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Pires, Michaël Viegas. "Culture de métier et intégration post fusion-acquisition." Annales des Mines - Gérer et comprendre 94, no. 4 (2008): 55. http://dx.doi.org/10.3917/geco.094.0055.
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Steiler, Dominique, and Charles-Clemens Rüling. "Stress et stratégies d'ajustement. Analyse en situation de fusion-acquisition." Management & Avenir 34, no. 4 (2010): 40. http://dx.doi.org/10.3917/mav.034.0040.
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Boisvert, Denis, and Benoit Seguin. "Implantation en mode coopératif d’un système de gestion de bibliothèques dans huit établissements du réseau de l’Université du Québec (UQTR, UQAC, UQAR, UQO, UQAT, ETS, INRS, ENAP)." Documentation et bibliothèques 56, no. 2 (2015): 49–62. http://dx.doi.org/10.7202/1029132ar.
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Historique de l’exploitation de systèmes intégrés de gestion de bibliothèques (SIGB) dans le réseau de l’Université du Québec. Choix et acquisition d’un SIGB commercial. Modèle de gestion à caractère participatif. Mise en oeuvre du projet d’implantation du nouveau SIGB en trois étapes. Mise sur pied d’un catalogue unifié : caractéristiques et défis surmontés dans le cadre de la fusion de huit banques de données. Équipe de soutien et environnement technologique à l’UQTR (Université du Québec à Trois-Rivières). Cadre financier et respect des contingences. Outils de gestion. Rôle du plan de communication. Impacts sur le personnel : processus d’apprentissage et formation. Utilisation d’un outil de gestion de projet.
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St-Louis, Antoine, Isabelle Gauthier, Sylvie Beaudet, et al. "L’EROP : 10 ans pour le rétablissement des oiseaux de proie au Québec." Le Naturaliste canadien 139, no. 1 (2014): 90–95. http://dx.doi.org/10.7202/1027675ar.
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L’Équipe de rétablissement des oiseaux de proie du Québec (EROP) a été fondée en 2004, à la suite de la fusion des équipes de rétablissement du faucon pèlerin (Falco peregrinus), du pygargue à tête blanche (Haliaeetus leucocephalus) et de l’aigle royal (Aquila chrysaetos). À ces espèces d’intérêt pour l’EROP s’est ajouté récemment le hibou des marais (Asio flammeus). À l’aide des plans de rétablissement de chacune des espèces, l’EROP veille à la mise en oeuvre de mesures de conservation (p. ex. acquisition de connaissances, sensibilisation, protection) visant à redresser la situation des populations d’oiseaux de proie en situation précaire au Québec. Cet article présente le mandat, le mode de fonctionnement et les principales réalisations de l’EROP au cours de la dernière décennie.
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Potter, Nicola E., Luca Ermini, Elli Papaemmanuil, et al. "Composite Single Cell Genetics and Clonal Phylogeny in Acute Lymphoblastic Leukaemia." Blood 120, no. 21 (2012): 122. http://dx.doi.org/10.1182/blood.v120.21.122.122.
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Abstract Abstract 122 Cancer clone development is widely regarded as an evolutionary or Darwinian process of genetic diversification and natural (or therapeutic) selection within tissue ecosystems. Emerging studies are providing strong evidence that dynamic and complex branching sub-clonal genetic architectures are a common feature of cancer (Greaves M and Maley CC Nature 2012). This complexity may underpin the intransigence of advanced cancer to therapeutic control, particularly as the critical 'driver' cells – cancer or leukaemic stem cells, also appear to be genetically diverse within individual patients (Anderson K et al Nature 2011, Notta F et al Nature 2011). Sub-clonal architecture can only be fully determined through the study of large numbers of single cells uniformly sampled from the individual cancer of interest and assessed for composite genotype. Various technologies and approaches from fluorescent in situ hybridisation (FISH) to whole-genome sequencing of single cells have been applied to cancer and leukaemic cells but each approach has limitations. We have developed a novel multiplex microfluidic Q-PCR approach that allows unbiased single cell sampling, high throughput analysis of hundreds of individual cells and simultaneous detection of multiple genetic alterations in a single cell, including fusion genes, DNA copy number alterations (CNAs) and sequence-based mutations. As a proof of principle study we have applied this technique to REH, an acute lymphoblastic leukaemia (ALL) cell line that harbors the ETV6-RUNX1 fusion and a SNP in the EPO receptor gene, which we used as a surrogate mutation. We further determined a detailed sub-clonal genetic architecture for two ETV6-RUNX1 positive ALL patient samples with multiple point mutations and copy number alterations (determined by whole-genome sequencing) by interrogating approximately 400 flow cytometry sorted single cells with validation by FISH and standard sequencing. Briefly, single cells were lysed prior to multiplex specific (DNA) target amplification (STA) and Q-PCR using the 96.96 dynamic microfluidic array and the BioMarkï HD (Fluidigm, UK). Phylogenetic trees were constructed using maximum parsimony with PAUP analysis software. Interrogation of REH revealed that all single cells registered the ETV6-RUNX1 fusion and EPO receptor SNP, but 42% of cells gained either 1 or 2 additional copies of chromosome 21. Patient sample data revealed branching sub-clonal architectures in Case A in which all leukaemic cells harbored the fusion with additional point mutations but only sub-clones showed CNAs. In contrast, the sub-clonal architecture of Case B showed that whilst the ETV6-RUNX1 fusion was the earliest (or universal) genomic event, CNAs were relatively early events preceding the acquisition of point mutations (Figure 1). In both cases, the numerically predominant sub-clone harbored both point mutations and CNAs in addition to the presumptive initiating lesion, ETV6-RUNX1. These detailed and complex sub-clonal architectures would be masked by other genetic techniques. Single cell genetics coupled with deep genome sequencing is now technically feasible and provides an accurate portrait of the dynamic clonal complexity in leukaemia (and other cancers). Variegated genetics and clonal complexity in individual leukaemias has important implications for our understanding of molecular pathogenesis and for therapeutic targeting. Figure 1. This sub-clonal genetic architecture depicts the branching structure found for Case B, illustrating that in this case the ETV6-RUNX1 fusion was the earliest genomic event, followed by CNAs and the acquisition of point mutations. Those populations highlighted grey are within the experimental error rate but potentially true populations. Figure 1. This sub-clonal genetic architecture depicts the branching structure found for Case B, illustrating that in this case the ETV6-RUNX1 fusion was the earliest genomic event, followed by CNAs and the acquisition of point mutations. Those populations highlighted grey are within the experimental error rate but potentially true populations. Disclosures: No relevant conflicts of interest to declare.
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Souchon, Jean-Philippe, Christian Thom, Christophe Meynard, and Olivier Martin. "A large format camera system for national mapping purposes." Revue Française de Photogrammétrie et de Télédétection, no. 200 (April 19, 2014): 48–53. http://dx.doi.org/10.52638/rfpt.2012.61.
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Le projet CAMv2 de l'IGN a débuté en 2006 et est composé de deux parties principales. Tout d'abord, une caméra quatre canaux de format moyen a été développée. Les éléments de base de ce nouveau système sont une tête de caméra construite autour du Kodak KAF-39 000, un capteur à barrettes de 39 megapixels (7216 x 5412 pixels). Trois systèmes opérèrent dans cette configuration à l'été 2009 pour la production nationale d'orthophotographies de l'IGN avec des têtes de caméra quadricolores (RVB et proche infra-rouge). Grâce à la polyvalence et à l'aspect modulaire de ce nouveau système de caméra, la seconde étape de notre projet a pu être atteinte: le regroupement de huit têtes de caméra sur le même élément gyro-stabilisé, permettant ainsi d'obtenir des images fusionnées de 155 megapixels, avec un rapport de fusion de 2à— 2 et une fauchée finale d'environ 14400 pixels. Cette configuration à large champ a été établie avec deux combinaisons de longueurs de focale. Une version 45-90 mm permet une acquisition dédiée aux modèles 3D de villes et une version 60-120 mm sert à la production d'orthophotographies. Une bonne qualité colorimétrique est obtenue avec ce système grâce à la création spécifique de filtres de couleur. Enfin, le système peut être relié à un FMS/INS afin d'obtenir un géoréférencement direct des images et une interface facile d'accès et de prise en main pour des opérateurs grâce à un logiciel de planification de vol dernier cri.
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Guiotte, F., M. B. Rao, S. Lefèvre, P. Tang, and T. Corpetti. "RELATION NETWORK FOR FULL-WAVEFORMS LIDAR CLASSIFICATION." ISPRS - International Archives of the Photogrammetry, Remote Sensing and Spatial Information Sciences XLIII-B3-2020 (August 21, 2020): 515–20. http://dx.doi.org/10.5194/isprs-archives-xliii-b3-2020-515-2020.
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Abstract. LiDAR data are widely used in various domains related to geosciences (flow, erosion, rock deformations, etc.), computer graphics (3D reconstruction) or earth observation (detection of trees, roads, buildings, etc.). Because of the unstructured nature of remaining 3D points and because of the cost of acquisition, the LiDAR data processing is still challenging (few learning data, difficult spatial neighboring relationships, etc.). In practice, one can directly analyze the 3D points using feature extraction and then classify the points via machine learning techniques (Brodu, Lague, 2012, Niemeyer et al., 2014, Mallet et al., 2011). In addition, recent neural network developments have allowed precise point cloud segmentation, especially using the seminal pointnet network and its extensions (Qi et al., 2017a, Riegler et al., 2017). Other authors rather prefer to rasterize / voxelize the point cloud and use more conventional computers vision strategies to analyze structures (Lodha et al., 2006). In a recent work, we demonstrated that Digital Elevation Models (DEM) is reductive of the vertical component complexity describing objects in urban environments (Guiotte et al., 2020). These results highlighted the necessity to preserve the 3D structure of the point cloud as long as possible in the processing. In this paper, we therefore rely on ortho-waveforms to compute a land cover map. Ortho-waveforms are directly computed from the waveforms in a regular 3D grid. This method provides volumes somehow “similar” to hyperspectral data where each pixel is here associated with one ortho-waveform. Then, we exploit efficient neural networks adapted to the classification of hyperspectral data when few samples are available. Our results, obtained on the 2018 Data Fusion Contest dataset (DFC), demonstrate the efficiency of the approach.
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Normandin, François. "Fusions et acquisitions." Gestion 40, no. 4 (2015): 44. http://dx.doi.org/10.3917/riges.404.0044.
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Derbaix, Christian, Ingrid Poncin, Maud Derbaix, Alice Naglieri, and Arlène Derbaix. "Fusions et acquisitions." Revue Française de Gestion 43, no. 268 (2017): 97–132. http://dx.doi.org/10.3166/rfg.2017.00177.
