Transduction of fetal mice with a feline lentiviral vector induces liver tumors which exhibit an E2F activation signature

This article is available open access through the publisher’s website at the link below. Copyright @ 2014 The American Society of Gene & Cell Therapy.Lentiviral vectors are widely used in basic research and clinical applications for gene transfer and long-term expression; however, safety issues have not yet been completely resolved. In this study, we characterized hepatocarcinomas that developed in mice 1 year after in utero administration of a feline-derived lentiviral vector. Mapped viral integration sites differed among tumors and did not coincide with the regions of chromosomal aberrations. Furthermore, gene expression profiling revealed that no known cancer-associated genes were deregulated in the vicinity of viral integrations. Nevertheless, five of the six tumors exhibited highly significant upregulation of E2F target genes, of which a majority are associated with oncogenesis, DNA damage response, and chromosomal instability. We further show in vivo and in vitro that E2F activation occurs early on following transduction of both fetal mice and cultured human hepatocytes. On the basis of the similarities in E2F target gene expression patterns among tumors and the lack of evidence implicating insertional mutagenesis, we propose that transduction of fetal mice with a feline lentiviral vector induces E2F-mediated major cellular processes that drive hepatocytes toward uncontrolled proliferation culminating in tumorigenesis.ISF, DFG, the Kamea Scientific Foundation, the European Research Council, the Lillyan & Alfy Nathan, Barbara Fox Miller, and Wolfson Foundations

Beta functional connectivity modulation during the maintenance of motion information in working memory: Importance of the familiarity of the visual context

International audience—The purpose of this study was to examine whether mechanisms, involved during the maintenance of familiar movement information in memory, were influenced by the degree of familiarity of the display in which the movements were embedded. Twelve gymnasts who possessed high visual and motor familiarity with the movements employed in this study, were recruited. They were invited to retain for a short period of time familiar movements viewed previously and presented under different displays with the aim of recognizing them at a later stage. The first display was a realistic, familiar display which presented videos of movements. The second display was an unfamiliar impoverished display never experienced in every day life which showed point-light movements. Activity during the maintenance period was considered in five frequency bands (4–8Hz, 8–10Hz, 10–13Hz, 13–20Hz, 20–30Hz) using a non-linear measure of functional connectivity. The results in the 13–20Hz frequency band showed that functional connectivity was greater within the frontal and right temporal areas during the unfamiliar display (i.e., point-light maintenance condition) compared to the familiar display (i.e., video maintenance condition). Differences in functional connectivity between the two maintenance conditions in the beta frequency band are mainly discussed in the light of the process of anticipation. Subjects' perception of the expected difficulty of the upcoming recognition task is discussed

Influences of Instructions and Expertise on the Mechanisms Involved During a Working Memory Task An EEG Study

International audienceThe purpose of this study was to examine the effects of instructions and expertise upon cortical mechanisms during a working memory task. Ten professional pianists and ten musically naïve subjects were instructed to retain for a short period of time, sequential finger movements viewed previously with the aim of either replicating them or recognizing them at a later stage. The results showed that in the 20–30 Hz frequency band and in musically naı¨venaı¨ve subjects, functional connectivity was greater within the occipital, parietal, central, frontal, right, and left temporal areas when the subjects were invited to remember the observed movement in order to replicate it compared to the recognition condition in which they had to recognize it. In professional pianists, incomplete connectivity equivalence was detected between the two conditions. In addition, under the condition for replica, functional connectivity in musically naïve subjects was greater in the central area compared to professional pianists. Explanations related to the: (i) level of expertise, (ii) nature of operations involved during the retention period, and (iii) task demand are discussed

Mécanismes impliqués lors de la mémorisation de mouvements sportifs

L’objet de ce projet était d’examiner l’influence de l’environnement visuel sur lesactivités électro-corticales lors de tâches de mémorisation de mouvements sportifs.Douze sportifs experts pratiquant des activités de productions de formes (i.e.,activités morphocinétiques) ont été invités à retenir des séquences de gestes sportifsqu’ils devaient reconnaître ultérieurement. Ces séquences étaient enchâsséesdans des environnements différents : un environnement habituel, écologique(vidéo «classique») et un environnement inhabituel, minimaliste i.e. appauvri eninformations visuelles (vidéo animée de points lumineux). L’activité cérébrale a étéenregistrée à partir de 64 électrodes. Cinq bandes de fréquence (4-8 Hz, 8-10 Hz,10-13 Hz, 13-20 Hz, et 20-30 Hz) ont été considérées. Une mesure de connectivitéfonctionnelle, l’indice de décalage de phase (IDP), a été utilisée. Les résultats ontmontré que, dans la bande de fréquence 13-20 Hz, la connectivité fonctionnelleétait plus importante au sein des zones frontale et temporale droite lors de lamémorisation de séquences animées de points lumineux que lors de séquencesde vidéos «classiques.» Les données ont également mis en évidence que les sujetsemployaient les mêmes stratégies pour retenir ces séquences et ceci quelque soit lecontexte considéré. Les résultats ont été discutés en relation avec les travaux récentsréalisés dans le domaine des neurosciences cognitives et plus particulièrement dela littérature sur la mémoire de travail. Des applications pratiques ont été suggérées

