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Lahlali, Mustapha. "Démarche Qualité et pratiques de l'évaluation de l'enseignement." Journal of Quality in Education 5, no. 6BIS (2015): 12. http://dx.doi.org/10.37870/joqie.v2i2.107.
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Qu'il s'agisse de l'évaluation des formations ou de celle des enseignements voire des établissements, l'évaluation est un moyen de prêter attention à la qualité de la prestation fournie. Le problême actuel des établissements d'enseignement supérieur n>étant plus uniquement de gérer l'afflux des étudiants, mais aussi et surtout de se focaliser sur la qualité de l'enseignement proposé.Les démarches d>évaluation des enseignements dans le cadre d'une approche globale et évolutive sont un moyen de sensibiliser toutes les parties prenantes dans le processus de formation à cette qualité, pour améliorer les pratiques d'enseignement et donc pour améliorer la formation des étudiants.Le présent article porte sur les points suivants :- De l'évaluation des enseignements ;- De l'évaluation à la démarche qualité ;- La politique des évaluations des enseignements au sein du groupe ESIG- De l'évaluation à l'accréditation des établissements d'enseignement supérieur- Le projet d'accréditation des établissements privés d'enseignement supérieur au Maroc.
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Forestier, Christian. "Les enseignements techniques et professionnels�: vers une ��adaptation d�imp�dances���?" Apr�s-demain N�21,NF, no. 1 (2012): 34. http://dx.doi.org/10.3917/apdem.021.0034.
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Will, Pierre-Étienne. "Chine Moderne et Sinologie." Annales. Histoire, Sciences Sociales 49, no. 1 (1994): 7–26. http://dx.doi.org/10.3406/ahess.1994.279244.
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La notion, à première vue si banale, d'« histoire de la Chine moderne » est en réalité grevée d'ambiguïtés. La question qui sera posée ici est la suivante : que peut signifier la notion de modernité aux yeux d'un historien du monde chinois pour qui ce dernier ne saurait être envisagé autrement que dans la longue durée, et dans un dialogue permanent avec les autres cultures ?L'historique des enseignements du Collège de France —l'institution à laquelle fut d'abord soumis le présent essai — révèle qu'aujourd'hui encore les intitulés des chaires dites d'« orientalisme » sont très rarement contraints dans les limites d'une « époque », ancienne, moderne, ou toute autre.
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Silva, Juliano Quarteroli, Mario Ivo Tavares de Souza, Paulo de Souza Gonçalves, and Raquel Nakazato Pinotti. "Sistemas de explotação de seringueira utilizados em clones asiáticos Prang Besar no Oeste paulista." Pesquisa Agropecuária Brasileira 42, no. 7 (2007): 949–55. http://dx.doi.org/10.1590/s0100-204x2007000700006.
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O objetivo deste trabalho foi avaliar o desempenho produtivo e os aspectos fisiológicos e econômicos de quatro clones asiáticos Prang Besar de seringueira [Hevea brasiliensis (Willd. ex A. Juss.) Muell. Arg.], sob diferentes sistemas de sangria. O experimento foi instalado na Fazenda Santa Gilda, Município de Guararapes, SP, em delineamento de blocos ao acaso, com parcelas subdivididas no tempo. Os tratamentos principais foram os clones PB 260, PB 235, PB 330 e PB 217, submetidos a nove sistemas de sangria: ½S d/3.ET 2,5% 8/y; ½S d/3.ET 5% 8/y; ½S d/4.ET 2,5% 8/y; ½S d/4.ET 5% 8/y; ½S d/5.ET 2,5% 8/y; ½S d/5.ET 5% 8/y; ½S d/7.ET 2,5% 8/y; ½S d/7.ET 5% 8/y e ½S d/2 (testemunha). As variáveis avaliadas foram: perímetro do caule, produção de borracha seca, secamento do painel; foi avaliada, também, a viabilidade econômica. Os resultados mostram a superioridade econômica dos sistemas ½S d/5.ET 2,5% 8/y e ½S d/7.ET 5% 8/y, para o clone PB 260; ½S d/7.ET 2,5% 8/y para o clone PB 235; e ½S d/3.ET 2,5% 8/y e ½S d/3.ET 5% 8/y, para os clones PB 330 e PB 217, comparados com a testemunha. A menor incidência de secamento do painel foi observada no sistema ½S d/7.ET 5% 8/y, exceto para o clone PB 235.
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Sénégas, Marc-Alexandre, and Paul de Grauwe. "Asymétries de transmission, incertitude additive et stabilisation monétaire en UEM : les enseignements dun modèle théorique." Économie & prévision 173, no. 2 (2006): 27–41. http://dx.doi.org/10.3406/ecop.2006.7937.
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Quelin, Bertrand. "L'actualité des rapports - Industries high-tech et consortium de R&D : les enseignements de Sematech." Revue d’économie industrielle 80, no. 1 (1997): 115–28. http://dx.doi.org/10.3406/rei.1997.1672.
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Chabchoub, Ahmed. "Les enquêtes de satisfaction des étudiants, une démarche pour mesurer la Qualité de l'enseignement." Journal of Quality in Education 5, no. 6BIS (2015): 17. http://dx.doi.org/10.37870/joqie.v4i4.66.
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Fondée en 2003, l'école des ingénieurs Esprit a longtemps fonctionné avec de petits effectifs (200 à 300 étudiants) ce qui lui a permis de donner à ses élêves une formation de qualité et de garantir l'employabilité à la plupart de ses diplômés. Avec 1656 étudiants inscrits actuellement, et 78 enseignants exerçant au sein de l'établissement, l'école est entrée en phase de massification. Cela nécessite donc une pause de réflexion et d'ajustement car toute massification non contrôlée risque de porter préjudice à la qualité de la formation. Cela est d'autant plus impérieux que l'école s'est ouverte depuis 2005 sur une clientêle internationale, notamment africaine. Cette ouverture vers une clientêle assez exigeante la pousse aujourd'hui à adopter une politique d' «accountement» et de transparence garantes de qualité et de fidélisation de sa clientêle. Ainsi, l'évaluation réguliêre des pratiques pédagogiques, l'innovation de ces pratiques, l'amélioration du taux d'encadrement des étudiants, peuvent être d'excellentes pistes pour sauvegarder la qualité de la formation des étudiants au sein de l'école, fidéliser ses clients et gagner de nouvelles parts de marché, dans un secteur de plus en plus concurrentiel. Le présent papier s'intéresse à la premiêre phase de cette démarche innovatrice : l'évaluation des enseignements et des pratiques pédagogiques des enseignants, à travers une enquête de satisfaction. Cette démarche s'inscrit d'ailleurs dans un courant pédagogique international qui s'intéresse à la fois à l'évaluation des enseignements à l'université (resté longtemps à l'abri de l'inspection pédagogique) et à la démarche qualité dans l'enseignement supérieur (De Ketele, 2007).
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Pageau, Laurie. "Éthier, M., Lefrançois, D. et Joly-Lavoie, A. (dir.). (2018). Mondes profanes. Enseignements, fiction et histoire. Québec, Québec : Presses de l’Université Laval." Revue des sciences de l'éducation 44, no. 3 (2018): 192. http://dx.doi.org/10.7202/1059959ar.
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GONÇALVES, PAULO DE SOUZA, SÉRGIO RICARDO DE SOUZA, AFONSO PEDRO BRIOSCHI, ADONIAS DE CASTRO VIRGENS FILHO, ANDRÉ MAY, and RICARDO SANCHES CAPEL ALARCON. "Efeito da freqüência de sangria e estimulação no desempenho produtivo e econômico de clones de seringueira." Pesquisa Agropecuária Brasileira 35, no. 6 (2000): 1081–91. http://dx.doi.org/10.1590/s0100-204x2000000600003.