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Becker, Heiko, Keisuke Kataoka, Gabriele Greve, et al. "Identification of a Novel Chromosomal Translocation t(11;16)(q23;q22) Fusing MLL to Enhancer of mRNA Decapping (EDC)-4 in Smoldering Acute Myeloid Leukemia." Blood 128, no. 22 (2016): 1696. http://dx.doi.org/10.1182/blood.v128.22.1696.1696.
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Abstract Background: Translocations involving the MLL gene located on chromosome 11q23 are usually found in de novo acute myeloid leukemia (AML) and generally confer a dismal prognosis unless the AF9 gene is involved (Döhner et al., Blood 2010;115:453-74). MLL can be fused to multiple different genes, resulting in the large and growing "MLL recombinome" (Meyer et al., Leukemia 2013;27:2165-76). Thus far, only two genes encoding proteins that are part of the mRNA decapping protein complex (i.e., DCP1A, DCPS) have been described as rarely being fused to MLL. Here, we describe an AML with an indolent disease course arising from myelodysplastic syndrome (MDS) that disclosed a unique MLL fusion with another component of the mRNA decapping complex, i.e., EDC4. Patient and Methods: Briefly, a 55 year-old female patient presented with an MDS [timepoint (t) -1] that within 10 months progressed to an AML with 2% blood and 40% bone marrow myeloblasts (t0). The patient refused treatment beyond supportive care. Six months later, a marked blast expansion of 80% was detectable in the blood (t1). The patient received 5 cycles of decitabine (t2, cycle 5), followed by 3 months of hydroxyurea (t3). Samples were depleted from CD3+ cells via MACS; CD3+ cells served as germline control. RNA sequencing libraries were prepared using the NEBNext Ultra RNA Library Prep Kit for Illumina (New England Biolabs), and the SureSelect Human All Exon v5 kit (Agilent Technologies) was used for exome capturing from gDNA. Next generation sequencing was performed on an Illumina Hiseq 2500. The analyses were performed as previously described (Kataoka et al. Nature Genetics 2015;47:1304-15, Becker et al. Blood 2014;123:1883-6). NOD scid gamma mice were used as hosts for patient derived tumor xenografts (PDX). Results: Standard metaphase cytogenetics at the diagnosis of AML (t0) revealed a previously undescribed translocation involving the MLL gene, i.e., t(11;16)(q23;q22), as the sole cytogenetic abnormality. The unknown fusion partner on chromosome 16 was identified by RNA-sequencing as the EDC4 gene (a.k.a. Ge-1), which encodes a key scaffold protein of the mRNA decapping complex; the fusion was confirmed by PCR on cDNA. The translocation led to the in-frame fusion of MLL exon 13 to EDC4 exon 6 which was linked by 19 nucleotides from EDC4 intron 5. The predicted amino acid sequence of the linker was ALNTLLR. Further analyses including exome sequencing on the samples collected over the disease course demonstrated STAG2 as a potential founder mutation that was already present during the MDS (t-1) and persisted throughout the disease course at variant allele frequencies (VAFs) of approximately 45-50%. At the time of transformation to AML (t0), the MLL-EDC4 and two RAS mutations (KRAS p.G13D, NRAS p.G12C) were detectable. Towards the terminal phase (t3), the RAS mutations disappeared and a clone that acquired a mutation in the FLT3 tyrosine kinase domain (TKD; p.D835V; VAF 43%) expanded. Primary blasts from the patient engrafted in NOD scid gamma mice and established a stable PDX serial transplantation mouse model used for drug testing. Conclusions: This report provides the first demonstration of an MLL-EDC4 in-frame fusion, with potential cooperativity with a founder mutation in the STAG2 splicing factor gene during the transformation of MDS to AML and the additional acquisition of a FLT3-TKD mutation during disease progression. RNA sequencing proved to be a very feasible approach to identify novel fusion partners of known oncogenes such as MLL. Disclosures Becker: BMS: Honoraria; Novartis: Honoraria. Kataoka:Yakult: Honoraria; Boehringer Ingelheim: Honoraria; Kyowa Hakko Kirin: Honoraria. Schüler:Oncotest GmbH: Employment. Ogawa:Kan research institute: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding. Lübbert:Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid.
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Welch, John S., Li Ding, Ken Chen, et al. "Resolution of a Clinical Dilemma with Whole Genome Sequencing, and Discovery of a New Mechanism for Generating PML-Rara: Insertional Fusion." Blood 116, no. 21 (2010): 2755. http://dx.doi.org/10.1182/blood.v116.21.2755.2755.
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Abstract Abstract 2755 We describe a difficult diagnostic case of t(15;17)-negative acute promyelocytic leukemia (APL). A 39 year-old woman presented with pancytopenia and low grade DIC. Bone marrow biopsy revealed AML with promyelocytic features. She was treated with Cytarabine, Daunorubicin and ATRA. However, ATRA was discontinued after FISH revealed a possible RARA-PML, but no PML-RARA fusion (one fusion, one RARA and two PML signals), and cytogenetics did not demonstrate a translocation involving chromosome 15 or 17. In fact, her cytogenetics revealed a complex pattern that predicted poor prognosis (46 XX del(9)(q12q32),del(12)(q12q21)[6]/46,idem,-6,-16,add(16)(p13.2),+2 mar[13]/46 XX[1]). Following reinduction, she entered complete remission and was empirically consolidated with arsenic. RT-PCR for PML-RARA was not performed at diagnosis, and was negative at the time of consultation in remission. Her complex cytogenetics and uncertain FISH status posed a diagnostic and therapeutic dilemma that could only be resolved by whole genome sequencing in the time frame required for a clinical decision to be made (i.e. allogeneic transplantation vs. ATRA-based consolidation). DNA was therefore generated from bone marrow (cryopreserved at the time of diagnosis) and a skin sample (obtained in remission), and subjected to massively parallel sequencing using paired-end reads (Mardis et al, NEJM 2009). We generated 187 billion bp (tumor) and 200 billion bp (skin) of sequence, corresponding to 43.7x and 46.8x haploid coverage (99.76% and 99.74% diploid coverage) for the respective samples. Within six weeks of sample receipt, validated results were available. We confirmed the del(9)(q12q32) and del(12)(q12q21) somatic events and identified a novel oncogenic form of chromosomal rearrangement, an insertional fusion: 77 Kb of chromosome 15 (chr15:72027045–72104108 containing LOXL1 exon 6 through PML exon 3) were inserted en bloc into RARA intron 2 (chr17:35742678–35742683). This event resulted in the expression of PML-RARA (bcr3 isoform) and two novel fusion transcripts (RARA-LOXL1 and LOXL1-PML), which were all successfully amplified by RT-PCR and sequenced. The RARA-LOXL1 and LOXL1-PML fusions both created stop codons shortly after the fusion events. Re-evaluation of the FISH results revealed that the insertion generated a fusion signal, while loss of 77 Kb from the PML locus did not prevent binding of the 239 Kb commercial PML probe to chromosome 15 (thus generating 1 fusion, 1 RARA and 2 PML signals). These signals represented the PML-RARA insertional fusion event, not the RARA-PML translocation that was originally reported. We further identified and validated deletions on chromosomes 12 (60 Mb), 14 (22 Kb) and 19 (30 Kb) and non-synonymous, somatic single nucleotide variants (SNVs) in the coding regions of ZNF687, DYTN, C3orf54, CH3D19, SLC35A4, GPRC6A, ZFHX4, PTK2, PITPNM1, DEGS2, PCSK2, CDC45L, although the clinical relevance of these deletions and point mutations is not yet known. After validating PML-RARA bcr3 expression, a decision was made to consolidate the patient with an ATRA-containing regimen. Using whole genome sequencing with paired end reads, we have identified a novel oncogenic form of chromosomal rearrangement, an insertional fusion. Similar insertional events may occur in other loci. Small structural events (under a few megabases in size) are often undetectable by conventional cytogenetics and FISH, and are expected to be invisible to standard break-apart probes (commonly used to evaluate the RARA and MYC loci). This case highlights the clinical relevance of whole genome sequencing for informing diagnostic and therapeutic decisions that must be made within weeks after sample acquisition. Disclosures: Off Label Use: Decitabine, Arsenic and Ascorbic acid for the treatment of AML. DiPersio:Genzyme: Honoraria. Westervelt:Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau.
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Carnicer, Maria-Jose, Frederik W. van Delft, Lyndal Kearney, and Mel Greaves. "Sub-Clonal Genetic Heterogeneity in BCR-ABL1 Positive Acute Lymphoblastic Leukaemia." Blood 118, no. 21 (2011): 1348. http://dx.doi.org/10.1182/blood.v118.21.1348.1348.
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Abstract Abstract 1348 Philadelphia-positive (Ph+) acute lymphoblastic leukaemia (ALL), characterised by the BCR-ABL1 fusion gene, occurs in approximately 30% of adult and 5% of childhood ALL and is associated with a poor prognosis. It is considered a single clinical entity with identifiable and recurrent copy number alterations (CNA); notably deletions of the lymphoid transcriptional regulator IKAROS (encoded by IKZF1), PAX5, and CDKN2A/B that are presumed to cooperate with BCR–ABL 1 in lymphoid leukaemogenesis. In particular, IKZF1 deletions are present in 80% of BCR-ABL1 positive ALL cases, and have been implicated as an independent indicator of poor prognosis in childhood ALL. Our previous studies of twin pairs either concordant or discordant for BCR-ABL1+ ALL indicate that the fusion gene is a first hit that occurs prenatally. However, the order and sequence of acquisition of CNA is unknown. We recently reported a complex sub-clonal genetic architecture for leukaemic blasts and leukaemia-propagating (‘stem’) cells in childhood ETV6-RUNX1-positive ALL (Anderson et al., Nature 469: 356–361, 2011). In the present study, we aimed to determine whether similar sub-clonal genetic diversity occurs in BCR-ABL1+ ALL. We carried out five colour FISH to diagnostic blast cells from eight BCR-ABL1 positive cases with differentially-labelled probes for BCR, ABL1, IKZF1, CDKN2A and PAX5. In a subset of cases we also performed Affymetrix single nucleotide polymorphism (SNP 6.0) arrays to determine the specific boundaries of deletions. Four out of the eight cases screened had concurrent IKZF1, PAX5 and CDKN2A deletions. In one case the order of acquisition of these deletions was uninformative, with 97% of cells exhibiting a single FISH pattern (BCR-ABL1+ with monoallelic deletions of all three genes). In the second case, a linear clonal progression was observed with IKZF1 deleted first, PAX5 second and CDKN2A third. In the two remaining cases a branching sub-clonal pattern was observed. In one of these monoallelic IKZF1, CDKN2A and PAX5 deletions all arose independently in different sub-clones; i.e. IKZF1 was deleted first in one subclone, CDKN2A first in another and PAX5 first in a third sub-clone. In the final case we also studied matched diagnosis and relapse samples. Here, SNP array analysis revealed different deletions in all three genes at diagnosis and relapse. Genomic fusion breakpoint analysis revealed an identical BCR-ABL1 genomic sequence at diagnosis and relapse, confirming the same clonal origin of leukaemia. The different deletion boundaries in IKZF1, PAX5 and CDKN2A permitted us to design specific FISH probes to distinguish between ‘diagnostic’ and ‘relapse’ deletions and to track their evolution. The predominant clone at relapse was not a direct evolutionary product of any of the major clones found at diagnosis. The dominant sub-clone at diagnosis was BCR-ABL1+, with a large 9p deletion (encompassing PAX5 and CDKN2A) and a focal CDKN2A deletion, all sub-clonal to a focal IKZF1 deletion. At relapse, the dominant sub-clone had acquired a different IKZF1 deletion, which was sub-clonal to two different (focal, biallelic) deletions of CDKN2A and a different monoallelic PAX5 deletion. The large 9p deletion was not present at relapse. These results indicate the existence of a pre-leukaemic BCR-ABL1 fusion gene positive clone that has given rise to at least two sub-clones, each with different IKZF1, PAX5 and CDKN2A deletions, that have evolved independently. These data indicate that the sub-clonal architecture in this poor prognosis subtype of ALL is genetically diverse, and that key ‘driver’ CNA can arise independently and in no preferential order. Disclosures: No relevant conflicts of interest to declare.
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Bateman, Caroline M., Sharon W. Horsley, Tracy Chaplin, et al. "Sequence of Genetic Events in ETV6-RUNX1 Positive B Precursor ALL: Insights from Identical Twins with Concordant Leukaemia." Blood 112, no. 11 (2008): 2. http://dx.doi.org/10.1182/blood.v112.11.2.2.
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Abstract Monozygotic twin pairs with concordant ALL have provided unique insights into the molecular pathogenesis and natural history of childhood leukaemia. Data from twin pair studies and neonatal blood spot screening indicate that ETV6-RUNX1 usually arises as an early or initiating pre-natal event. Its consequence appears to be the generation of a clinically silent or covert but persistent pre-leukaemic clone. Conversion to overt, clinical ALL then requires the acquisition of one or more additional genetic lesions that functionally complement ETV6-RUNX1, often including deletions of the non-rearranged ETV6 allele. Recent genome wide single nucleotide polymorphism (SNP) array based studies have revealed considerably more genetic complexity than previously suspected, with ETV6-RUNX1 cases having an average of 6 (range 1–21) genomic losses or gains (Mullighan et al., Nature2007, 446: 758). It is however unclear from these descriptive screens or audits when these multiple changes arise in relation to the presumed initiating gene fusion and what functional contribution they make. We have used a series of identical twin pairs with ETV6-RUNX1 positive B precursor ALL to test the proposition that, as we reported previously for ETV6 deletion (Maia et al., Blood2001, 98: 478), all presumed functional or ‘driver’ genomic changes are post-natal in origin and therefore secondary to ETV6-RUNX1 fusion. If this were to be correct then we anticipated that genomic deletions and gains should be different or distinct within each twin pair. We used 250K Sty and 250K Nsp Affymetrix SNP mapping arrays on 5 pairs of identical twins concordant for ETV6-RUNX1 gene fusion positive ALL. We identified copy number variation using the “in-house” Genome Orientated Laboratory File v2.2.9 software package. The SNP array was performed using leukaemic DNA compared to matched remission DNA for 4 out of 5 cases. The fifth case was compared to a pool of remission DNA. The total number of genetic aberrations found was 51 (excluding T cell receptor and immunoglobulin rearrangements): 36 of these lesions were deletions (mean = 7.2) and 15 amplifications. The commonest aberration, found in 8 out of the 10 children, was a deletion on 12p13.2 involving the ETV6 gene. This was discordant in all cases, consistent with our previous reports using microsatellite markers. Other aberrations included deletions of PAX5, CDKN1B, CDKN2A and CD200/BTLA. The status of these, and other, presumed ‘drivers’ of leukaemogenesis were always different when diagnostic DNA of twins, within a pair, were compared i.e. either the genetic change was absent in one but present in the other, or the alteration was present in both but had distinct genomic boundaries. However in 2 of 5 twin pairs concordant, identical lesions were detected. These were idiosyncratic or very rare genomic changes in ALL and were either in gene sparse regions or involved loci with no known or likely contribution to B cell regulation or leukaemogenesis (e.g. CRYGD). We consider the most likely explanation for these shared genetic events in twin cases is that they arise simultaneously with (or immediately prior to) ETV6-RUNX1 fusion, and in the same incipient pre-ALL stem cell, as collateral damage or ‘passenger’ mutations. These data indicate that the common and presumed ‘driver’ genetic changes that accompany ETV6-RUNX1 in ALL are all secondary to gene fusion and most probably post-natal in origin. It remains to be established whether they contribute at all to the sustained pre-leukaemic state and whether they arise independently of each other and sequentially or as a timed suite or bolus perhaps proximate to diagnosis.
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Alvarez, Sara, Javier Suela, Ana Valencia, et al. "Epigenomic Analysis of Acute Myeloid Leukemia Identifies Specific Patterns and Markes with Clinical and Biological Relevance." Blood 114, no. 22 (2009): 2394. http://dx.doi.org/10.1182/blood.v114.22.2394.2394.
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Abstract Abstract 2394 Poster Board II-371 Introduction: Genomic aberrations resulting in activation of oncogenes, inactivation of tumor suppressor genes or in the formation of novel chimeric genes are currently considered the main cause of the malignant phenotype of the AML cells. There is now increasing evidence that in addition to genetic aberrations, therapeutically reversible epigenetic events also play a critical role in the pathogenesis of human leukemias. Aims: We used a high-throughout methylation profiling to explore systematically the epigenomic variation underlying the biologic and clinical heterogeneity in AML. Patients and Methods: Using the Illumina GoldenGate Methylation Cancer Panel that spans 1,505 CpG loci, a detailed methylation profile of 116 AML patients distributed along all the cytogenetic prognostic subgroups was established. In addition, controls (BM and CB) and human progenitor cells expressing AML1/ETO, CBFβ/MYH11 or MLL/AF9 fusion proteins were analysed. Unsupervised and supervised hierarchical cluster were performed, and a selection of the most significantly differentially methylated loci (Δβ of at least 0.34 and FDR <0.05) calculated as ψβ=(sample mean bvalue)–(control mean bvalue) was done. Candidate genes were validated by MSP in an independent cohort of 244 AML cases. Bisulphite sequencing and quantitative RT-PCR were carried in selected cases. Results: AML samples were correctly separated from BM controls and segregated in two main categories. While one of them showed a rather plane profile (Group I) similar to the one observed in the control bone marrow samples (only 7 probes showed a mean Δβ>0.34), the other (Group II) presented dramatic changes with an aberrant methylation signature (24 probes showed a mean Δβ>0.34). These two methylation categories showed significant differences in their distribution accross the prognosis cytogenetic groups. Eighty percent of the cases included on the adverse cytogenetic prognostic group clustered in one arm (Group I) and 80% of the cases included on the good prognosis cytogenetic group clustered in the other one (Group II). The normal karyotype (NK) cases were evenly distributed among the Groups I and II. No significant differences were observed for other variables as FLT3 mutational status. Kaplan-Meier analysis did not identified significant differences on the overall survival between the AML Group I and II. Focussing on the NK cases, two CpGs (from DBC1 and CDKN2B genes) were identified as statistically significant predictors of 5-year overall survival (OS). On the independent AML series, only the promoter methylation status of DBC1 retained statistical significance as predictor of the EFS and OS on NK cases. Expression studies showed a significant silencing of DBC1 on the aberrantly methylated samples. Taking advantage of our model of hematopoietic stem cells, stably transfected with the fusion proteins1-3 we observed that the epigenetic signature of the MLL leukemias is also observed on human progenitor cells fully transformed “in vitro” by this single oncogenic event. However, HSC expressing the AML1/ETO and CBFβ/MYH11 fusion proteins, which did not showed a full transformed phenotype, did not recapitulate the methylation signature observed on the AML primary cases. Conclusions: These results allowed us to conclude that: (1) The aberrant methylation of DBC1 gene among the NK AML cases is associated with a poor outcome. Therefore, the identification of patients with DNA epigenetic aberrations that have predictive value in determining survival should be essential in the forthcoming designs of clinical trials with demethylating agents. (2) A larger number of epigenetically modified genes is observed in the presence of single genetic abnormalities as t(8;21), t(15;17) or MLL rearrangements. However, a full leukemic transformation is require for the acquisition of a specific aberrant methylation profile, suggesting than the presence of fusion proteins as AML1/ETO or CBF/MYH11 is not sufficient to acquire a full aberrant methylation signature. 1. Wunderlich M, et al .et al Blood 2006;108:1690-7. 2. Wei J, et al . Cancer Cell 3. Mulloy JC et al Blood 2002;99:15-23. Disclosures: No relevant conflicts of interest to declare.
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Shima, Takahiro, Yoshikane Kikushige, Toshihiro Miyamoto, and Koichi Akashi. "The First Demonstration of Sequential Acquisition of Class I and Class II Gene Mutations in Formation of Human Acute Myeloid Leukemia Stem Cells." Blood 120, no. 21 (2012): 859. http://dx.doi.org/10.1182/blood.v120.21.859.859.
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Abstract Abstract 859 Hematopoietic stem cells (HSCs) should be the main target for accumulation of mutational events, which eventually leads to formation of leukemic stem cells. These leukemogenic mutations have been classified at least into class I (providing the proliferative and survival advantage) and class II (impairing the differentiation activity) gene abnormalities. It has been proposed that acquisition of both class I and class II mutation are essential for the development of leukemia. Although several experimental animal studies suggest this model, there is no direct evidence that class I and class II mutations collaborate to contribute to development of human leukemias. Here we demonstrate that the acquisition of 8;21 translocation, which encodes the AML1-ETO (a class II chimeric fusion gene), and of mutational c-Kit (a class I mutation) is sequentially occurred in human acute myelogenous leukemia (AML). It has been shown that in t(8;21) AML patients treated with chemotherapy, a small amount of AML1-ETO mRNA was never disappeared even in patients maintaining remission for more than 10 years. We have demonstrated that this AML1-ETO mRNA in “cured” patients is derived from t(8;21)+ HSCs that consisted only a few percent of HSCs in remission (Miyamoto et al., PNAS 2000; 97: 7521–7526). The t(8;21)+ HSCs possessed normal differentiation at least into myeloerythroid cells and B cells. These data strongly suggest that acquisition of the AML1-ETO fusion is not sufficient for development of t(8;21) AML, and that t(8;21)+ HSCs are preleukemic HSCs. We hypothesized that acquisition of additional class I mutation might transform the AML1-ETO+ preleukemic HSCs into AML stem cells. We therefore searched for class I mutations in t(8;21) AML samples, and found that in 13 out of 33 t(8;21) AML patients, AML cells have c-Kit mutations (but not other class I such as FLT3-ITD and N-Ras mutations) at diagnosis. We then tested whether the AML1-ETO+ preleukemic HSCs in remission marrow have the c-Kit mutation. Six out of these 13 t(8;21) AML patients with c-Kit mutation maintaining long-term remission were enrolled in this study. To confirm the coexistence of AML1-ETO and c-Kit mutation in single leukemic stem cells, CD34+CD38− AML cells were purified from the bone marrow of patients at diagnosis, and tested for the presence of AML1-ETO and c-Kit mutation by single cell PCR. In all of 910 single CD34+CD38− AML cells, both AML1-ETO and c-Kit mutations were detected. Then, CD34+CD38− HSCs in remission were tested for the presence of AML1-ETO and c-Kit mutation. In 1728 single CD34+CD38− HSCs of remission marrow, 0.9% (16 cells) of these cells expressed AML1-ETO. Surprisingly, none of these AML1-ETO+ preleukemic HSCs possessed c-Kit mutation, indicating that AML1-ETO+ clones in long-term remission are independent from the original t(8;21) AML clones in terms of the presence of c-Kit mutation. We then performed colony-forming assays to evaluate the differentiation potential of these AML1-ETO+ preleukemic HSCs. HSCs of remission marrow-derived colonies were picked up, and tested for the presence of AML1-ETO and c-Kit mutation. In 7187 colonies formed in the culture of remission marrow, 1.2% (89 colonies) of these colonies were positive for AML1-ETO, and all of these colonies were negative for c-Kit mutation. These data collectively suggest that the acquisition of c-Kit mutation is the second step for formation of t(8;21) AML stem cells: Normal HSCs acquire t(8;21) and express resultant AML1-ETO (Class II) but it is not sufficient for full transformation into AML stem cells. These preleukemic HSCs possess normal differentiation activity, but additional c-Kit mutation (Class I) might be critical in transforming into AML stem cells. This is the first clear-cut evidence that HSCs transform into AML stem cells by stepwise acquisition of Class I and Class II mutations. Disclosures: No relevant conflicts of interest to declare.
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De Bodt, Éric, Jean-Gabriel Cousin, and Gaël Imad-Eddine. "Fusions-acquisitions et efficience allocationnelle." Revue d'économie financière 110, no. 2 (2013): 15. http://dx.doi.org/10.3917/ecofi.110.0015.
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Shawky Elsharkawy, Ahmed, Mohamed Elhabiby, and Naser El-Sheimy. "Second Generation Curvelet Transform for Building Extraction from High Resolution Satellite Imagery." GEOMATICA 65, no. 4 (2011): 387–99. http://dx.doi.org/10.5623/cig2011-061.
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The process of automatic extraction of buildings from digital imagery has had major practical importance for many years in the area of data acquisition and updating of geographic information system (GIS) databases. This process also presents a huge scientific challenge for researchers as a result of the heterogeneous nature of the buildings, especially in the developing countries[Aytekin et al. 2009]. Several techniques were used in building extraction for satellite images in this research paper, second generation curvelet transform will be introduced as an edge detection tool helping in the detection of buildings boundaries. Second generation curvelet transform provides optimally sparse representations of objects, which display smoothness except for discontinuity along the curve with bounded curvature [Candes et al. 2006]. Some papers have investigated this technique for edge detection in high resolution satellite imagery such as IKONOS or QuickBird, and microscopic imagery [Geback and Koumoutsakos 2009; Guha and Wu 2010; Zhenghai and Jianxiong 2009; Xiao et al. 2008], which show great potential of using curvelet transform in solving edge detection problems. However, until now, there is no research tackling the building detection problem using the curvelet transform in high resolution satellite imagery. The algorithm consists of four main parts; first, data fusion between the panchromatic band (0.50 m resolution) and the multispectral ones (2.00 m resolution), to generate 8-spectral bands with a resolution of 0.50 m. Second, a Gaussian high pass filter is applied to enhance the edges. Third, using the curvelet transform, edges will be detected based on the fact that the values of curvelet coefficients are determined by how they are aligned in the real image. The more accurately a curvelet is aligned with a given curve in an image, the higher its coefficient value. Fourth, a filling process is performed for every closed boundary followed by calculation of statistics for these enclosed boundaries; such as area, major and minor axis, and compactness to extract the buildings.
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Garella, Paolo. "Fusions et acquisitions dans l'industrie européenne." Revue de l'OFCE 29, no. 1 (1989): 185–219. http://dx.doi.org/10.3406/ofce.1989.1193.
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Bertrand, Olivier, Jean-Louis Mucchielli, and Habib Zitouna. "Fusions et acquisitions transfrontalières des années 1990." Revue de l'OFCE 94, no. 3 (2005): 45. http://dx.doi.org/10.3917/reof.094.0045.
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Peltier, Stéphanie. "Fusions et acquisitions dans les industries culturelles : attraits et risques." Mouvements 17, no. 4 (2001): 26. http://dx.doi.org/10.3917/mouv.017.0026.
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Ferchichi, Rania, and Saïd Souam. "Caractéristiques, motivations et performances des fusions et acquisitions en Tunisie." Revue d'économie industrielle, no. 150 (June 30, 2015): 9–50. http://dx.doi.org/10.4000/rei.6109.
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Legault, Albert. "Les fusions-acquisitions en matière de gaz et de pétrole." Études internationales 35, no. 3 (2005): 435–68. http://dx.doi.org/10.7202/009906ar.
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Résumé Cette étude vise à retracer l’évolution des F-A (fusions-acquisitions) en Amérique du Nord, plus particulièrement en matière de gaz et de pétrole. Le phénomène se situe dans la foulée de la restructuration des industries et dans le cadre d’une déréglementation généralisée de l’énergie, visant à encourager la concurrence sur un plan national et international. Dans un premier temps, nous tenterons de voir quelle est la part du secteur de l’énergie dans le cadre général des fusions-acquisitions, et de constater dans quelle mesure ces dernières correspondent ou non aux différents cycles d’évolution des prix en matière d’énergie. Dans un second temps, nous nous pencherons sur les raisons et les motifs avancés pour justifier les F-A et tenterons de répondre aux trois questions suivantes. En se restructurant, l’industrie pétrolière* a-t-elle réussi à accroître la valeur de ses entreprises, à faire profiter ses investissements, et à augmenter ses réserves ? Enfin, nous verrons quelles sont les conséquences les plus immédiates des F-A sur l’industrie pétrolière au Canada. En effet, elle doit relever deux défis majeurs : comment rester compétitive, alors que les coûts de production augmentent, d’une part, et que le rendement sur les investissements tend à diminuer plutôt qu’à augmenter, d’autre part ?
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Ibrahimi, Mohammed, and Abdellatif Taghzouti. "Les fusions et acquisitions : un paradoxe toujours inexpliqué." Recherches en Sciences de Gestion 102, no. 3 (2014): 99. http://dx.doi.org/10.3917/resg.102.0099.
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Albouy, Michel, and Mohamed Thraya. "Fusions-acquisitions et bénéfices privés : le cas Wendel." Management & Avenir 81, no. 7 (2015): 101. http://dx.doi.org/10.3917/mav.081.0101.
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Swaminathan, Srividya, Lars Klemm, Anthony M. Ford, et al. "Cooperation Between Aid and the Rag1/Rag2 V(D)J Recombinase Drives Clonal Evolution of Childhood Acute Lymphoblastic Leukemia." Blood 120, no. 21 (2012): 519. http://dx.doi.org/10.1182/blood.v120.21.519.519.
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Abstract Abstract 519 Background and Rationale: In many cases, childhood acute lymphoblastic leukemia (ALL) can be retraced to a recurrent genetic lesion in utero which establishes a pre-leukemic clone. The TEL-AML1 fusion gene for instance, arises prenatally and defines the most frequent subtype of childhood ALL. Strikingly, ∼1 of 100 healthy newborns carry a TEL-AML1 pre-leukemic clone, but only less than 1% of these children eventually develop leukemia. Encounter of infectious antigen leads to activation of the mutator enzyme AID in mature B cells. While AID is required for somatic hypermutation and class switching during late stages of B cell development, its pre-mature activation may be deleterious. The underlying questions for this project were: (1) how are B cells safeguarded from pre-mature AID expression during their early development and (2) whether pre-mature AID expression during early B cell development is deleterious in the sense that it promotes the clonal evolution of a pre-leukemic B cell clone in the bone marrow. Results: Studying gene expression in a clinical trial for children with high risk pre-B ALL (COG P9906; n=207), we found that high expression levels of AID at the time of diagnosis is predictive of poor overall survival and a higher frequency of leukemia relapse. These findings suggest that AID may be a contributing factor to the clonal evolution of childhood pre-B ALL. Previous work by Michael Lieber's group proposed cooperation of AID and the V(D)J recombinase Rag1/Rag2 as a key mechanism leading to the acquisition of chromosomal translocations in human B cell malignancies (Tsai et al., 2008). Activity of Rag1/Rag2 V(D)J recombinase and AID is segregated to early and late stages of B cell development, respectively. However, we found that experimental withdrawal of IL7 receptor (IL7R) signaling in pre-B cells not only activates Rag1/Rag2 expression and V(D)J recombinase but also rendered pre-B cells responsive to antigen (LPS) encounter with strong upregulation of AID. We found that upon withdrawal of IL7, transcription of AID and Rag1/Rag2 is activated by the same elements through a Pten/FoxO-dependent pathway. To test whether IL7R signaling also negatively regulates AID activation in human pre-B cells, we performed a comprehensive analysis of human B cell development in bone marrow samples from two children carrying deleterious mutations of the IL7RA and IL2RG genes encoding the two chains of the human IL7R. As opposed to normal human pre-B cells, pre-B cells from IL7RA and IL2RG-mutant patients carried somatically mutated immunoglobulin genes consistent with aberrant expression of AID in these cells. Based on these observations, we propose that Fraction D pre-B cells represent a subset of increased genetic vulnerability owing to concomitant expression of both AID and Rag1/Rag2. To test whether the vulnerability of Fraction D pre-B cells is relevant in the clonal evolution of childhood ALL, we challenged pre-B cells carrying the TEL-AML1 fusion gene with 5 consecutive cycles of IL7 withdrawal (−IL7) and LPS stimulation (+LPS). To distinguish between the potential contribution of AID and Rag1/Rag2 to secondary genetic lesions, -IL7/+LPS-challenges were performed with wildtype pre-B cells, AID−/−, Rag1−/− and AID−/− Rag1−/− double knockout pre-B cells. TEL-AML1-bearing pre-B cells were labeled with firefly luciferase and then 25 million cells were injected into 7 recipient animals per group. While wildtype TEL-AML1 pre-B cells that went through 5 rounds of -IL7/+LPS-challenge caused leukemia in all recipient mice, TEL-AML1 pre-B cells lacking either AID or Rag1 failed to give rise to full-blown leukemia in transplant recipients. Conclusion: While one in 100 newborns carry the TEL-AML1 fusion molecule, the mechanisms that lead to the acquisition of critical secondary genetic lesions are not known. Here, we report a novel, IL7R/Stat5-dependent mechanism by which pre-B cells are rendered non-responsive to LPS-dependent upregulation of AID. We propose that Fraction D pre-B cells represent a subset of increased natural genetic vulnerability in the context of concomitant activativity of AID and Rag1/Rag2. Frequent exposure to infectious antigens (e.g. LPS) in this constellation may propagate clonal evolution towards full-blown leukemia. Disclosures: No relevant conflicts of interest to declare.
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Aribou, Mohamed Larbi. "Fusions-Acquisitions et Creation de Valeur : Bilan des Recherches et Perspectives d’Evolution." Finance and Finance Internationale, no. 6 (January 2017): 1–25. http://dx.doi.org/10.12816/0040539.
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Maroo, Kalpesh, Bobby Parikh, and Sharath Rao. "Fusions et acquisitions en Inde : un aperçu des aspects réglementaires et fiscaux." Revue d'économie financière 107, no. 3 (2012): 199. http://dx.doi.org/10.3917/ecofi.107.0199.
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Francœur, Claude. "Les opérations de fusions et acquisitions internationales sont-elles rentables?" Gestion 30, no. 3 (2005): 97. http://dx.doi.org/10.3917/riges.303.0097.
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Lestavel, Thomas. "Fusions-acquisitions : mariages de raison et lendemains qui (dé)chantent." Alternatives Économiques N° 334, no. 4 (2014): 74. http://dx.doi.org/10.3917/ae.334.0074.
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Derhy, Armand. "Les fusions et acquisitions en France de 1959 à 1992 : évolution et caractéristiques." Revue d’économie industrielle 73, no. 1 (1995): 19–44. http://dx.doi.org/10.3406/rei.1995.1583.
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Fornari, Luca, and Denis Toson. "Organisations en situation de blocage. Turbulences culturelles : fusions et acquisitions d’organisations." Actualités en analyse transactionnelle 159, no. 3 (2017): 28. http://dx.doi.org/10.3917/aatc.159.0028.
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Bunel, Matthieu, Richard Duhautois, and Lucie Gonzalez. "Types de fusions-acquisitions et évolution de l’emploi des entreprises restructurées." Travail et emploi, no. 117 (March 30, 2009): 53–65. http://dx.doi.org/10.4000/travailemploi.4123.
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Meier, Olivier. "Intention, mouvement et innovation stratégique dans le cas de fusions acquisitions." Gestion 2000 29, no. 1 (2012): 23. http://dx.doi.org/10.3917/g2000.291.0023.
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Mailly, Laurent, Celine Leboeuf, Christophe Ferrand, et al. "Allogeneic Suicide Gene-Modified T Cells (aSGMTC) Are Highly Cytotoxic to Non-Hematopoietic Tumor Cell Lines: Rationale for the Production of a Bank of aSGMTC for the Treatment of Solid Tumors." Blood 114, no. 22 (2009): 2459. http://dx.doi.org/10.1182/blood.v114.22.2459.2459.
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Abstract Abstract 2459 Poster Board II-436 Suicide gene therapy using alloreactive T cells is an efficient immunotherapeutic strategy for hematologic malignancies (Tiberghien et al, Blood 2001). We hypothesized that solid tumors, such as hepatocellular carcinoma (HCC) could be targeted by intratumoral infusion of allogeneic T cells produced from normal donors: the tumor cells would be recognized, not as being tumoral, but as being allogeneic. The prior introduction into such T cells of a suicide gene encoding the herpes simplex virus thymidine kinase (HSV-tk) that confers sensitivity to a pro-drug, ganciclovir, would allow controlling their potentially deleterious alloreactivity toward normal patient's tissues, as we demonstrated in bone marrow-transplanted patients with >10 years follow-up (Deschamps et al, Blood 2007). Our aim is to demonstrate the feasibility of this approach and to create a bank of “ready-to-use” allogeneic gene-modified T cells (GMC) for potential future in vivo evaluation and clinical use. Normal donors' peripheral blood mononuclear cells (PBMC) activated by CD3 monoclonal antibodies and Interleukin (IL)-2 were retrovirally transduced at d3 with a vector encoding a CD34/HSV-tk fusion protein. CD34+ sorted GMC were expanded with IL-2 until d14 and assessed for cytotoxicity against HeLa cells (human epithelial adenocarcinoma) and Huh7 cells (human hepatoma) by coincubation for 1-6 days at different effector:target (E:T) ratios, then staining of residual viable adherent targets by crystal violet. Allogeneic GMC (>90% T cells with a reversed CD4:CD8 ratio (0.58+/-0.06, n=9) and a predominant CD45RA- CD27- effector/memory phenotype) exhibited a strong and ganciclovir-sensitive cytotoxicity against Huh7 cells : >80% cell lysis of Huh7 cells were usually observed at an E:T ratio = 4:1 after 24h of co-incubation. Ex vivo-expanded, but non transduced, control cells were similarly cytotoxic, indicating that the retroviral transduction did not affect the cytotoxic activity of GMC. By contrast, PBMC were weakly cytotoxic, since no lysis of Huh7 cells was detectable after 24h co-incubation and <30% lysis were observed at d6 at an E:T ratio = 40:1. Similar results were observed with HeLa cells, that were even more sensitive to GMC-mediated lysis than Huh7. Acquisition of a cytotoxic activity was dependent upon the cell culture conditions: replacing the CD3 activation by CD3/CD28 or IL-2 by IL-7 was associated with increased proliferative potential and frequencies of cells with a so-called “naïve” (CD45RA+ CD27+) and central memory (CD45RA- CD27+) phenotype, but with a decreased cytotoxic activity. In vivo studies demonstrated that GMC induce tumor cell regression when coinfused with luciderase-expressing HeLa cells. Our results suggest that alloreactive GMC may represent a novel strategy for treatment of solid tumors which deserves further evaluation in vivo. Disclosures: No relevant conflicts of interest to declare.
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Favre-Bonté, Véronique, and Catherine Thévenard-Puthod. "La cession à un groupe: quelles conséquences pour une PMI sous-traitante du secteur automobile?" Revue internationale P.M.E. 19, no. 2 (2012): 49–78. http://dx.doi.org/10.7202/1008495ar.
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Récemment, l’industrie automobile a été particulièrement touchée par les fusions et acquisitions et a vu son paysage se modifier profondément. En France, de nombreuses PMI sous-traitantes ont ainsi changé de propriétaires et sont passées dans le giron de groupes. Face aux études s’intéressant aux acquisitions qui font état d’un très grand nombre de désillusions quant au succès de ces opérations et dans un contexte où la transmission d’entreprises représente des enjeux importants dans de nombreux pays occidentaux, nous avons voulu porter notre regard sur ces PMI acquises. En nous fondant sur 14 cas d’entreprises ayant été achetées entre 1995 et 2002, nous tentons de cerner l’impact de ces changements de propriétaires sur les PMI sous-traitantes. Nous verrons que la cession à un groupe représente un choix stratégique louable, si l’acquéreur est en mesure de transférer les ressources et compétences permettant aux entreprises achetées de réduire leur dépendance commerciale et de mieux se positionner dans la filière automobile.
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Kipping, Matthias. "Assurer le succès des fusions et acquisitions : les contributions d'une approche historique." Le journal de l'école de Paris du management 86, no. 6 (2010): 14. http://dx.doi.org/10.3917/jepam.086.0014.
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Sghaier, Adnène, and Taher Hamza. "Les gains de synergie des fusions-acquisitions bancaires européennes : sources et déterminants." Gestion 2000 35, no. 2 (2018): 145. http://dx.doi.org/10.3917/g2000.352.0145.
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Tong, Lillian, William Guido, Nina Tumosa, Peter D. Spear, and Susan Heidenreich. "Binocular interactions in the cat's dorsal lateral geniculate nucleus, II: Effects on dominant-eye spatial-frequency and contrast processing." Visual Neuroscience 8, no. 6 (1992): 557–66. http://dx.doi.org/10.1017/s0952523800005654.
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AbstractThe present study tested the hypothesis that nondominant-eye influences on lateral geniculate nucleus (LGN) neurons affect the processing of spatial and contrast information from the dominant eye. To do this, we determined the effects of stimulating the nondominant eye at its optimal spatial frequency on the responses of LGN cells to sine-wave gratings of different spatial frequency and contrast presented to the dominant eye. Detailed testing was carried out on 49 cells that had statistically significant responses to stimulation of the nondominant eye alone.Spatial-frequency response functions to nondominant-eye stimulation indicated that the responses were spatially tuned, as reported previously (Guido et al., 1989). Optimal spatial frequencies through the nondominant eye were significantly correlated with the optimal spatial frequencies through the dominant eye (r = 0.54; P < 0.0001), and the optimal spatial frequencies were fairly similar for the two eyes.Nondominant-eye stimulation changed the maximal amplitude of the fundamental (Fl) response to dominant-eye stimulation for only about 45% (22 of 49) of the cells that responded to nondominant-eye stimulation alone. The response vs. contrast function through the dominant eye was altered for 73% of the cells (51% independent of spatial frequency). Three types of effects were observed: a change in the initial slope of the response vs. contrast function (contrast gain), a change in the response amplitude at which saturation occurred, or an overall change in response at all contrasts. The incidence of these changes was similar for X and Y cells in LGN layers A, Al, and C (only four W cells were tested).Nondominant-eye stimulation had little or no effect on the sizes or sensitivities of the receptive-field centers or surrounds for the dominant eye. In addition, nondominant-eye stimulation had little or no effect on optimal spatial frequency, spatial resolution, or the bandwidth of spatial-frequency contrast sensitivity curves for the dominant eye.Possible functions of binocular interactions in the LGN are considered. The present results suggest a role in interocular contrast-gain control. Interocular contrast differences can occur before the acquisition of binocular fusion, when the two eyes are viewing different aspects of a visual stimulus. Psychophysical and physiological studies suggest that an interocular mechanism exists to maintain relatively constant binocular interactions despite differences in interocular contrast. The present results suggest that at least part of this mechanism occurs in the LGN.
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Zhao, Guowei, Duonan Yu, Lionel Blanc, Michael S. Marks, and Mitchell J. Weiss. "MiR-144/451 Facilitates Erythroid Cellular Iron Uptake by Targeting Rab14." Blood 120, no. 21 (2012): 609. http://dx.doi.org/10.1182/blood.v120.21.609.609.
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Abstract Abstract 609 The miR-144/451 locus is abundantly expressed during erythropoiesis where it regulates terminal maturation and anti-oxidant pathways. Here we report a role for miR-144/451 in erythroid iron uptake. MiR-144/451−/− (KO) mice exhibit mild microcytic hypochromic anemia, consistent with erythroid iron deficiency (Yu et al., G&D, 2008), although serum ferritin levels reflecting body iron stores are normal (674ng/ml vs. 790ng/ml in wild type (WT) controls, p=0.36, n=6/6). Expression of the major iron importer, transferrin receptor 1 (TfR1), is ∼50% reduced on KO reticulocytes (p<0.05, n=4/4), suggesting that iron import may be compromised. In fetal liver KO erythroblasts, cell surface TfR1 is ∼35% reduced (p<0.01, n=11/7 control/KO), although the corresponding mRNA level is normal. Mutant fetal liver erythroblasts exhibit impaired maturation in vitro, as reflected by reduced proportion of reticulocytes produced after two days of culture with erythropoietin (12.8% vs. 51.1% in controls, p<0.001, n=7/7). The maturation of KO cells is partially rescued to 17% reticulocytes by addition of iron-saturated transferrin (holo-Tf). Conversely, maturation of the KO erythroblasts is markedly impaired by the iron chelator deferoxamine (DFO) (12.8% reticulocytes –DFO vs. 2.2% +DFO), compared to WT erythroblast cultures where DFO has minimal effect (51.1% reticulocytes –DFO vs. 47.5% +DFO). In murine erythroleukemia (MEL) cells, retroviral expression of miR-144 or miR-451 increases TfR1 expression by 1.3 (p=0.07) and 1.5-fold (p<0.05) respectively, with no effects on Tfr1mRNA levels or differentiation markers (n=3 separate experiments). Together, these results indicate that miR-144/451 enhances erythropoiesis by augmenting TfR1 expression post transcriptionally. Expression of TfR1 is highly regulated via intracellular endosomal trafficking, which can enhance the level of TfR1 expression by delivering the protein to the cell surface. Alternatively, endosomal TfR1 can be directed to lysosomes for degradation, or secreted via exosomes, small vesicles released by the fusion of multivesicular endosomes (MVE) with the plasma membrane. A family of Ras-related small GTPases, termed Rabs, regulates endosomal trafficking. In fibroblasts, Rab14 has been shown to inhibit TfR1 expression (Matsui et al., Traffic, 2011). The seed sequences of miR-144 and 451 both exhibit Watson-Crick homology to human and mouse Rab14 mRNAs. Moreover, miR-451 has been shown to directly inhibit Rab14 mRNA in lung carcinoma (Wang et al., Oncogene, 2011). Both Rab14 mRNA and protein levels are increased in miR-144/451−/− fetal liver erythroblasts by 2.1 and 2.3-fold respectively. In MEL cells, TfR1 expression is enhanced by expression of Rab14 shRNAs (up to 2-fold, p<0.0001, n=6). In agreement, in cultured fetal liver erythroblasts, the Rab14 dominant negative mutant N124I increases TfR1 protein expression ∼1.4-fold (p<0.05, n=5), compared to controls. These manipulations do not induce erythroid maturation, which can be associated with altered TfR1 expression. Thus, we propose that miR-144/451 enhances erythroid TfR1 expression and subsequent iron uptake by directly targeting Rab14 mRNA. Future studies are directed toward investigating further the in vivo significance of miR-144/451 on erythroid iron acquisition and characterizing the mechanism(s) by which Rab14 alters endosomal trafficking to inhibit TfR1 protein level. Overall, our studies identify a newly discovered pathway for miRNA-mediated erythroid iron metabolism. These findings provide new insights into normal erythropoiesis and have potential implications for the pathophysiology of various iron deficiency and iron overload states. Disclosures: No relevant conflicts of interest to declare.
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Jo, Tatsuro, Yohei Kaneko, Kazuhiro Noguchi, et al. "Cytotoxic Immune Response Can be Obtained Earlier in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Dasatinib Than with Other Tyrosine Kinase Inhibitors." Blood 132, Supplement 1 (2018): 3016. http://dx.doi.org/10.1182/blood-2018-99-113316.
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Abstract Introduction: Generation of BCR-ABL fusion gene by reciprocal translocation of chromosomes 9 and 22 immortalizes hematopoietic stem cells by mechanisms such as activation of the JAK-STAT pathway, translational activation of BCL-XL, and inhibition of DNA repair, thereby leading to chronic myeloid leukemia (CML). Amazing improvement in the prognosis of CML has been achieved since the introduction of tyrosine kinase inhibitors (TKIs). Imatinib, a 1st-generation TKI, and dasatinib and nilotinib, 2nd-generation TKIs, are generally used for chronic phase (CP) CML as induction therapy. However, to date, no consensus about the cessation of TKIs in CP-CML patients has been obtained. We recently reported the case of a CP-CML patient with long-term complete molecular response (MR) after cessation of dasatinib, who has been maintaining memory CTLs with T cell receptor (TCR) clonality (Jo et al. Oncology Letters 15: 2935-2938, 2018). Here, we show that up-regulation of memory CTLs occurs early in dasatinib-treated patients compared with those treated with other TKIs. Methods: We examined the TCR V beta gene repertoire to analyze TCR clonality of CD8-positive T cells in TKI-treated CP-CML patients using flow cytometry. Results: Table 1 summarizes the data comparing patients treated with TKIs including dasatinib (Dasa group) and those treated with TKIs without dasatinib (non-Dasa group). Seven patients were treated with dasatinib only; 7, with imatinib only; 8, with multiple TKIs, including dasatinib; and 1, with multiple TKIs without dasatinib. The median age at first TKI administration was 57 years in the Dasa group and 69 years in the non-Dasa group. No significant statistical difference was observed in age at first TKI administration. The time of TCR clonality assay was significantly earlier in the Dasa group than in the non-Dasa group (P = 0.0013). There was no significant difference in the MR at the time of TCR clonality assay between the 2 groups. Figure 1 shows representative data of the TCR clonality assay of the patients in the non-Dasa group. We defined a TCR V beta gene percentage of 10% and above as being positive for monoclonality in this study. The time of analysis was at 116th month (Mo) after the 1st imatinib administration, and NK cell percentage was 30.2% at that time. TCR monoclonality was observed in neither effector CTLs (upper panel) nor memory CTLs (lower panel), although the patient had gained MR5. Figure 2 shows representative time-course data of the patients in the Dasa group. MR levels were MR4.5 (13th Mo), MR5 (16th Mo), and MR5 (19th Mo). Interestingly, memory CTL clonality with the TCR V beta 20 gene had already been observed in the 13th Mo, and it had been continuously observed in the 16th and 19th Mo. NK cell percentages were less than 24% throughout the observation period. Table 2 summarizes the CTL clonality assay results and NK cell percentages. There was no significant change in the NK cell percentages between the 2 groups. Although no statistical significance was observed in both effector and memory CTL clonality between the 2 groups, it is notable that approximately 73% and 87% positivity of effector and memory CTL clonality was observed in the Dasa group. Approximately 38% and 50% positivity of effector and memory CTL clonality was observed in the non-Dasa group, although the TKI exposure time for this group was significantly longer. Notably, the positive percentages of effector and memory CTL clonality in the non-Dasa group are quite similar to the overall probabilities of maintenance of deep MR reported in various imatinib-stop studies such as the STIM study (Mahon et al. Lancet Oncol 11: 1029-1035, 2010) and the TWISTER study (Ross et al. Blood 122: 515-522, 2013). These results suggest that acquisition of CTL clonality may correlate with treatment-free remission (TFR) in CP-CML patients treated with TKIs. Conclusions: Effector and memory CTL clonality was attained more rapidly and frequently in dasatinib-treated CP-CML patients than in patients treated with TKIs without dasatinib. There was no significant difference in the NK cell percentages. The positive percentages of CTL clonality resembled the percentages of TFR in various TKI-stop studies. These results suggest that the acquisition of CTL clonality may provide long-term remission and TFR to CP-CML patients and that cessation of TKIs should be considered in patients with clonal expansion of memory CTLs, irrespective of NK cells. Disclosures Jo: Bristol-Myers Squibb: Honoraria.
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Desai, Megha, Kyung-Hee Chang, E. David Muench, et al. "Upregulation of Vav3 Is Required for Leukemogenesis By BCR-ABL through Polycomb Repression Complex Dependent De-Repression of the Cdkn2a Locus." Blood 126, no. 23 (2015): 3661. http://dx.doi.org/10.1182/blood.v126.23.3661.3661.
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Abstract Activating mutations of Rho-family of small GTPases have been linked to lymphoproliferative disorders, although the pathogenesis mechanism involved is unknown. BCR-ABL (p190) B-cell acute lymphoblastic leukemia (B-ALL) arises from the expression of the oncofusion protein BCR-ABL in a B-cell progenitor. The transforming effect of BCR-ABL is dependent on the tyrosine kinase (TK) activity of the fusion protein that leads to autophosphorylation, recruitment of adaptor proteins, and subsequent activation of downstream signaling. TK inhibitors (TKIs) have been used as frontline treatment for Ph+ B-ALL patients. However, relapse is common in Ph+ B-ALL despite high rates of complete response with initial therapy, probably because of survival of leukemic progenitors. These BCR-ABL+ progenitors appear to develop additional epigenetic and genetic alterations that result in proliferative advantage frequently associated with silencing of the cyclin dependent kinase inhibitor Cdkn2a, even before mutant Cdkn2a gene deleted cells are selected during clonal evolution. Recent work by our group (Chang KH et al., Blood 2012) identified the Rho GTPase guanine nucleotide exchange factor Vav3 in BCR-ABL mediated lymphoid leukemogenesis. We showed that the deficiency of the guanosine nucleotide exchange factor Vav3 delays leukemogenesis and phenocopies the effect of Rac2 (and combined Rac2/Rac1) deficiency (Thomas EK et al., Cancer Cell 2007; Sengupta A et al., Blood 2010), a downstream effector of Vav3. Upregulated Vav3 expression and activation only partly depend on ABL TK activity, and Vav3 deficiency collaborates with tyrosine kinase inhibitors to impair leukemogenesis in vitro and in vivo through impaired proliferation and survival. On the other hand, our group has demonstrated that Bmi1 overexpression frequently found in BCR-ABL+ B-ALL results in B-cell progenitor reprogramming through acquisition of a stem cell-like phenotype (Sengupta A et al., Blood 2012). Bmi1 forms part of the classical polycomb repression complex 1 (PRC1) where its component Ring1A/B catalyzes histone H2A mono-ubiquitination at lysine 119, which in conjunction with the PRC2 complex activity leads to chromatin compaction and repression of target genes. Through epistasis experiments, we found that Vav3 or Rac2 deficiency abrogates the oncogenic effect of Bmi1 overexpression. Co-immunoprecipitation experiments in nuclear and cytoplasmic cell extracts demonstrated that Vav3 and Rac1/Rac2 co-immunoprecipitate with Bmi1 in the nucleus but not in the cytosol of BCR-ABL+ leukemic cells. Interestingly, control non-BCR-ABL expressing nuclear extracts show minimal, if any, level of co-immunoprecipitation. This co-immunoprecipitation is not directly induced by BCR-ABL since BCR-ABL does not co-immunoprecipitate with Vav3/Rac1/Rac2 but does with Bmi1, suggesting that nuclear Vav3 activity may be dissected from the TK activity of BCR-ABL. Biochemically, the overexpression of Bmi1 results in increased activation of nuclear Rac which is practically abrogated by the deficiency of Vav3 as assessed in cellular pulldown assays of primary leukemic B-cell progenitors. As expected, downstream expression of Cdkn2a is repressed by overexpression by Bmi1. Deficiency of Vav3 restores the expression of Cdkn2a to control levels. This data suggests a transcriptional regulatory role of the signaling proteins Vav3/Rac2 in the nucleus. Chromatin immunoprecipitation (ChIP)-qPCR for Bmi1, Ring1B and polycomb repressive histone marks (H2AK119 and H3K27me3) and the assay for Tn5-transposase accessible chromatin (ATAQ)-qPCR for the Cdkn2a locus in Vav3- or Rac2-deficient, BCR-ABL+ primary B-cell progenitors were compared with their BCR-ABL, Vav3/Rac2 expressing counterparts. These assays confirmed that Vav3 and Rac2 are essential for PRC dependent transcriptional repression of Cdkn2a through occupancy of the Cdkn2a promoter and decreased accessibility to Cdkn2a chromatin. In conclusion, our studies establish for the first time an association between nuclear Vav3/Rac and polycomb repressive activities in p190-BCR-ABL+ leukemogenesis through their activity on the Cdkn2a locus. Vav3 may represent a novel target for adjuvant therapy with TKI in BCR-ABL+ lymphoblastic leukemia. Disclosures No relevant conflicts of interest to declare.
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Kato, Keisuke, Ai Yoshimi, Norihito Ikenobe, Chie Kobayashi, Kazutoshi Koike, and Masahiro Tsuchida. "Additional Evidence of Mismatch Repair Pathway As Relapse-Specific Alteration in B-Cell Precursor Acute Lymphoblastic Leukemia: Discovery of Novel Somatic Mutation in MLH1 and Establishment of New Cell Line with MLH1 Mutation." Blood 136, Supplement 1 (2020): 10. http://dx.doi.org/10.1182/blood-2020-142122.
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&lt;Introduction&gt;Extensive molecular analysis revealed genetic alterations related to relapse such as mutations of CREEB, MSH2, or NT5C2 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Recently Li B, et al. have established relationship between relapse-specific somatic alterations and timing of relapse (Blood 2020;135:41-55). They identified close link between alterations of DNA mismatch repair genes, including MSH2, MSH6, and PMS2 and early relapse of BCP-ALL as a result of alteration of thiopurine response and resistance to treatment. However, it remains to be clarified which subtype of BCP-ALL is prone to acquisition of particular type of relapse-specific molecular alteration. To further elucidate mechanism of recurrence we have analyzed childhood BCP-ALL cases, particularly focusing on DNA mismatch repair pathway. &lt;Procedure&gt; We analyzed diagnosis-relapse pair samples of recurrent 16 BCP-ALL cases, who had been treated in our institution to find single nucleotide variant (SNV), small Indel, and copy number variation in the coding exons, particularly focusing on mismatch repair pathway using the data captured by Ion AmpliSeq Exome kit and Ion Proton (Thermo Fisher Scientific, MA, USA). The identified variants were confirmed by Sanger sequence. Additionally, we performed RNA-seq using SMART-Seq Ultra Low Input RNA Kit (Clontech Laboratories, Inc, CA, USA), Ion Plus Fragment Library Kit, and Ion Proton, and in vitro cell culture of the leukemic blasts for several cases. &lt;Result&gt; Of several DNA mismatch repair pathway genes, we have identified somatic SNV of MLH1 in a case. The index case, three years old male had diploid BCP-ALL with t(7;9) and PAX5 alteration at diagnosis, who developed early relapse (11 months from diagnosis) and died of the disease. From the sample at 1st and 2nd relapse we have identified somatic MLH1 variant (NM_000249.4:c.901C&gt;T;p.Gln301*). This SNV was detected in small fraction of the diagnostic sample. Furthermore, we have established permanently growing cell line, ICH-BCP-1 from the sample obtained at 2nd relapse. The doubling time is approximately 37 hours and the karyotype was, 46,XY. The same MLH1 variant was identified in the cell line. Of note is that the number of detected SNV increased rapidly at 1st relapse and 2nd relapse as suggested by function of MLH1 product. No other alteration of DNA mismatch repair pathway was observed in the cohort. As previously discovered relapse-specific alterations, we identified somatic SNV of NT5C2 in one hyperdiploid BCP-ALL case and somatic SNV of CREBBP in one hyperdiploid BCP-ALL case. The former case with SNV of NT5C2 gained deletion of IKZF1 and formation of P2RY8-CRLF2 fusion gene at recurrence. Throughout the cohort, hyperdiploid BCP-ALL cases had tendency to have RAS pathway somatic SNVs (KRAS, NRAS, FLT3, and PTPN11). In addition, one low hypodiploid BCP-ALL case had germline small Indel of TP53 and somatic SNV of RB. &lt;Discussion&gt; We add MLH1 alteration to the list of DNA repair pathway relapse-specific somatic alterations, further supporting the particular significance of DNA repair pathway as mechanism of BCP-ALL recurrence, probably related to massive acquisition of complex genetic alteration as a result of loss of DNA repair. In our cohort, the prevalence of previously reported relapse-specific mutation is relatively low, which may be caused by detection method and different ethnicity. Our novel cell line is useful staff for investigation to identify the role of DNA mismatch repair pathway in BCP-ALL leukemogenesis. Disclosures No relevant conflicts of interest to declare.
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Guglielmelli, Paola, Tiziana Fanelli, Valentina Ariu, et al. "Comparative Genomic and Expression Analysis of Chronic and Blast-Phase Cells in Patients with Myeloproliferative Neoplasms." Blood 132, Supplement 1 (2018): 1777. http://dx.doi.org/10.1182/blood-2018-99-112894.
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Abstract Background. Progression to acute myeloid leukemia (sAML) occurs in 20% of myelofibrosis (MF) and 10% of polycythemia vera (PV) or essential thrombocythemia (ET). sAML has dismal outcome with median survival of <6 months. We recently reported that a restricted set of mutations predict for leukemic transformation in MPN (Vannucchi AM, Leukemia 2013; Tefferi A, Blood Adv. 2016). However, the molecular mechanisms underlying transformation to sAML are poorly characterized, in particular the relationships between the clones establishing the chronic phase and the one dominating the leukemic phase. Aim. To study clonal heterogeneity and clonal progression in the leukemic transformation of MPN we performed whole exome (WES) and trascriptome (RNAseq) sequencing of paired samples (chronic (CP)/blast phase(BP). Patients and Methods. WES and RNAseq was done on CD34+ or blast cells of 12 paired samples from 5 PMF, 3 PET-MF, 1 PPV-MF, 3 ET pts who transformed to sAML. In addition, a myeloid neoplasm-relevant 34-gene panel was used for target NGS sequencing of paired samples plus an additional 23 samples collected from MPN pts at leukemic phase (15 PMF, 3 PET-MF, 3 ET, 2 PV). Results. In the entire series, 20 pts (57%) were JAK2 V617F mutated at CP, 8 CALR (23%; 6 type-1 and 2 type-2) and 7 (8.6%) MPL mut, while 4 (11.4%) were triple-negative. JAK2 variant allele frequency (VAF) declined by ≥50% (n=3; 15%) or became undetectable (n=4; 20%) whereas 3 heterozygous pts (15%) became homozygous at the time of BP. One of the 8 CALR mut cases halved its VAF, whereas no meaningful VAF changes were observed in MPL mut pts. The most frequent mutated genes detected by NGS at BP, other than driver mutations, were ASXL1 (51.4%), RUNX1 (37.1%), TET2 (17%), SRSF2 (16%), IDH1 (14%), TP53 (14%), NRAS (14%), FLT3 (14%), U2AF1 (11%) and KRAS (11%); three (8%) cases were mutated for EZH2DNMT3A, CBL and PTPN11, 2 cases for IDH2, SH2B3, SF3B1 IKZF1, SETBP1 and ZRSR2, and 1 case for ABL1, ATV6, BRAF and ARID1A. There were also 5 CEBPA-mutated pts, 3 of which, unlike none of 27 CEBPA-mutated de novo AML, showed an in-frame 6-bp duplication polymorphism (p. P196_197insHP) reported in 20-40% of all de novo AML and <1% of healthy population (rs762459325). Compared to the CP of the 12 paired samples, 10 pts (83%) acquired novel mutations, 3 of which acquired ≥3 variants. RUNX1 and ASXL1 were those with the highest number of acquisition (n=7 and 5, respectively). Conversely, loss of variants was observed only in ASXL1 (n=3). By WES analysis, on average 60.000 variants per paired sample unique to the BP compared with CP were identified. However, no recurrent abnormalities were found in the 12 paired samples outside the above listed mutations found by target sequencing. For RNAseq analysis, transcripts were annotated according to UCSC hg19 for a total of 25,369 genes. We found large transcriptional differences between CP and BP with 129 transcripts differentially expressed (23 up- and 106 down-regulated) and 4,155 isoforms (2,120 up- and 2,035 down-regulated). Among the most abnormally expressed transcripts we selected 8 genes (5 down-regulated: LCN2, PDGFB, PRTG, CRISP3, PF4; 3 up-regulated CDKN2, SH2D1A and LIN28) for validation by QRT-PCR based on the extent of differential expression. PF4 and CDKN2 were confirmed to be down-regulated and over-expressed in BP, respectively (P<0.0001). Analysis of RNA-seq data for fusion genes revealed 10 fusion genes acquired during BP; however, only 3 of them were confirmed by Sanger sequencing (2 cases of BCR-ABL, 1 case of KMT2A- MLLT3 and 1 case of CBFB-MYH11). Pathway analysis included Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis. Six pathways were significantly deregulated in BP compared with CP: Mitotic Spindle (P<0.0001); Androgen response (P=0.004); TGF-beta signaling (P=0.04); Apoptosis (P=0.03); PI3K-AKT-MTOR signaling (P=0.04); Reactive Oxygen Species- Pathway (P=0.03). Conclusions. Comprehensive comparative analysis of genomic and RNA abnormalities acquired in the transition from CP to BP in MPN has not been previously reported. Our data indicate that BP is associated with significant changes in mutation complexity and RNA expression, overall affecting different intracellular pathways whose further characterization might help to identifying potential targets for therapy. Disclosures No relevant conflicts of interest to declare.
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Sbai, Hicham. "La performance boursière des opérations de fusions et acquisitions : une revue de la littérature." Question(s) de management 24, no. 2 (2019): 37. http://dx.doi.org/10.3917/qdm.192.0037.
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Briciu, Lucian, and Sophie Nivoix. "Mise en perspective d'un siècle de fusions-acquisitions en Europe et aux Etats-Unis." Management & Avenir 26, no. 6 (2009): 52. http://dx.doi.org/10.3917/mav.026.0052.
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Jaussaud, Jacques, and Ulrike Mayrhofer. "Fusions-Acquisitions : stratégie, finance, management, Olivier Meier et Guillaume Schier, 4 éd., Dunod, 2012." Management international 18, no. 1 (2013): 170. http://dx.doi.org/10.7202/1022230ar.
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Albouy, Michel. "Fusions-acquisitions et salariés. Les leçons de l’OPA de Schneider sur Télémécanique en 1988." Revue française de gestion 40, no. 241 (2014): 45–62. http://dx.doi.org/10.3166/rfg.241.45-62.
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Thine, Sylvain, and Yamina Tadjeddine. "Organisations financières et diversité du capitalisme financier : le cas des fusions-acquisitions en France." Revue Française de Socio-Économie 24, no. 1 (2020): 41. http://dx.doi.org/10.3917/rfse.024.0041.
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Spitzer, Barbara, Gunes Gundem, Noushin Farnoud, et al. "Early Detection and Molecular Characterization of Therapy-Related Leukemia in Children Reveals Patterns of Disease Transformation and Guides Future Surveillance Protocols." Blood 132, Supplement 1 (2018): 291. http://dx.doi.org/10.1182/blood-2018-99-120005.
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Abstract Background Therapy-related myelodysplastic syndrome (MDS) and acute leukemias represent a major cause of non-relapse morbidity and mortality in childhood cancer survivors, and have been associated with exposure to cytotoxic therapies (e.g. radiation, alkylators, topoisomerase inhibitors). Neuroblastoma (NB) patients receive multimodality therapy with intensive chemotherapy, radiation, and immunotherapy, and have had high rates of treatment-related leukemias (Kushner, Cheung et al. 1998). Whilst specific therapeutic modalities have been associated with distinct cytogenetic and molecular abnormalities, our understanding of the relationships between timing of mutation acquisition, dynamics of clonal selection in relation to specific therapeutic modalities, and how these in unison result in overt leukemia, remains limited. Motivated to study these relationships and inform future screening guidelines, we characterized serial bone marrow (BM) samples obtained during surveillance for NB recurrence and therapy-related leukemias. Methods We studied a total of 219 serial samples from 55 NB patients treated at MSKCC over a 21-year period. These included 19 patients with MDS or leukemic transformation (median time following NB diagnosis 4.4 years), 15 with transient cytogenetic abnormalities (median time to abnormality 3.1 years), and 21 matched controls (median disease-free follow-up 8.1 years). On average, we analyzed 4 samples per transformation patient, representative of pre-treatment timepoints at NB diagnosis, during NB treatment, and throughout follow-up, with a lead time of 18 years - 1 month prior to transformation, and at time of leukemic transformation. Comprehensive genomic profiling with targeted gene sequencing (MSK-IMPACT Heme), RNA-seq, and Archer FusionPlex was performed to capture acquired gene mutations, chromosome-level copy number alterations (CNA), and fusion genes at the time of diagnosis. Backtracking studies were performed in longitudinal samples with complete molecular and clonal characterization. Results We detected at least one disease-defining alteration in all cases with MDS or leukemic transformation at time of diagnosis, with a total of 61 putative oncogenic events across all patients (median 3 alterations per patient, range 1-12). As expected, the most frequent events were MLL fusions (n=6 patients), and mutations in TP53 (n=5 patients). The remaining cases harbored chromosomal aneuploidies or acquired gene mutations in NPM1, IDH1, PTPN11, NRAS, BCOR, CUX1, STAG2, WT1, amongst other genes, at a median variant allele frequency 24% (range 4-68%). Backtracking studies identified at least one of these mutations in 81% of patients at a sampling time point prior to diagnosis. In contrast, only two patients (2/15) from the cohort with transient cytogenetic abnormalities had acquired somatic mutations detected at a median VAF of 3%, with resolution of the molecular alterations in subsequent samples. One of the control cases also had an identified mutation, though this patient died of NB with limited hematologic follow-up. The median time of detection of a putative driver alteration was 6 months prior to leukemic transformation, with the earliest identified at 2.8 years prior to disease transformation. At least 3 cases of MLL fusions were detected 2.2, 14.5, and 20.9 months prior to diagnosis. Mutations in TP53 co-occurred with CNAs in all patients in our cohort, and has been shown to be predictive of chemoresistant disease. Mutations in TP53 were also identified in at least 2 pre-leukemic samples per patient in 4 of 5 cases, at a median VAF 5% (range 5-20%). In all of these cases, TP53 mutations preceded clinically detectable CNA. Genetic evolution led clonal dominance, which, intriguingly, often preceded disease presentation in the context of normal hematopoeisis. We also found evidence of clonal drifts, possibly as a consequence of treatment effects. Conclusions Our preliminary data demonstrate that NB patients at risk of developing secondary leukemia can be identified by molecular profiling of BM aspirates obtained during routine disease surveillance for NB. These findings present an opportunity for the development of early detection studies for patients with pediatric malignancies undergoing intensive therapy and importantly inform studies into mechanisms of leukemic transformation and specific gene-treatment effects. Disclosures Cheung: Ymabs: Patents & Royalties.
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Nguyen-Khac, Florence, Lucile Couronne, Virginie Eclache, et al. "Chromosomal Abnormalities in Transformed Ph-Negative Myeloproliferative Neoplasm Are Independent of the JAK2 and the TET2 Statuses." Blood 114, no. 22 (2009): 2900. http://dx.doi.org/10.1182/blood.v114.22.2900.2900.
Full textAbstract:
Abstract Abstract 2900 Poster Board II-876 Ph-negative myeloproliferative neoplasms: polycythemia vera (PV), essential thrombocythemia (ET) and primitive myelofibrosis (PMF) carry an acquired somatic mutation JAK2V617F in 95% (PV), and in 50 to 60% (ET or PMF) of the patients. Mutations of the TET2 gene have been observed with roughly similar frequencies in the three MPN, irrespective of the presence of JAK2V617F. Evolution to myelofibrosis or acute leukemia may occur with time in MPN patients. Although its molecular bases are poorly understood, the evolution is likely due to the acquisition of additional mutations. To investigate whether cytogenetic abnormalities are distributed differently according to type of transformation and to the JAK2 and TET2 statuses, the Groupe Francophone de Cytogénétique Hématologique has collected 82 patients with transformation of MPN. There were 66 (80%) acute myeloid leukemia or myelodysplastic syndromes (AML/MDS) and 16 (20%) myelofibroses (MF). Of note pipobroman (Pi) treatment seems to be associated with MF, and hydroxyuera (Hu) with AML/MDS evolution in our series. Statistical analyses of clinical, cytogenetic and molecular data are shown Table 1. On the cytogenetical point of view, several points are noteworthy. Some abnormalities were unevenly distributed: there were significantly more -7/del7q and -5/del5q in AML/MDS and tri1q and tri9 in MF. MF and PMF cytogenetic profile looked similar, suggesting a potential link between cytogenetic markers and the phenotype. Although the derivative chromosome der(1;7), observed in 9 patients, is responsible for a loss of 7q, it seemed different from patients with -7/del7q [excluding der(1;7)]. In the -7/del7q group, AML/MDS patients were more numerous than MF patients and the overall survival was shorter compared with the der(1;7) group (22/22 (100%) vs 6/9 (67%) AML/MDS, p=0.02; median: 4 vs 41 months, p=0.0007 respectively). Some specific associations could be observed, such as 17p deletions with 5q deletion (12/30, 40% vs 4/48, 8%, p=0.0007) and 20q deletion with der(1;7) (4/9 (44%) vs11/69 (16%), p=0.03). We detected 24/40 (60%) JAK2V617F and 8/25 (32%) TET2 mutations in transformed MPN, with all possible combinations between the wildtype and mutated forms of both genes. For one post-ET AML patient, JAK2V617F had been observed in a fraction of the granulocytes at the chronic phase. Analysis of blood cDNA obtained at chronic phase showed the same TET2 mutation as observed at acute phase. Because the blast cells were JAK2wt-TET2mut and carried a t(10;16)(q22;q23) affecting the CBFB gene, it is likely that the resulting non-MYH11 CBFB fusion gene transformed a JAK2wt-TET2 mutated progenitor that predominated in the chronic phase. In conclusion, no specific chromosomal abnormality was associated with TET2 or JAK2 mutations. Chromosomal abnormalities were associated with a type of transformation (AML/MDS or MF), suggesting a specific role in the process. In addition, association between some chromosomal abnormalities suggest a specific oncogenic cooperation.Table 1.n=82AML/MDS n=66 MF n=16 p univariate p multivariate Sex F39 (59%)5 (31%)nsnsPV/ET/PMF30/26/1013/3/0nsnsAge at diagnosis of MPN54 [20-82]55.5 [31-69]nsnsChronic Phase (duration, years)12 [2-34]14.5 [3-28]nsnsPrior treatments (n=73*)57*16..No treatment (n=6)60nsnsOne treatment (n=40)33 (58%)7 (44%)nsnsTreatments with Hu (n=57)48 (73%)9 (56%)0.03Treatments with Pi (n=41)26 (46%)15 (93%)0.00060.05Age at transformation66.5[37-92]68 [45-80]nsnsAbnormal karyotype62 (94%)16 (100%)nsnsComplex karyotype45 (68%)7 (44%)nsns-7/del7q28 (42%)3 (18%)0.07ns-7/del7q[without der(1;7)]22 (33%)00.0040.04-5/del5q28 (42%)2 (12%)0.03ns-13/del13q5 (8%)3 (19%)nsns-20/del20q11 (17%)4 (25%)nsns-17/del17p15 (23%)1(6%)nsns+1q14 (22%)9 (56%)0.01ns+95 (8%)4 (25%)0.04ns+811 (17%)3 (19%)nsnsdic17 (26%)3 (19%)nsnsder(1;7)6 (9%)3 (19%)nsnsAmplification MLL0 (0%)nsnsJAK2mut17/31 (55%)7/9 (78%)nsnsTET2mut6/19 (32%)2/6 (33%)nsnsMedian overall survival (months)448<0.00010.001*treatment unknown for 3 patients Disclosures: No relevant conflicts of interest to declare.