Mécanismes impliqués lors de la mémorisation de mouvements sportifs

L’objet de ce projet était d’examiner l’influence de l’environnement visuel sur lesactivités électro-corticales lors de tâches de mémorisation de mouvements sportifs.Douze sportifs experts pratiquant des activités de productions de formes (i.e.,activités morphocinétiques) ont été invités à retenir des séquences de gestes sportifsqu’ils devaient reconnaître ultérieurement. Ces séquences étaient enchâsséesdans des environnements différents : un environnement habituel, écologique(vidéo «classique») et un environnement inhabituel, minimaliste i.e. appauvri eninformations visuelles (vidéo animée de points lumineux). L’activité cérébrale a étéenregistrée à partir de 64 électrodes. Cinq bandes de fréquence (4-8 Hz, 8-10 Hz,10-13 Hz, 13-20 Hz, et 20-30 Hz) ont été considérées. Une mesure de connectivitéfonctionnelle, l’indice de décalage de phase (IDP), a été utilisée. Les résultats ontmontré que, dans la bande de fréquence 13-20 Hz, la connectivité fonctionnelleétait plus importante au sein des zones frontale et temporale droite lors de lamémorisation de séquences animées de points lumineux que lors de séquencesde vidéos «classiques.» Les données ont également mis en évidence que les sujetsemployaient les mêmes stratégies pour retenir ces séquences et ceci quelque soit lecontexte considéré. Les résultats ont été discutés en relation avec les travaux récentsréalisés dans le domaine des neurosciences cognitives et plus particulièrement dela littérature sur la mémoire de travail. Des applications pratiques ont été suggérées

Characterization of a pressure measuring system for the evaluation of medical devices

International audienceThe purpose of this study is to evaluate the possible use of four “FSA” thin and flexible resistive pressure mapping systems, designed by Vista Medical (Winnipeg, Manitoba, Canada), for the measurement of interface pressure exerted by lumbar belts onto the trunk. These sensors were originally designed for the measurement of low pressure applied by medical devices on the skin. Two types of tests were performed: standard metrology tests such as linearity, hysteresis, repeatability, reproducibility and drift, and specific tests for this application such as curvature, surface condition and mapping system superposition.The linear regression coefficient is between 0.86 and 0.98; hysteresis is between 6.29% and 9.41%. Measurements are repeatable. The location, time and operator, measurement surface condition and mapping system superposition have a statistically significant influence on the results. A stable measure is verified over the period defined in the calibration procedure, but unacceptable drift is observed afterward. The measurement stays suitable on a curved surface for an applied pressure above 50mmHg.To conclude, the sensor has acceptable linearity, hysteresis and repeatability. Calibration must be adapted to avoid drift. Moreover, when comparing different measurements with this sensor the location, the time, the operator and the measurement surface condition should not change; the mapping system must not be superimposed

Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells

Recent reports linking insertional activation of LMO2 following gene therapy for X-linked severe combined immunodeficiency (X-SCID) have led to a re-evaluation of risks following gene therapy with retroviral vectors. In our analysis of 702 integration sites in rhesus macaques that underwent transplantation up to 7 years earlier with autologous CD34+ cells transduced with amphotropic murine leukemia virus (MLV)-derived retroviral vectors containing marker genes, we detected insertion into one locus, the Mds1/Evi1 region, a total of 14 times in 9 animals. Mds1/Evi1 integrations were observed stably long term, primarily in myeloid cells. We hypothesize that this over-representation likely results from an impact on the self-renewal and engraftment potential of CD34+ progenitor cells via insertional mutagenesis at this specific locus. There is no evidence of ongoing in vivo clonal expansion of the Mds1/Evi1 populations, and all animals are hematologically normal without evidence for leukemia. Characterization of integration sites in this relevant preclinical model provides critical information for gene therapy risk assessment as well as identification of genes controlling hematopoiesis. (Blood. 2005;106:2530-2533

Bodyweight loss estimation of Holstein dairy cows using milk-analysis prediction of bodyweight

peer reviewe

Impact of viable CD45 cells infused on lymphocyte subset recovery after unrelated cord blood transplantation in children

International audienceWe studied lymphocyte recovery in 88 children who consecutively underwent unrelated cord blood transplantation for malignant (n = 64) or nonmalignant (n = 24) diseases. All children but 3 received myeloablative conditioning regimens with pretransplant antithymocyte globulin. Median age was 5.6 years (0.1-18 years) and median follow-up was 40 months (10-136 months). The median dose of infused viable CD45(+) cells (vCD45) was 3.35 × 10(7)/kg with a ratio infused vCD45/collected total nucleated cell at 0.46. Immunologic endpoints were: time to achieve CD3(+) >500 and 1500/mm(3), CD4(+) >500/mm(3), CD8(+) >250/mm(3), CD19(+) >200/mm(3), natural killer >100/mm(3). These endpoints were analyzed through the use of cumulative curves for estimating incidence over time in the context of competing risks, and through Fine and Gray models to assess prognostic factors. The median time to reach these endpoints was 33, 97, 214, and 340 days for natural killer, B, CD8, and CD4 cells, respectively. In multivariate analysis, a high infused vCD45 cell dose improved CD3 (P = .014) and CD4 (P = .032) reconstitutions. A young recipient age also favored CD3 recovery (P = .013). With patients grouped according to vCD45 cell dose quartiles, the threshold for a better recovery was 3.35 × 10(7)/kg. Considering the ratio vCD45/TNC, this "immune recovery based" threshold corresponds to a higher cell dose than the minimum usually recommended dose for myelogenous engraftment. This may have important implication for UCB selection. 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved