
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Class of 2012 AbstractSpecific Aims: The objectives of this study were to determine the financial impact and mortality of CLL and Richter’s transformation in CLL in the inpatient setting in the payer’s perspective, the common diagnoses at discharge for patients with CLL, and to compare demographics, hospital characteristics, and co-morbidities for CLL cases versus Richter’s only cases. Methods: This study was a retrospective cohort of inpatient hospital charges and mortality of CLL patients and CLL patients with Richter’s transformation in the United States in the perspective of the payer. Using weighted statistical methods, results of this investigation yielded nationally-representative findings. The hospital charges were analyzed with a gamma regression with log link, and mortality was analyzed with a generalized linear regression. Main Results: There were total of 391,287 cases and 7% (27,259) were Richter’s cases. The overall hospital charges for CLL and CLL patients with Richter’s transformation from 2005 to 2009 were $38,735 (±58859) per case and $53,118 (±77993) per case, respectively. The mortality was 6.3% (24,520 deaths) overall and 9.1% mortality (2,485 deaths) for Richter’s transformation patients. The significant predictors (p < 0.05) that were associated with an increase the hospital charges for Richter’s patients was sepsis while sepsis and weight loss were associated with an increase in mortality. Conclusions This study adds to the few studies published to show the impact of CLL and Richter’s. However, due to the limitation on pharmacotherapies, it was not possible to determine therapeutic cost drivers for these cases. Future studies are warranted to determine the cost of therapies associated to the different stages of CLL.
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Apichella, Michael. "Interstate '69 : the separation, initiation, and transformation of the fatherless hero in myth and literature". Thesis, Aberystwyth University, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.742419.
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Kennah, Erin. "Identification of differentially expressed genes in AHI-1-mediated leukemic transformation in cutaneous t-cell lymphoma". Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/962.
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The oncogene Ahi-1 was recently identified through provirus insertional mutagenesis in murine leukemias and lymphomas. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in several leukemic cells lines, particularly in cutaneous T-cell lymphoma (CTCL) cell lines (Hut 78 and Hut 102). Hut 78 is derived from a patient with Sezary syndrome, a common leukemic variant of the human CTCL mycosis fungoides. Aberrant expression of AHI-1 mRNA and protein has been found in CD4⁺CD7⁻ leukemic Sezary cells from patients with Sezary syndrome. Moreover, stable suppression of AHI-1 using retroviral-mediated RNA interference in Hut 78 cells inhibits their transforming activity in vitro and in vivo. In an effort to identify genes involved in AHI-1-mediated leukemic transformation in CTCL, microarray analysis was performed to compare six RNA samples from AHI-1 suppressed Hut 78/sh4 cells to five samples from Hut 78 control cells. Limma and dChip analyses identified 218 and 95 differentially expressed genes, respectively, using a fold change criteria of > or < 2 and a p-value threshold of ≤ 0.01. After evaluation of both analyses, 21 genes were selected based upon interesting structural and functional information, specificity to hematopoietic cells or T-cells, and previous connections to cancer. Expression patterns of these 21 genes were validated by qRT-PCR with p-values < 0.05 ranging from 1.97 x 10⁻¹⁰ to 6.55 x 10⁻³, with the exception of BRDG1 at 5.88 x 10⁻². The observed up-regulation of both BIN1 and HCK in AHI-1 suppressed Hut 78/sh4 cells as compared to control cells further confirmed at the protein level. The tumor suppressor BIN1 is known to physically interact with c-MYC, which also exhibits differential protein expression in these cells. Characterization of BIN1 identified 4 isoforms all of which contain exon 10 and demonstrate alternative splicing of exons 12A and 13. Additionally, qRT-PCR results from primary Sezary samples indicate there is clinical significance in the expression changes detected for BIN1, HCK, REPS2, BRDG1, NKG7 and SPIB. These findings identify several new differentially expressed genes that may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells.
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Ye, Jianxin. "Transformation studies of human t-cell leukemia virus with emplhasis on the role of tax and rex". The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1060451751.
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Je, Jianxin. "Transformation studies of human t-cell leukemia virus with emphasis on the role of tax and rex". Columbus, Ohio : Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1060451751.
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Thesis (Ph. D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xii, 133 p.; also includes graphics. Includes abstract and vita. Advisor:, Dept. of Molecular, Cellular, and Developmental Biology. Includes bibliographical references (p. 108-133).
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Ruggero, Katia. "Role of microRNAs in T-cell activation and transformation by human T-cell Leukemia virus type 1". Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422191.
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Human T-Lymphotropic virus type 1 (HTLV-1) is the causative agent of two distinct pathologies, adult T-cell leukemia/lymphoma (ATLL), an aggressive malignancy of mature CD4+ T-cells, and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM), a demyelinating neurodegenerative disease. Despite intense study, many aspects of HTLV-1 replication, persistence and pathogenesis remain to be understood. The work described in the present thesis was aimed at defining the role of microRNAs (miRNAs) in HTLV-1 infection and ATLL pathogenesis.
We generated small RNA libraries from normal CD4+ cells (resting and stimulated) and two T-cell lines chronically infected with HTLV-1 (MT-2 and C91PL). Libraries were analyzed by 454 mass sequencing and data were processed through a series of computational steps to identify known and candidate new miRNAs for each library. Comparison of frequencies of known miRNAs in the different libraries led to the identification of 14 downregulated miRNAs and 4 upregulated species in infected cell lines vs. resting CD4+ cells, while 21 miRNAs were differentially expressed (16 downregulated, 5 upregulated) in stimulated compared to resting CD4+ cells. We validated the expression of some new miRNA candidates identified by bioinformatic analysis of the libraries through end point and quantitative RT-PCR. Two sequences mapped to the HTLV-1 genome, suggesting that the virus may produce its own miRNAs under certain conditions.
We examined the profiles of known miRNA expression in ATLL cells and normal resting and activated T CD4+ lymphocytes using microarrays. On the basis of miRNA expression, cluster analysis of ATLL samples and CD4+ controls showed that the resting controls were highly related to each other, while the tumor samples exhibited some heterogeneity. Statistical analysis revealed 6 upregulated and 21 downregulated miRNAs in ATLL cells compared to CD4+ T-cell controls. Several of the differentially expressed miRNAs identified in the libraries and by microarray analysis were validated by real time RT-PCR.
Since miRNA-mRNA interactions often result in degradation of the target mRNA, integration of results from target prediction programs with expression profiles for miRNAs and mRNAs can aid in identifying genuine mRNA targets. This approach was applied to miRNA and mRNA microarray data obtained for our ATLL and resting CD4+ samples. Potential targets for 12 miRNAs differentially expressed in ATLL cells were identified by integrating miRNA and mRNA expression profiles. Functional enrichment analysis of predicted targets revealed the presence of several genes belonging to the cAMP signalling pathway, which is known to be activated upon HTLV-1 transformation. We also investigated the role of miR-34a, consistently upregulated in ATLL samples and HTLV-1 infected cells lines. Knockdown of miR-34a in infected cell lines determined an increased in cell death, suggesting that miR-34a could play an important role in the expansion of HTLV-1 infected cells and thereby in ATLL development.Il virus T-linfotropico umano di tipo 1 (HTLV-1) è l’agente eziologico della leucemia/linfoma a cellule T dell’adulto (ATLL, adult T-cell leukemia/lymphoma) e della paraparesi spastica tropicale/mielopatia associata ad HTLV (TSP/HAM, Tropical spastic paraparesis/HTLV-associated myelopathy), una patologia degenerativa del sistema nervoso centrale. Recenti evidenze suggeriscono che i microRNA (miRNA) contribuiscano a questo processo di trasformazione mediata da HTLV-1. Le ricerche condotte nel corso del mio dottorato sono state mirate ad approfondire il ruolo dei microRNA (miRNA) nell’infezione di cellule T da parte di HTLV-1 e nella patogenesi dell’ATLL. Sono state realizzate librerie di cDNA di piccoli RNA, a partire da linfociti T CD4+ normali (resting e attivati) e da due linee cellulari cronicamente infettate con HTLV-1 (C91PL e MT-2). Le librerie sono state analizzate attraverso il sequenziamento di massa 454 e l’analisi bioinformatica delle sequenze ottenute ha permesso l’identificazione dei miRNA noti e nuovi miRNA candidati presenti in ciascuna libreria. Il confronto delle frequenze dei miRNA noti nelle diverse librerie ha evidenziato la presenza di 14 e 4 miRNA rispettivamente downregolati e upregolati nelle linee cellulari infettare rispetto ai linofociti T CD4+ resting, mentre 21 miRNA sono risultati differenzialmente espressi in linfociti T CD4+ stimolati in confronto ai linfociti T CD4+ resting (16 downregolati, 5 upregolati). L’espressione di diversi nuovi miRNA, individuati dall’analisi bioinformatica delle librerie, è stata validata attraverso RT-PCR end-point o RT-PCR quantitativa. Inoltre la nostra analisi ha rivelato nelle librerie da cellule infettate 2 sequenze che mappano in regioni trascritte del genoma di HTLV-1 e che potrebbero rappresentare dei miRNA virali. Attraverso l’impiego di microarray il profilo di espressione dei miRNA noti è stato analizzato in pazienti ATLL e in linfociti T CD4+ resting e stimolati. In base ai profili di espressione di miRNA ottenuti i campioni sono stati raggruppati in cluster che indicano una forte similitudine all’interno dei campioni di linfocititi T CD4+ resting, mentre i campioni di ATLL hanno profili di espressione di miRNA più eterogenei. L’analisi statistica ha evidenziato 21 miRNA downregolati e 6 upregolati nei pazienti ATLL vs linfociti T CD4+ resting. Diversi miRNA differenzialmente espressi identificati attraverso l’analisi delle librerie e dei microarray sono stati validati tramite RT-PCR quantitativa. Dal momento che l’interazione miRNA-mRNA spesso comporta la degradazione del messaggero bersaglio, l’analisi integrata dei risultati dei programmi di predizione di bersagli con i profili di espressione di miRNA e geni può aiutare nell’identificazione di target. Abbiamo applicato questo approccio ai dati di espressione di miRNA e geni ottenuti per i nostri campioni di ATLL e linfociti T CD4+ resting. Dall’integrazione dei profili di espressione di miRNA e mRNA sono stati identificati i target putativi per 12 miRNA differenzialmente espressi nei pazienti ATLL. L’arricchimento funzionale dei geni bersaglio predetti ha evidenziato la presenza di diversi geni coinvolti nella via di segnale di cAMP, noto per essere presente ad alti livelli in cellule trasformate da HTLV-1. Infine abbiamo indagato il significato funzionale di miR-34a, che risulta essere consistentemente upregolato in pazienti ATLL e linee cellulari infettate. Il silenziamento di miR-34a in linee cellulari infettate determina un aumento della morte cellulare, suggerendo che la deregolazione di questo miRNA possa svolgere un ruolo importante nell’espansione della popolazione di cellule infettate da HTLV-1 e quindi nello sviluppo dell’ATLL.
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Turok, Karina. "Social skin : initiation through the bodily transformation of four South African women : an exploration using documentary photography". Master's thesis, University of Cape Town, 2002. http://hdl.handle.net/11427/17244.
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Bibliography: p. 92-93.My work questions social and cultural constructs of 'normality' and, by focusing on the practices of marginalised communities, questions dominant cultural conventions of female identity, beauty and sexuality. Within visual media, if the private or unsaid of female experience is said, it is seen as subversive. By focusing on four female initiations, my intention is to develop a specific yet complex comparison of different types of initiations. Embedded within the communities I have photographed are unique perceptions of beauty, each of which differs from mainstream notions. My intention is not to exoticise any particular community, but to explore some sub-cultures of female youth in South Africa, and to unfold how these women position themselves in post-Apartheid South Africa. An important component of the work is the relationship of the subject to the documentary process. I hope both to raise questions and also provide some answers concerning how the means of signification functions for the subjects. As the photographer of their transformation process, I am positioned as an outsider in their lives. As a means of acknowledging this, I include a series of photographs taken or directed by the women themselves, alongside my own. In doing so, my intention is to create a visual dialogue with the subjects, effectively offering them the opportunity to reply to my images with their own. This is not meant as a patronising gesture of political correctness, but as a means of attaining a more complete narrative while at the same time exploring complexities inherent in the play between 'inside' and 'outside' perspectives. My editing of their self-portraits positions me as a curator in this facet of the project.
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Zhou, Jun. "Exploration de la fonction de PML/RARA (Promyelocytic Leukemia/Retinoic Acid Receptor Alpha) dans les progéniteurs hématopoïétiques". Paris 7, 2005. http://www.theses.fr/2005PA077174.
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Christensen, Kimberly Laura. "The developmental regulator SIX1 plays multiple roles in breast cancer initiation and progression /". Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Biophysics & Genetics, Program in Molecular Biology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 115-132). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Sharma, Varun Kumar. "The role of small non-coding RNAs in human T-cell leukemia virus type 1 (HTLV-1) infection and transformation". Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423709.
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Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of two distinct pathologies, adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells, and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM), a demyelinating neurodegenerative disease. The emerging importance of small noncoding RNAs in normal cell physiology and disease has prompted studies of their role in T-cell activation and transformation. The work described in the present thesis was aimed at understanding the role of small noncoding RNAs, in particular microRNAs and tRNA fragments (tRFs), in HTLV-1 infection and ATLL pathogenesis.
The laboratory generated small RNA libraries to identify the repertoire of small noncoding RNAs expressed in two HTLV-1-infected T-cell lines (C91PL and MT-2) compared to normal CD4+ T-cells. Results revealed upregulation of miR-34a in the cell lines. Many tRFs were identified in both uninfected and infected cells. One of the most abundant tRFs (tRF-3019) was derived from the 3’ end of tRNA-proline, which is considered to be the primer for HTLV-1 reverse transcriptase. Results of an in vitro reverse transcriptase assay verified that tRF-3019 was capable of priming HTLV-1 reverse transcriptase. Both tRNA-proline and tRF-3019 were detected in HTLV-1 virus particles. tRF-3019 may thus play an important role in HTLV-1 reverse transcription and could represent a target to control HTLV-1 infection.
Data from a microarray-based analysis of microRNA expression in ATLL samples compared to normal CD4+ T-cells revealed 21 downregulated microRNAs and 6 upregulated microRNAs. Upregulated microRNAs included miR-34a, which is a member of the highly conserved miR-34 family that acts as a tumor suppressor induced by p53 in other cell types. However, p53 is known to be functionally inactivated or mutated in ATLL cells and HTLV-1-infected cell lines. Treatment of infected cell lines with nutlin-3a, a drug that restores p53 activity by interfering with MDM2, resulted in an upregulation of miR-34a and strong downregulation of several of its predicted targets. These findings indicate that unblocking the p53 pathway in HTLV-1-infected cells promotes engagement of the miR-34a/mRNA regulatory network.
The final aim of the project was to identify microRNAs regulated by the viral regulatory protein Tax. To this end the HTLV-1-negative T-cell line Jurkat was transfected with a Tax expression plasmid and assayed for changes in mRNA and microRNA expression by quantitative RT-PCR. Results revealed significant alterations in the levels of 7 microRNAs in the presence of Tax. These included let-7g, whose levels were reduced in the Tax-expressing cells. Let-7g was also found to be downregulated in ATLL samples compared to normal CD4 cells analysed by microarrays, suggesting that this microRNA might play a tumor suppressor role in HTLV-1-mediated transformation. Experiments are currently underway to identify targets of let-7g in infected cells using as a starting point 14 genes identified by integrating results from microRNA target prediction programs with expression profiles for microRNAs and mRNAs in ATLL cells vs. CD4 controls.Il virus T-linfotropico umano di tipo 1 (HTLV-1) è l’agente eziologico della leucemia/linfoma a cellule T dell’adulto (ATLL, Adult T-cell leukemia/lymphoma), un’aggressiva neoplasia a carico dei linfociti T CD4+ maturi, e della paraparesi spastica tropicale/mielopatia associata ad HTLV (TSP/HAM, Tropical spastic paraparesis/HTLV-associated myelopathy), una patologia degenerativa del sistema nervoso centrale. L’interesse crescente nello studio e nella comprensione della funzione degli “small non-coding RNA” in cellule normali e tumorali ci ha spinto ad uno studio del loro ruolo nell’ attivazione e nella trasformazione delle cellule T. Il lavoro descritto nella presente tesi mira a comprendere il ruolo degli “small non-coding RNA” (sncRNA), in particolare microRNA e frammenti tRNA (tRFs), nell’ infezione da HTLV-1 e nella patogenesi dell’ATLL. Nel nostro laboratorio sono state generate librerie di “small RNA” per identificare il repertorio di sncRNA espressi in due linee cellulari infettate con HTLV-1 (C91PL e MT-2) rispetto alle cellule T CD4 + normali. I risultati hanno rivelato un’aumentata espressione del miR-34a nelle linee cellulari infettate. Molti frammenti di tRNA (tRFs) sono stati identificati sia nelle cellule infettate che non infettate. Uno dei tRFs più abbondanti (tRF-3019) è derivato dall’ estremità 3’ del tRNA-prolina, che è considerato il primer per la trascrittasi inversa dell’HTLV-1. I risultati ottenuti da un saggio di trascrittasi inversa in vitro hanno dimostrato che il tRF-3019 è in grado di funzionare da primer nella trascrizione inversa di HTLV-1. La presenza sia del tRNA-prolina che del tRF-3019 è stata evidenziata nelle particelle virali. Il tRF-3019 potrebbe quindi svolgere un ruolo importante nella retrotrascrizione del virus e potrebbe rappresentare un “target” terapeutico nell’infezione da HTLV-1. I dati ottenuti dall’ analisi con microarray sull’ espressione di microRNA in campioni di ATLL e in campioni di cellule T-CD4 + normali ha rivelato una diminuzione nell’espressione di 21 microRNA e un’aumentata espressione di 6 microRNA. I microRNA sovraespressi comprendono anche il miR-34a, che è un membro della famiglia dei miR-34, altamente conservati, che agiscono come oncosoppressori indotti da p53 in diversi tipi cellulari. Tuttavia, p53 è inattiva o mutata in cellule ATLL e in linee cellulari HTLV-1-infettate. Il trattamento di linee cellulari infettate con Nutlin-3a, un farmaco che ripristina l'attività di p53 legandosi a MDM2, ha rivelato un aumeto di espressione di miR-34a e una forte riduzione dell’espressione di alcuni dei suoi target. Questi risultati suggeriscono che attivando il pathway di p53 in cellule HTLV-1-infettate si potrebbe promuovere l’ingaggio del network regolatorio del miR-34a. Infine, ci siamo proposti di identificare i microRNA regolati dalla proteina virale Tax. A tal fine la linea cellulare T non infetta, Jurkat, è stata transfettata con un plasmide di espressione per Tax e sono state testate le variazioni di espressione di mRNA e microRNA mediante RT-PCR. I risultati hanno rivelato che in presenza di Tax ci sono alterazioni significative nei livelli di espressione di 7 microRNA. Queste variazioni includono il microRNA let-7g, i cui livelli sono ridotti nelle cellule che esprimono Tax. Da studi effettuati su microrrays, let-7g risulta sottoespresso in campioni ATLL rispetto alle cellule CD4 normali, suggerendo che questo microRNA potrebbe svolgere un ruolo di oncosoppressore nella trasformazione mediata da HTLV-1. Gli esperimenti, attualmente in corso, permetteranno di identificare i target di let-7g in cellule infettate utilizzando come punto di partenza 14 geni ottenuti dall’integrazione dei risultati dei programmi di predizione dei target dei microRNA con i profili di espressione di microRNA e mRNA in cellule ATLL rispetto ai controlli CD4.
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FRIGE', GIANMARIA. "EPIGENETIC ALTERATIONS INDUCED BY THE PML-RAR ONCOGENE DURING THE TRANSFORMATION PROCESS OF ITS TARGET CELLS". Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/219071.
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Acute promyelocytic leukaemia (APL) is a subtype of acute myeloid leukaemia, caused by the t(15;17) translocation that generates an aberrant transcription factor PML-RARα. Owing to its ability to affect gene expression through chromatin modifications, PML-RARα is potentially capable of a multitude of alterations in the chromatin landscape, most of which are still poorly characterized. To investigate PML-RARα mechanistical activity at early stages of tumor initiation, first we started elucidating the target cell(s) in which the leukemogenesis takes place. Our results showed that phenotypically defined common myeloid progenitor hematopoietic (CMPs), are capable of initiating leukemogenesis. We found that PML-RARα can induce an adult stem cell signature in normal myeloid progenitors, distinct from that observed in frankly established leukemic stem cells. Among the transcriptional targets identified, the cell cycle inhibitor p21, required for self-renewal of normal and leukemic stem cells, was shown to be indispensable for this phenomenon. To mechanistically dissect the pre-leukemic epigenome of the identified hematopoietic subpopulation, we developed ad hoc technological approaches to study small population of cells (miniChIP-sequencing, Nuclease Accessible Site Sequencing and DNA methylation sequencing). The analysis of the changes between chromatin states show that the oncogene in the pre-leukemic state does not impose a global alteration of chromatin but, rather, it functions as a local modulator of chromatin accessibility involving genomic regions enriched in important regulators of normal and aberrant hematopoiesis.
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Lu, Chang-Tsan. "Atomistic Study of Motion of Twin Boundaries: Nucleation, Initiation of Motion, and Steady Kinetics". Research Showcase @ CMU, 2013. http://repository.cmu.edu/dissertations/297.
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The materials that exhibit martensite transformation have very important applications in engineering, and the microstructures of the materials play a key role foraffecting their mechanical behavior in macroscope. Therefore many attentions havebeen drawn for studying the related problems. This work focuses on the motion oftwin boundaries. Three questions are being asked: how is a twin boundary is nucleated in a homogenous (untwinned) material? After the twin boundary is nucleated,how is its motion initiated? How fast does it move? This study provides an atomisticunderstanding for these three questions.
Linear stability analysis is firstly applied to capture the initiation of motion of atwin boundary. When a twin boundary is about to move, the lowest eigenvalue of thesystem Hessian drops to zero. And the corresponding eigenvector predicts accuratelythe way in which the twin boundary is going to move. The same idea is applied toinvestigate how motion of an irrational twin boundary is initiated. Atomic modelsof irrational twin boundaries are constructed by employment of continuum models,provided that the point group of rotations which relate two variants is extended toany rotations in plane. The zero eigenvectors reveal the complicated behavior ofmotion of irrational twin boundaries.
The problem of nonuniqueness of kinetic relations proposed by Schwetlick andZimmer is solved in a thermoelasticity framework. By calculating the net heat fluxcrossing the phase boundary which is carried by the phonons, a unique kinetic relationcan be determined. Finally, a nonlocal criterion for nucleation of twin boundariesis proposed. By checking the stiffness of each unit cell evaluated with respect to asingle variable that represents the displacement along the unit cell diagonal direction,locations and the orientations of nucleated twin boundaries can be predicted.
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Eiring, Anna Marie. "Altered mRNA Metabolism in Chronic Myelogenous Leukemia: Loss of MicroRNA-328 Decoy Activity is Important for Blastic Transformation of Leukemic Progenitors". The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1250701551.
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Courtier, Frédéric. "Caractérisation moléculaire des néoplasies myéloprolifératives et de leur transformation en leucémie aigüe myéloïde". Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0651.
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Les néoplasies myéloprolifératives classiques (NMP) Philadelphie négative, thrombocytémie essentielle, polyglobulie de Vaquez et myélofibrose primaire, sont des hémopathies chroniques de bon pronostic dues à l'altération de l'un de ces trois gènes JAK2, CALR ou MPL. Cependant, d'autres anomalies génétiques peuvent survenir au cours de la maladie et entraîner une aggravation, dont le stade ultime est la transformation en leucémie myéloïde aigüe (LAM).Pour mieux comprendre les mécanismes responsables de cette transformation, j'ai utilisé le séquençage de l'ADN pour identifier les mutations responsables de chaque stade de la maladie.Un grand nombre de mutations est associé à un risque plus élevé d'évolution de la maladie. Des mutations dans les fonctions de l’épigénétique des histones et de l'épissage de l'ARN sont associées à la myélofibrose (MF). Ces mutations de l’épigénétique des histones (mutations d'ASXL1, EZH2) et l'épissage d'ARN (mutations de SRSF2, U2AF1, SF3B1) semblent prédisposer à la transformation en LAM, laquelle nécessite la survenue d'autres anomalies affectant d'autres fonctions, telles que la méthylation de l'ADN (mutations d’IDH1/2, TET2, DNMT3A), des facteurs de transcription (mutations de RUNX1, CUX1, ...) ou des mutations de TP53. Ces mutations pourraient être retrouvées durant la phase chronique avant le diagnostic d'évolution, ce qui pourrait les identifier comme marqueurs prédictifs.La connaissance des mécanismes de transformation et l'identification de marqueurs associés peuvent améliorer la prise en charge des patients et aider à leur proposer un traitement spécifique dans le cadre de la médecine personnaliséeClassical Philadelphia-negative Myeloproliferative Neoplasms (MPN) include essential thrombocythemia, polycythemia vera and primary myelofibrosis and are slow evolving and good prognostic blood cancers due to the alteration of one of three driver genes JAK2, CALR or MPL. However, other genetic abnormalities may occur and lead to an aggravation, of which the worst stage is transformation to Acute Myeloid Leukemia (AML).To better understand the mechanisms responsible for this transformation, I used DNA sequencing to identify mutations and abnormalities responsible for each stage of the disease.Chronic phase of an MPN results from a small number of additional mutations outside the drivers, and a large number of mutations is associated with a higher risk of evolution of the disease. Mutations in the functions of chromatin modifiers and RNA splicing are associated with myelofibrosis. These mutations in chromatin modifiers (mutations in ASXL1, EZH2) and RNA splicing (mutations in SRSF2, U2AF1, SF3B1) seem to predispose to transformation to AML, which requires the occurrence of other abnormalities affecting other functions, such as DNA methylation (mutations in IDH1/2, TET2, DNMT3A), transcription factors (mutations in RUNX1, CUX1,...), or TP53 mutations. These mutations associated with MF or acute phases could be found during chronic phase before the diagnosis of evolution, which could identify them as predictive markers.Knowledge of the mechanisms of transformation and the identification of associated markers may improve the care of patients with poor prognosis and help offer them specific treatment in the context of personalized medicine
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Gras, Baptiste. "Étude des propriétés oncogéniques des membres de la famille SNAIL". Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10291.
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En parallèle à son rôle dans l’initiation de la cascade métastatique, la transition épithéliomésenchymateuse est capable de faciliter la transformation néoplasique par le biais de mécanismes encore indéfinis. Nous avons démontré que, comme SNAIL1 et SNAIL2, l’expression de SNAIL3 est réactivée de façon aberrante dans les cancers humains, en particulier dans les carcinomes mammaires, établissant un lien entre l’ensemble des membres de la famille SNAIL et la tumorigénèse. Expérimentalement, les trois protéines SNAIL induisent une EMT avec des efficacités différentes. Ce différentiel reflète leur capacité à protéger les cellules de l’anoikis et à favoriser la prolifération dans des conditions de faible adhérence en absence d’altération oncogénique. La réversion partielle du processus d’EMT en réponse à l’expression ectopique des protéines ST14/Matriptase ou de l’E-cadhérine inhibe le potentiel oncogénique des protéines SNAIL. Nous avons donc démontré que la perte de protéines responsables du maintien de l’intégrité de l’épithélium contribue à l’activité pro-tumorale des inducteurs d’EMTBeyond its role in initiating the metastatic cascade, cell commitment to the epithelial-to-mesenchymal transition program has been shown to facilitate neoplastic transformation, the underlying mechanisms yet remaining elusive. We herein demonstrate that likewise SNAI1 and SNAI2, the expression of SNAI3 is aberrantly reactivated in human cancers, mainly in breast carcinomas, linking all members of the SNAIL family to tumorigenesis. Experimentally, the three SNAIL proteins trigger EMT with unequal efficiencies. This differential mirrors their ability to protect cells from anoikis and to sustain proliferation in low-adherent conditions in absence of an oncogenic insult. Partial reversion of the EMT-process, achieved through forced expression of the ST14/Matriptase or E-cadherin proteins, alleviates the SNAIL oncogenic potential. We thus demonstrate that loss of epithelial integrity gatekeepers contributes to the tumor promoting activity of embryonic EMT-inducers
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Sola, Brigitte. "Transformation in vitro des cellules de la lignee myeloblastique par le virus leucemogene murin de friend (f-mulv) : analyse des mecanismes moleculaires de cette transformation". Paris 7, 1987. http://www.theses.fr/1987PA077242.
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Le retrovirus leucemogene murin f-mulv, competent pour la replication, entraine des leucemies myeloblastiques apres un temps de latence de plusieurs mois. L'infection de culture de cellules medullaires par ce virus entraine la transformation des cellules de la lignee myeloblastique apres une latence equivalente. En utilisant une sonde specifique du f-mulv, l'analyse du spectre d'integration des provirus dans les lignees obtenues in vitro a montre qu'il y a proliferation d'un clone cellulaire tres tot pendant le processus de leucemogenese. Une banque d'adn genomique a ete construite a partir d'une lignee ayant 5 provirus integres; les f-mulvs s'integrent preferentiellement dans 3 regions appelees fim-1, fim-2 et fim-3, fim-2 est la partie 5' de l'oncogene c-fms qui code pour le recepteur au csf1. L'integration d'un f-mulv dans la gene fim-2/cfms entraine sa surexpression sans apparente modification de structure. Role possible d'un recepteur a facteur de croissance physiologique dans un processus leucemogene
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Hess, Patricia M. "Role of c-Jun NH-terminal Kinase in Bcr/Abl Induced Cell Transformation: a dissertation". eScholarship@UMMS, 2003. https://escholarship.umassmed.edu/gsbs_diss/88.
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The c-Jun NH2-terminal kinase (JNK) group of kinases include ten members that are created by alternative splicing of transcripts derived from Jnk1, Jnk2 and Jnk3 genes. The JNK1 and JNK2 protein kinases are ubiquitously expressed while JNK3 is expressed in a limited number of tissues. The JNK signaling pathway is implicated in multiple physiological processes including cell transformation. There is growing evidence that JNK signaling is involved in oncogenesis. Nevertheless, the role that JNK plays in malignant transformation is still unclear. The aim of this thesis is to examine the role of JNK in malignant transformation. For this purpose, I used the Bcr/Abl oncogene as a transforming agent. Bcr/Abl is a leukemogenic oncogene that is created by reciprocal translocation between chromosome 9 and 22. The translocation breakpoint is variable and several different Bcr/Abl isoforms have been identified such as Bcr/AblP185 and Bcr/AblP210, whose expression is associated with different types of leukemia. Bcr/Abl activates the JNK signaling pathway in hematopoietic cells and increases AP-1 transcription activity. Furthermore, dominant negative approaches demonstrate that inhibition of c-Jun or JNK prevents Bcr/ Abl-induced cell transformation in vitro. These data implicate the JNK signaling pathway in Bcr/Abl transformation although the role that JNK might have in this process is unclear. Thus, I examined the importance of JNK signaling in Bcr/Abl-induced lymphoid or myeloid transformation. For this purpose I compared Bcr/AblP185- and Bcr/AblP210- induced transformation of wild-type and JNK1-deficient cells using three approaches: in vitro, in vivo and ex vivo. The results obtained with the in vitro approach suggest that both Bcr/AblP185 and Bcr/AblP210 require JNK activity to induce lymphoid transformation. While JNK1-deficiency inhibits Bcr/AblP210 oncogenic potential in lymphoid cells both in vitro and in vivo, pharmacological inhibition of JNK activity (JNK1 and/or JNK2) blocked Bcr/AblP185 induced malignant proliferation in vitro. The differential requirement for JNK observed in the two Bcr/Abl isoforms can be ascribed to the presence in Bcr/AblP210 of the Dbl domain which can activate the JNK pathway in vitro. In the case of Bcr/AblP210, JNK1 is critical for the survival of the ex vivo derived transformed lymphoblasts upon growth factor removal. This result correlates with the fact that mice reconstituted with Bcr/AblP210 transformed Jnk1-l- bone marrow showed normal malignant lymphoid expansion in the bone marrow yet they had reduced numbers of lymphoblast in the bloodstream and lacked peripheral organ infiltration. Thus JNK1 is essential for the survival of the transformed lymphoblast outside the bone marrow microenvironment in Bcr/AblP210induced lymphoid leukemia. Interestingly, while JNK1 is essential for lymphoid transformation, it is dispensable for the proliferation of transformed myeloblasts.
Taken together these results indicate that the JNK signaling pathway plays an essential role in the survival of Bcr/AblP210 lymphoblasts and that JNK-deficiency decreases the leukomogenic potential of Bcr/AblP210 in vivo. Thus, cell survival mediated by JNK may contribute to the pathogenesis of proliferative diseases.
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Martin, Mickael. "Expression de ZAP-70 dans les lymphocytes B non tumoraux : implications dans la rupture de tolérance et la transformation néoplasique". Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ079.
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L’expression de ZAP-70 dans la leucémie lymphoïde chronique (LLC) est associée à une hypersignalisation du BCR et à la survenue de cytopénies auto-immunes (CAI). Les LB non tumoraux expriment aussi ZAP-70, expression corrélée à celle dans les LB tumoraux et aux CAI. Nous avons montré que ces LB non tumoraux ZAP-70+ sont polyclonaux, sans lien moléculaire entre eux ni avec le clone tumoral et qu’il n’existe pas de stéréotypie de leur BCR. Ces LB présentent par contre un enrichissement en BCR autoréactifs. Notre modèle murin knock in Zap-70+/- // Mb1-Cre+/- a montré qu’une forte expression précoce de ZAP-70 dans les LB est associée à un avantage sélectif médullaire, un enrichissement en cellules potentiellement autoréactives de type zone marginale, à un blocage partiel de la maturation et de la différentiation périphérique, ainsi qu’au développement de caractéristiques de la LLC : hypogammaglobulinémie, enrichissement en auto-anticorps circulants, hyperactivation et prolifération cellulaires augmentées. Ces résultats ouvrent de nouvelles perspectives impliquant ZAP-70 dans la compréhension du développement B et de la physiopathologie de la rupture de tolérance et de la transformation néoplasiqueZAP-70 expression in chronic lymphocytic leukemia (CLL) is associated with BCR hypersignalling and autoimmune cytopenia (AIC) occurrence. Non tumoral B cells also express ZAP-70, which is correlated with those in tumoral B cells and AIC. We have shown that these non tumoral B cells ZAP-70+ are polyclonal, without molecular link between each other and tumoral B cells, and without BCR stereotypy. These cells are however enriched in autoreactive BCR. Our mouse model knock in Zap-70+/- // Mb1-Cre+/- revealed that a high and early ZAP-70 expression is associated with medullar selective advantage, enrichment in potential autoreactive B cells of marginal zone subtype, partial block for peripheral maturation and differentiation, along with some LLC characteristics: hypogammaglobulinemia, enrichment in circulating auto-antibodies, increase in cellular activation and proliferation. These results open new opportunities involving ZAP-70 in the understanding of B cell development and physiopathology of tolerance breakdown and neoplastic transformation
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Moreau-Gachelin, Françoise. "Le processus de la transformation maligne au cours de la leucemie erythroblastique de friend". Paris 7, 1987. http://www.theses.fr/1987PA077038.
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La leucemie erythroblastique de friend est une leucemienurine aigue provoquee par un complexe retroviral (sffv-mulv). Cette maladie evolue en 2 etapes successives: une etape precoce au cours de laquelle les organes hematopoietiques des animaux infectes sont envahis par des cellules proerythroblastiques a duree de vie breve qui differencient en globules rouges en absence d'erythropoietine ou meurent "in situ"; une etape tardive au cours de laquelle apparaissent des cellules cancereuses qui croissent indefiniment "in vivo" et "in vitro". La transformation maligne resulte d'un processus clonal ou oligoclonal. Des sites d'integration du sffv ont permis d'identifier un locus genonique denomme spi-1 pour sffv provirus spi-1 est different des oncogenes connus et des sites d'insertin provirale decrits. Ceci suggere que le rearrangement de ce locus genomique est un evenement initial dans le processus de la tumorigenese au cours de la leucemie de friend
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Ivory, Brian Thomas. "A phenomenological inquiry into the spiritual qualities and transformational themes associated with a self-styled rite of passage into adulthood". The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1055769211.
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Ladyguina, Anna. "Le processus de transformation intérieure inscrit dans les grandes mythologies : illustration par la psychothérapie du jeu de sable". Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00803268.
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But : comparer le processus de transformation intérieure au cours de la psychothérapie par le Jeu de Sable avec la transformation du néophyte au cours des rites d'initiation chez les Chamans, dans l'Alchimie et dans les cultes à mystères en Egypte et en Grèce. Méthodologie : Analyse de 856 photos des jeux de sable construits par 28 enfants de 4 à 12 ans. Conclusion : Il existe une similitude entre le processus de transformation vécu en psychothérapie et la première des trois étapes de l'initiation vécue par le néophyte. On retrouve dans les jeux de sable des scénarios archétypiques qui peuvent être classés dans des catégories spécifiques associées aux différentes étapes de la transformation intérieure décrites dans les mythes initiatiques.
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Crémel, Françoise. "Être paysage, un exercice pluriel : Sans le corps, pas d'accès communautaire au paysage". Electronic Thesis or Diss., Paris, AgroParisTech, 2016. http://www.theses.fr/2016AGPT0045.
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La recherche en paysage habite le dehors mentalement. Le paysage, celui qui nous émeut ou nous dégoûte, sensoriel, est envisagé ici comme une fiction concrète du corps en voyage. Éprouvée, par les voies multiples qui escortent le paysage à chaque traversée, j’interroge la validité de cet objet d’étude. Et si le paysage échappait aussitôt à chaque essai de capture ? Et comment ses multiples formes se resserrent-elles autour de soi pour nicher une complétude de l’être ? C’est ici que peut se formuler une conception du paysage comme celle d’un tissu, non plus seulement déployé sur le fond géographique mais emprisonnant dans sa fibre les corps et âme de chaque être. Le dehors, comme habitat de chaque créature, n’est plus purement un environnement, il devient un paysage. Proposer des exercices d’accès au dehors, pour pouvoir adresser le paysage de manière collective, est l’objectif de ce travail de thèse. C’est dans le contexte où habiter n’est plus proclamé par un paysage d’accueil que mon travail cherche à remettre le corps en exercice, puis en capacité d’évaluer un paysage. Un paysage se dé- clare à la fois par des représentations et des façons. Les unes traitent des expressions, les autres des matières. Entre la locution et la substance, qu’est-ce qui fait motif ? Le corps est-il susceptible de s’avancer vers le paysage et celui-ci a-t-il des ressources pour le recevoir ? Dans une première partie, plutôt que le texte déployé et discuté par des voix dissidentes, je mets en jeu des mots clefs proposés par l’enseignement pour l’élaboration d’un discours. A l’angle de la recherche et de la pratique, je construis ma thèse depuis ma place de paysagiste praticienne et enseignante du projet de paysage à L’ENSP de Versailles. Je m’appuie sur une critique de « Mouvance, 50 mots pour le paysage » proposée en 1999 par six chercheurs en paysage qui ont construit une première proposition théorique. Après un exposé, ils sont mis en débat avec un lexique construit lors des quatre années de la préparation de cette thèse. J’éprouve enfin, avec mes étudiants, la vitalité de ces mots dans des lieux de paysage ou des situations de pratiques professionnelles afin de construire sur une base vivifiée, le corpus même de ce qui peut s’exprimer en paysage. Ces termes sont la base abstraite de travaux pédagogiques conduits sur le terrain présenté dans une seconde partie. Le Parc des Lilas, à Vitry-sur-Seine est le cadre d’étude des exercices donnés dans des ateliers de projets de paysage sur lesquels travaillent mes étudiants. Ce parc, amorcé en 1980, est en cours d’agencement. Sans effet de signature, il ne trouve pas son nom, est qualifié d’inattendu, d’alias, de tempo. Des qualités lui confèrent sa substance : il devient un produit allochtone en son propre lieu. Sa chronique permet de mettre au jour une façon mobile d’accréditer le paysage d’un lieu. Le parc des Lilas sert d’appui à l’épreuve de définition des termes du lexique et se mesure à la pensée du Parc, en tant qu’objet de paysage produit. La proposition, développée en troisième partie, place le corps dans un acte de perception pour expertiser le paysage. Le protocole de recherche, immédiat, se définit à partir des produits successifs du geste, du discours oral, puis de la production écrite. La production est celle de la recherche en marche, arrêtée, glosée ; elle même projetant plus loin l’énoncé. Je présente ici une notice pour l’usage du commentaire composé de paysage (CCP), un avatar vers le projet en pédagogie appliquée. Proposition d’innovation pédagogique où protocoles et préalables participent à la remise de l’énoncé. Niveaux de langue et niveaux d’abstraction ne sont plus des obstacles à un entendement du paysage. Le CCP tient le cadre d’un don du paysage à une population entière. Réel et imaginaire revigorés sont redistribués par le jeu de leur apparition. Corps et paysage s’alimentent en une « physiologie du paysage » qui s’enseigne par fréquentationThe research in landscape mentally inhabits the outside. The landscape, the one which moves us or disgusts us, sensory, is here envisaged as a realistic fction of the traveling body. Experienced with the multiple paths which go alongside the landscape with each crossing, I question the validity of this research topic. What if the landscape escaped straight away at each attempt to capture it? How do its multiple shapes gather around themselves to nest the wholeness of one being? Here, we can try to phrase a conception of the landscape as a fabric, not only spread at a geographical level but also imprisoning in its fbers the body and the soul of each being. The outside, as the habitat of each creature, is no longer just an environment, but becomes a landscape. Suggesting exercises to access the outside to address the landscape collectively is the aim of this Ph.D. research. It is in this context where living is no longer claimed by a welcoming landscape that my work attempts to put the body back in movement and then to render it able to assess a landscape. A landscape is expressed both through representations and ways. The former are about expressions and the latter are about materials. Between the locution and the substance, what is the pattern? Is the body susceptible to move towards the landscape and does the landscape have the resources to receive it? In the frst part, rather than a text displayed and discussed by dissident voices, I involve the keywords offered by education to develop a discourse. At a crossroad between research and practice, I build my thesis from my position as a practicing landscaper and as a landscape project teacher at the ENSP in Versailles. My work relies on a criticism of Mouvance, 50 mots pour le paysage, written in 1999 by six landscape researchers, who built a frst theoretical approach. After a presentation, their views are debated with a lexicon elaborated during the four years spent working on this thesis. At last, I test with my students the vitality of these words in different landscape places or professional practice situations, in order to build on a freshened basis the very corpus of what can be expressed in the landscape. These words are the abstract basis of feldwork teaching sessions detailed in the second part. The Parc des Lilas, in Vitry-sur-Seine is the study framework of exercises done with my students in a landscape project. This park, started in 1980, is still under arrangement. Without a signature, it has no name and is defned as unexpected, an alias, a tempo. Its qualitiesualities give it its substance: it has become allochtonous, an alien product in its own place. Its chronicles enables one to unearth a changing way to ascertain the landscape of a place. The Parc des Lilas is used as a basis for the lexicon’s defnition and evaluation of the Parc’s conception as a produced landscape. In the third part, the proposition is to place the body in a landscape in order to assess it. The research protocol is immediate and is defned from successive products of movements, of speech and then of written production. The production is that of a research in action, stopped and commented, the research itself going further than its formulation. I offer here a guide for the commentaire composé de paysage (CCP), the composed commentary of the landscape, an avatar towards educational applied project, a proposition of educational innovation, where protocols and prerequisites are part of the formulation. Linguistic and abstraction levels are no longer obstacles to understanding the landscape. The CCP is the frame of a landscape offered to everyone. The real and the imaginary are redistributed as they appear. Body and landscape feed into a «landscape physiology», which is taught through attendance
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Lodewick, Julie. "Etude des rôles des modifications post-traductionnelles de la protéine Tax du virus HTLV-1 dans ses activités transcriptionnelles et transformantes". Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210502.
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La protéine Tax du virus HTLV-1 a les propriétés d'un oncogène viral et joue un rôle important dans l'induction de la transformation cellulaire menant à l'ATL. L'activité oncogène de Tax résulte d'effets pléiotropes sur divers mécanismes cellulaires y compris l'activation de l'expression de gènes cellulaires spécifiques par la voie NF-&61547;B et la dérégulation de la progression du cycle cellulaire. Dans ce travail, nous avons mis en évidence que Tax est une protéine hautement modifiée dans diverses lignées cellulaires y compris dans les lymphocytes T transformés par HTLV-1. L'ensemble des modifications post-traductionnelles de Tax forment une suite hiérarchisée qui contrôlent la localisation intracellulaire de Tax, sa capacité d'activer les kinases IKK et la voie de signalisation des facteurs NF-&61547;B et sa capacité d'induire un arrêt dans la progression de la mitose. En effet, la phosphorylation de Tax contrôle son ubiquitination et son passage dans le noyau où elle est sumoylée et acétylée. L’ubiquitination et la sumoylation de Tax agissent de manière concertée pour permettre l’activation de l’expression des gènes par la voie NF-&Doctorat en Sciences agronomiques et ingénierie biologique
info:eu-repo/semantics/nonPublished
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Yacek, Douglas W. "Transformative Education: A Philosophical Inquiry". The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500072204487494.
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Nadella, Murali Vara Prasad. "Expression and regulation of parathyroid hormone-related protein during lymphocyte transformation and development of humoral hypercalcemia of malignancy in lymphoma". Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1190131395.
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Silva, Ana Elisa Barreiros Bueno da. "Aspectos moleculares da transformação celular induzida por Bcr-Abl". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-03062008-153936/.
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As leucemias cromossomo Ph-positivas estão intimamente associadas à expressão da tirosina-quinase Bcr-Abl. Esta oncoproteína promove independência de fatores de crescimento, alterações na adesão e inibição da apoptose por mecanismos ainda não totalmente elucidados. O objetivo desse estudo foi avaliar a contribuição da atividade quinase de Bcr-Abl para seu potencial anti-apoptótico e identificar alterações moleculares envolvidas na transformação celular induzida por essa proteína. Nossos resultados sugerem que a resistência à apoptose não depende da manutenção constante da atividade tirosina-quinase de Bcr-Abl, tampouco da presença de proteínas fosforiladas em tirosina. A comparação do proteoma de células HL-60.vetor e HL-60.Bcr-Abl revelou que a presença de Bcr-Abl causa alterações profundas no padrão de expressão protéica. As proteínas afetadas estão associadas a diversos processos celulares, como adesão, transdução de sinais, proliferação e morte celular. Esses achados devem contribuir para a identificação de novos marcadores de prognóstico e alvos terapêuticos.Ph chromosome-positive leukemias are closely associated with the expression of Bcr-Abl tyrosine kinase. This oncoprotein promotes growth factor independence, alters cell adhesion and confers resistance to apoptosis by mechanisms that are not fully understood. The aim of this study was to evaluate the contribution of Bcr-Abl kinase activity for its antiapoptotic potential and identify molecular alterations involved in Bcr-Abl-induced cell malignant transformation. Our results suggest that Bcr-Abl is not required to be constantly active to maintain the resistance to apoptosis and pY-containing proteins may not be responsible for the antiapoptotic effect of Bcr-Abl. The comparison between the proteome of HL-60.vector and HL-60.Bcr-Abl cells revealed that the presence of Bcr-Abl alters the expression of a great variety of proteins. The affected molecules are associated with several cellular processes, including cell adhesion, signal transduction, proliferation and cell death. Our findings might help the identification of new prognostic markers and therapeutic targets.
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Lhoumeau], Anne-Catherine. "Rôle du récepteur PTK7 dans l'hématopoièse murine". Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5002.
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La tumorigenèse est un processus complexe provoqué par l'accumulation d'altérations génétiques contribuant à la transformation progressive d'une cellule normale en une cellule cancéreuse. Les travaux menés en hématologie ont permis d'identifier de nombreux mécanismes de signalisation impliqués dans des processus cellulaires clés comme la prolifération, la différenciation et la survie cellulaire, particulièrement au niveau des cellules souches hématopoïétiques (CSH). Parmi ces mécanismes, ceux déclenchés par les récepteurs à activité tyrosine kinase comme c-KIT ou FLT-3 ont été largement décrits au cours de ces dernières années. PTK7 est un récepteur tyrosine kinase de la famille des pseudokinases impliqué dans le développement embryonnaire qui joue un rôle important dans la polarité planaire. Le gène humain initialement cloné à partir de cellules de cancer du côlon code pour une protéine surexprimée dans de nombreuses tumeurs malignes. Nous avons confirmé sa surexpression dans les leucémies aiguës myéloïdes humaines et démontré que cet évènement représente un facteur indépendant de mauvais pronostic, en modulant la réponse aux agents cytotoxiques. Afin de mieux comprendre le rôle de PTK7 dans l'hématopoïèse physiologique, mon projet a consisté à générer une souris déficiente pour cette protéine et à étudier sa fonction dans la biologie des CSH. J'ai montré que les cellules déficientes pour PTK7 présentent un défaut de domiciliation vers la moelle osseuse. Ce travail contribue à mettre en évidence le rôle des protéines de la polarité dans le système hématopoïétique et, plus particulièrement, dans la biologie des CSHTumorigenesis is a multiple step process resulting from accumulation of genetic alterations leading to progressive transformation of normal cells into tumoral cells. Many signaling pathways have been described as key processes implicated in cell proliferation, cell differentiation and cell survival, in particular in mature hematotopoietic cells and hematopoietic stem cells (HSCs). Among these signaling pathways, those controlled by tyrosine kinase receptors such as c-KIT or FLT-3 have been extensively described during the last two decades.PTK7 is a pseudokinase receptor of the tyrosine kinase receptor family involved in embryonic development and described for its role in planar cell polarity. The human gene has been initially cloned from colon carcinoma cells and is frequently overexpressed in solid tumors. We described PTK7 overexpression in acute myeloid leukemia and demonstrated that it represents an independent poor prognosis factor acting as a modulator of the chemotherapeutic response.To better understand the physiological role of PTK7 in the hematopoietic system, my project consisted in the generation of a PTK7 deficient mouse model, and in the study of its function, in particular in HSC biology. My work demonstrated that PTK7 deficient HSCs have a general homing defect and poorly colonize hematopoietic organs including the bone marrow. This work contributes to a better understanding of PTK7 functions and, more generally, sheds light on the role of cell polarity proteins in the biology of HSCs
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Koubi, Myriam. "PLZF et les protéines du groupe Polycomb : interaction et implication dans la différenciation hématopoïétique normale et pathologique". Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5066/document.
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Les protéines du groupe Polycomb (PcG) sont des facteurs épigénétiques dont le rôle est de maintenir la répression de leurs gènes cibles au niveau de la chromatine via la modification des protéines histones. EZH2 est une protéine clé dans les mécanismes de régulation puisqu’elle catalyse la mise en place de la marque répressive H3K27me3. Dans le cadre de ma thèse, je me suis intéressée au modèle des leucémies aiguës myéloïdes (LAM) dans lesquelles, contrairement à d’autres pathologies myéloïdes, des mutations affectant EZH2 ou des membres Polycomb ne sont retrouvées que très rarement (˂1%). Des études ont montré que dans ce type de leucémies, de nombreux gènes cibles d’EZH2 sont dérégulés bien que son activité répressive soit toujours présente, mettant en évidence d’éventuels défauts de recrutement de cette protéine. Parmi les facteurs de transcription susceptibles de réguler l’association des protéines PcG à la chromatine, se trouve PLZF qui est un candidat intéressant. En effet, le laboratoire a mis en évidence une interaction entre PLZF et la protéine Polycomb BMI-1 et a montré que la distribution génomique de PLZF concorde avec celle de certains composants des Polycomb. L’objectif de mon travail de thèse a donc été de déterminer dans quelle mesure PLZF intervient dans le recrutement ou l’activité d’EZH2Polycomb group (PcG) proteins are epigenetic factors which play a major role in maintaining epigenetic silencing via histone modifications at the chromatin level. EZH2 is a key regulator that catalyzes the trimethylation of H3K27, which is a repressive mark. During my PhD, I was interested in the acute myeloid leukemia (AML) model in which, unlike other myeloid malignancies, EZH2 or other PcG protein mutations are very rare (˂1%). Studies have shown that in this type of leukemia, many of EZH2 target genes are deregulated although its repressive activity is still present highlighting possible EZH2 recruitment defects. Among the transcription factors that regulate the association of PcG proteins to chromatin, the transcription factor PLZF is an interesting candidate. Indeed, the laboratory has demonstrated an interaction between PLZF and the Polycomb protein BMI -1 and showed that the genomic distribution of PLZF is consistent with that of some Polycomb components. The aim of my thesis was therefore to determine in which extent PLZF is involved in the recruitment or activity of EZH2
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Green, Patrick Lee. "Cell transformation and tumor induction by Abelson murine leukemia virus". 1988. http://catalog.hathitrust.org/api/volumes/oclc/18536006.html.
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Thesis (Ph. D.)--University of Wisconsin--Madison, 1988.Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 153-167).
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Tse, Brenda. "IDENTIFICATION AND CHARACTERIZATION OF PROMYELOCYTIC LEUKEMIA (PML)-ISOFORM 1 SPECIFIC PROTEIN-PROTEIN INTERACTIONS". 2011. http://hdl.handle.net/10222/15493.
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Loss of the promyelocytic leukemia (PML) protein is associated with genomic instability/cancer. There are several isoforms of the PML protein that localize in PML nuclear bodies (PML NBs). How each individual isoform contributes to the functions of PML NBs is unknown. The objective of this study was to identify and characterize PML isoform-I (PML-I) specific protein-protein interactions. Using yeast two-hybrid screens, several interacting partners of PML-I were identified that play roles in translational regulation, including eukaryotic initiation factor 3 subunit K (eIF3K). Our studies demonstrated that eIF3K interacts with PML-I in vitro and in vivo. Through its interaction with eIF3K, overexpression of PML-I resulted in the concomitant increase in eIF3K protein levels in mammalian cells. This suggests that PML-I may be involved in regulating eIF3K protein translation or stability, which in turn could affect translation of specific mRNAs or global translation in cancer cells with reduced expression of PML-I.
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Zhang, Yu Wei. "H3K27M/I mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations". Thèse, 2017. http://hdl.handle.net/1866/20402.
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Woodcroft, MARK. "TOWARDS A B-LYMPHOID MODEL OF E2A-PBX1-MEDIATED LEUKEMOGENESIS: EVALUATING THE IMPACT OF HEMATOPOIETIC CELL OF ORIGIN ON THE TRANSFORMATION PROPERTIES OF A LEUKEMOGENIC TRANSCRIPTION FACTOR". Thesis, 2013. http://hdl.handle.net/1974/8243.
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The t(1;19) chromosomal translocation is present in 5% of acute lymphoblastic leukemia (ALL) cases and leads to expression of the oncogenic transcription factor, E2A-PBX1. Although t(1;19) is exclusively associated with pre-B ALL in clinical cases, murine models produce myeloid or T-lymphoid leukemias, which are not representative of the clinical disease. In this work, we have advanced progress towards the development an E2A-PBX1-driven experimental leukemia model. We initially determined that lineage-negative (lin-) hematopoietic progenitors expressing E2A-PBX1 expression fail to repopulate the B-lymphoid lineage when transplanted into irradiated recipient mice. Furthermore, E2A-PBX1 expressing, lin- fetal liver progenitors (FLPs) fail to differentiate into B-lymphocytes ex vivo. The majority of E2A-PBX1-expressing FLPs manifested an immature phenotype and displayed stem cell factor (SCF)-dependency and enhanced self-renewal. Additionally, these cells retained myeloid potential upon transplantation or stimulation with granulocyte macrophage colony-stimulating factor (GM-CSF). DNA binding was required for the differentiation block, suggesting that E2A-PBX1 target genes are incompatible with B-lineage specification. E2A-PBX1 FLPs had a stem cell like gene expression profile, including up-regulation of the leukemic transcription factors, Hoxa9 and Meis1. These findings explain why E2A-PBX1-driven bone marrow transplant models fail to generate B-lymphoid disease and suggest that future efforts in developing a model of E2A-PBX1-driven pre-B ALL leukemia should focus on expressing E2A-PBX1 subsequent to B-lymphoid commitment.
In an attempt to override the B-lymphoid differentiation block, we next expressed E2A-PBX1 in primary pre-B cells. E2A-PBX1 induced an apoptotic response in pre-B cells, which was consistent with previous observations. Since pre-B ALL induction requires secondary genetic events, we attempted to abrogate these E2A-PBX1-mediated effects by modulating expression of the Cdkn2a locus. Loss of Cdkn2a through deletion or Bmi1 overexpression failed to ameliorate the apoptotic response, suggesting that E2A-PBX1 mediated apoptosis occurs independently of Cdkn2a in murine pre-B cells. However, in the absence of Cdkn2a, co-expression of constitutively active MerTK or Ras attenuated the E2A-PBX1 mediated apoptosis.
Cumulatively, these results support the notion that t(1;19) occurs subsequent to B-lymphoid commitment and requires multiple secondary genetic lesions. Data presented in this thesis represents crucial initiating steps towards the development of a pre-B ALL model mediated by E2A-PBX1.Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-09-03 00:09:29.299
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Jambulosi, Mavuto. "Towards a theology of inculturation and transformation: theological reflections on the practice of initiation rites in Masasi district in Tanzania". Thesis, 2009. http://hdl.handle.net/11394/3223.
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Magister Philosophiae - MPhilThe aim of my research project is to give a theological reflection on the practice of initiation rites within Masasi district, in south-east Tanzania. While initiation remains a very significant tradition among the Yao, Makonde and Makua tribes in Masasi, the ancestral cult and the content of sex related education in these rites have presented challenges to the Christian communities. Some Christians do not feel comfortable with the inclusion of the ancestor cult since this does not immediately seem to agree with Christian doctrine. There is also a general acknowledgment that the rites could be partly responsible for the premature involvement in sexual activity by young people. In the past theological attempts were made to Christianise Masasi initiation rites with the hope of addressing these two issues highlighted above. This approach had its difficulties and limitations since not all communities in Masasi villages are Christian and since religious diversity has to be respected. Furthermore, in areas where Christianisation has been put into effect, not much change has been recorded with regards to the two main problems noted above. Christianisation simply touched on the form but did not influence the content of rites. Other theologies, especially in missionary circles, viewed initiation as an antithesis of Christianity, a view which undoubtedly discouraged constructive Christian dialogue with the practice. African theologians on the other hand seem not to have produced much systematised treatments on the subject of rites which otherwise would have been useful materials to various African Christian communities. As a result of these and other inadequacies we have a problem as far as what should be done to have the Christian faith inform the processes within the rites of passage. What kind of theology will respect the culture and yet uphold teachings of the biblical tradition in addressing cultural initiation? In this project I am proposing a theology of ‘inculturation and transformation’ to address the impasse described above. Inculturation “describes the process of integration of the faith and life of the church in a given culture” (Pobee 1992:35). The aim of inculturation is to express the Christian faith in a culturally relevant manner so as to transform the culture. Initiation rites will be made to engage with the Christian theology in such a way that the precepts of biblical theology will be applied to rites with a view to moulding those aspects of rites that are not consistent with the teachings of the Bible. The good elements already found in these rites will be maintained. The goal of inculturation is not to destroy the rites but to present the rites “in a far more perfect way on an essentially different and infinitely higher level” (Nyamiti 1971:6). Through inculturation the underlying cultural worldview behind rites is taken into account. Inculturationtransformation theology aims at addressing the inner levels of culture. For this to happen the Gospel has to go in-culture and mould it from within.September 2009
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Groenewald, Jonanda. "Baptism, Eucharist, and the earliest Jesus-groups – from the perspective of alternate states of consciousness". Thesis, 2006. http://hdl.handle.net/2263/28273.
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The purpose of this study is to examine the way in which the earliest followers of Jesus experienced the rites of baptism and the Eucharist, which in turn could aid us to comprehend what kind of value baptism and the Eucharist might add to our lives today. My point of entry reflects that of current research which indicates that baptism and the Eucharist can be perceived as symbolic rites. Rites consist of rituals and ceremonies, and in this case baptism can be described as an initiation and status transformation ritual, while the Eucharist can be seen as a ceremony of integration and participation. As with other symbols, the earliest baptism and Eucharist carried meaning because they were performed for a reason and they added value to people’s lives. Extensive research has already been carried out on the origins of baptism and the Eucharist. However, it has not been investigated whether this ritual of initiation and ceremony of participation could be understood anew if one takes the contemporary knowledge of alternate states of consciousness into consideration. As a result of cross-cultural anthropological investigations we know that only ten percent of people all over the world today do not experience common alternate states of consciousness, while the rest of humanity do. The premodern mythical world of the biblical period displays continuity with this finding – people who lived in the first-century Mediterranean world experienced alternate states of consciousness as an ordinary part of life. Only in the Eurocentric world have we – the ten percent exception to the rule – attempted to interpret baptism and the Eucharist as cognitive dogmatic constructs. The hypothesis of this study aims to demonstrate that the initiation and participation ritually expressed by the two “sacraments” can be “better” explained against the background of alternate states of consciousness. However, a model is necessary to verify or falsify the legitimacy of this hypothesis. Research into alternate states of consciousness creates a theoretical problem because, even though these states can be experienced simultaneously by more than one person in a group, experiences of alternate states of consciousness represent individual mental and psychological states. Each experience is unique and in the first instance a personal experience. In other words, without empirical evidence of what an individual has really experienced during an alternate state of consciousness, some research findings may be jeopardized, because of the impossibility of ascertaining the religious meaning and value attributed to a specific alternate state of consciousness experience. Yet, we do have access to texts as well as archeological and paleontological findings which show that there is a correlation between alternate states of consciousness and certain rites. The study illustrates that these alternate states of consciousness were verbalized in “anti-language”, which is the model I employ. “Anti-language” constitutes the language that is used by an anti-society, which in turn can be described as a conscious alternative to another society. The earliest Jesus-followers formed such an anti-society, into which they were initiated by means of baptism and in which they participated by means of the Eucharist. Consequently, the purpose of the study is to indicate that the ritual initiation and ceremonial participation of the earliest Jesus-followers were the result of alternate states of consciousness as expressed in anti-language. The study aims at redirecting extant research concerning the origins of the “Christian” baptism and the Eucharist by means of a multidisciplinary methodological approach. One of the import and relevant issues addressed in this study can be found in the enhancement of social inclusivity as an ideal in the present day.Thesis (DD (New Testament Studies))--University of Pretoria, 2007.
New Testament Studies
unrestricted
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Martin, Holly René. "Mechanism of Transformation and Therapeutic Targets for Hematological Neoplasms Harboring Oncogenic KIT Mutation". Thesis, 2014. http://hdl.handle.net/1805/5503.
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Indiana University-Purdue University Indianapolis (IUPUI)Gain-of-function mutations in the KIT receptor tyrosine kinase have been associated with highly malignant human neoplasms. In particular, an acquired somatic mutation at codon 816 in the second catalytic domain of KIT involving an aspartic acid to valine substitution is found in patients with systemic mastocytosis (SM) and acute myeloid leukemia (AML). The presence of this mutation in SM and AML is associated with poor prognosis and overall survival. This mutation changes the conformation of the KIT receptor resulting in altered substrate recognition and constitutive tyrosine autophosphorylation leading to constitutive ligand independent growth. As there are currently no efficacious therapeutic agents against this mutation, this study sought to define novel therapeutic targets that contribute to aberrant signaling downstream from KITD816V that promote transformation of primary hematopoietic stem/progenitor cells in diseases such as AML and SM. This study shows that oncogenic KITD814V (murine homolog) induced myeloproliferative neoplasms (MPN) occurs in the absence of ligand stimulation, and that intracellular tyrosines are important for KITD814V-induced MPN. Among the seven intracellular tyrosines examined, tyrosine 719 alone has a unique role in regulating KITD814V-induced proliferation and survival. Residue tyrosine 719 is vital for activation of the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), p85α, downstream from KITD814V. Downstream effectors of the PI3K signaling pathway, in of leukemic cells bearing KITD814V with an allosteric inhibitor of Pak or its genetic inactivation results in growth repression due to enhanced apoptosis. To assess the role of Rac GEFs in KITD814V induced transformation, EHop-016, an inhibitor of Rac, was used to specifically target Vav1, and found to be a potent inhibitor of human and murine leukemic cell growth. In vivo, the inhibition of Vav or Rac or Pak delayed the onset of MPN and rescued the associated pathology in mice. These studies provide insight on mechanisms and potential novel therapeutic targets for hematological malignancies harboring an oncogenic KIT mutation.
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Masumbe, Benneth Mhlakaza Chabalala. "The Swiss Missionaries' educational endeavour as a means for social transformation in South Africa (1873-1975)". 2000. http://hdl.handle.net/10500/18157.
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This research traces the developments in Europe that led to a rush for foreign missions i
different parts of the world, with specific reference to South Africa. It describes the operations
of the Swiss missionaries in South Africa from 1873 to 1975. This study also evaluates the motives
for the evangelization of the African masses, and contradictions th existed in the relations that
missionaries had with proselytes during the period under review. The sterling contributions of
black evangelists in this period are demonstrated. It cannot be denied that the Swiss missionaries
did a lot of good to the indigenous populac of South Africa-the importance of their services at
Lemana Training Institution (1906) and Elim Hospital (1899) are indelibly inscribed in our
historiography. They should also applauded for their response to the plight of the Shangaans, who
had for reasons unkno
to the researcher been by-passed by other missions during the "scramble for mission fields". But
the missionaries also had their shortcomings, for instance their failure to ind the state to remove
capital punishment from the statute books. They may nonetheless stil continue to be used by the
present government of South Africa to assist in carrying the social transformation process forward.Educational Studies
M. Ed. (History of Education)
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Melichová, Magda. "Cesty a zastavení: role hostince ve fantasy literatuře". Master's thesis, 2018. http://www.nusl.cz/ntk/nusl-388958.
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(in English) The thesis aimed to explore the topos of inn in relation to the topos of journey in fantasy literature. The first step was to define the term fantasy literature with regard to the set of texts selected for the analysis; namely their connection to mythology and fairy tales, genres working with hero's initiation journey. Integral part of the thesis was to consider theoretical works focused on the image of pubs in literature, as well as a short description of the form and function of this topos in other genres. The subject of the analysis were inns from six fictional worlds representing a cross-section of the genre from the half of the 20th century until present time, while the selected examples fall mostly into the sub-genre of epic fantasy. The analysis showed that the inns have four primary functions: hero's intimate space, place of meeting and cognition, place of transformation and place of stories. Each of these functions is connected to a specific part of the initiation journey and represents its beginning, or one of its tests. All these functions are also connected to certain issues related to hero's psychological journey, namely the issue of trust, identity and will. The inns which serve as hero's intimate space have a special position; they reflect his or her state of mind and...
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Slabbert, Mathilda. "Inventions and transformations : an exploration of mythification and remythification in four contemporary novels". Thesis, 2006. http://hdl.handle.net/10500/2267.
Texto completoResumen
The reading of four contemporary novels, namely: Credo by Melvyn Bragg, The Catastrophist by Ronan Bennett, Everything You Need by A.L. Kennedy and American Gods by Neil Gaiman explores the prominent position of mythification and remythification in contemporary literature. The discussion of Bragg's novel examines the significance of Celtic mythology and folklore and to what extent it influenced Christian mythology on the British Isles and vice versa. The presentation of the transition from a cyclical, pagan to a linear, Christian belief system is analysed. My analysis of Bennett's novel supports the observation that political myth as myth transformed contains elements and qualities embodied by sacred myths and investigates the relevance of Johan Degenaar's observation that "[p]ostmodernism emphasises the fact that myth is an ambiguous phenomenon" and practices an attitude of "eternal vigilance" (1995: 47), as is evident in the main protagonist's dispassionate stance. My reading of Kennedy's novel explores the bond that myth creates between the artist and the audience and argues that the writer as myth creator fulfils a restorative function through the mythical and symbolic qualities embedded in literature. Gaiman's novel American Gods focuses on the function of meta/multi-mythology in contemporary literature (especially the fantasy genre) and on what these qualities reveal about a society and its concerns and values. The thesis contemplates how in each case the original myths were substituted, modulated or transfigured to be presented as metamyth or myth transformed.
The analysis shows that myth can be used in various ways in literature: as the data or information that is recreated and transformed in the creative process to establish a common matrix of stories, symbols, images and motifs which represents a bond between the author and the reader in terms of the meaning-making process; to facilitate a spiritual enrichment in a demythologized world and for its restorative abilities. The study is confirmed by detailed mythical reference.English Studies
(D. Litt. et Phil. (English))