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Este trabalho teve como objetivo avaliar o desempenho produtivo e os aspectos econômicos de dez clones de seringueira [Hevea brasiliensis (Willd. ex Adr. de Juss.) Muell. Arg.] em diferentes freqüências de sangria e com estimulação à base de ethefon. O experimento foi instalado na Fazenda Indiana, no município de Indiana, SP, sob o delineamento de blocos ao acaso com parcelas subdivididas. Os tratamentos principais foram os clones GT 1, RRIM 701, RRIM 600, PB 235, PR 261, PB 252, Fx 4098, Fx 2261, Fx 3864 e IAN 873, submetidos a três sistemas de sangria: 1/2S d/2 6d/7 (testemunha), 1/2S d/4 6d/7.10m/y. ET 5,0% Ba 10y e 1/2S d/6 6d/7.10m/y. ET 5,0% Ba 10/y. As variáveis estudadas foram: perímetro do caule, produção, secamento do painel e os aspectos econômicos. Os resultados mostraram superioridade no sistema 1/2S d/2 6d/7 na maioria dos clones, exceto o GT 1 e o PB 235, que no sistema 1/2S d/4 ET 5,0% apresentaram ganhos líquidos de 12,0% e 54,0%, respectivamente, acima do obtido no sistema testemunha. Somente os clones Fx 3864 e PB 235 apresentaram ganhos líquidos de 18,0% e 28,0% no sistema 1/2S d/6 ET 5% superiores em relação ao obtido no sistema testemunha. A maior porcentagem de secamento do painel foi observada no clone PB 235 no sistema 1/2S d/4 ET 5,0%.
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Leclercq, Gilles, Anne-Catherine Oudart, and Thérèse Marois. "« L’accompagnabilité », une propriété des dispositifs de formation en alternance." Éducation et francophonie 42, no. 1 (2014): 136–50. http://dx.doi.org/10.7202/1024569ar.
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Dans cette contribution, les auteurs étudient la propriété d’« accompagnabilité ». Ils la définissent comme la propension des dispositifs de formation en alternance à distribuer l’activité d’accompagnement, mais aussi comme celle des usagers à la redistribuer, à accompagner, à se faire accompagner, à s’accompagner soi-même. Pour étudier cette propriété dans sa diversité, ils ont d’abord identifié des logiques d’intervention différentes qu’ils nomment « spéculative », « normative » et « dialogique ». La logique d’intervention dialogique est plus spécifiquement étudiée, avec la collaboration de l’accompagnante qui a servi à la modéliser. Celle-ci revisite elle-même sa pratique avec l’outillage conceptuel et le matériau empirique issus de la recherche. La dernière partie du texte est conclusive. Elle porte sur les enseignements, les insuffisances et les perspectives de la démarche de recherche.
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Khand, Kul, Nishan Bhattarai, Saleh Taghvaeian, Pradeep Wagle, Prasanna H. Gowda, and Phillip D. Alderman. "Modeling Evapotranspiration of Winter Wheat Using Contextual and Pixel-Based Surface Energy Balance Models." Transactions of the ASABE 64, no. 2 (2021): 507–19. http://dx.doi.org/10.13031/trans.14087.
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HighlightsThree contextual-based (CB) and two pixel-based (PB) models were evaluated to estimate ET of rainfed winter wheat.Instantaneous available energy estimation and ET upscaling impacted model performance.The CB models performed better at instantaneous and daily scales compared to the PB models.ET estimation biases increased during low vegetation and drier conditions, especially for the PB models.Abstract. Surface energy balance (SEB) models based on thermal remote sensing data are widely used in research applications to map evapotranspiration (ET) across various landscapes. However, their ability to capture ET from winter wheat remains underexplored, especially in practical applications such as integrated resource management and drought preparedness. Investigating winter wheat ET dynamics is important in agricultural regions such as the Southern Great Plains of the U.S., where winter wheat is extensively cultivated. The goal of this study was to evaluate the performance of five fully automated SEB models, three contextual-based (CB) and two pixel-based (PB), in estimating instantaneous and daily ET of winter wheat by comparing the model results with flux tower observations. The CB models included Surface Energy Balance Algorithm for Land (SEBAL), Mapping Evapotranspiration at high Resolution with Internalized Calibration (METRIC), and Triangular Vegetation Temperature (TVT). The PB models included Surface Energy Balance System (SEBS) and Two-Source Energy Balance (TSEB). Model evaluation during two winter wheat growing seasons (2016-2018) using 28 Landsat images showed that the instantaneous ET estimates from METRIC and TSEB had the smallest (RMSE = 0.14 mm h-1) and largest (RMSE = 0.27 mm h-1) errors, respectively. At the daily scale, SEBAL was the best performing model (RMSE = 1.0 mm d-1), followed by TVT (RMSE = 1.1 mm d-1), METRIC (RMSE = 1.2 mm d-1), SEBS (RMSE = 1.3 mm d-1), and TSEB (RMSE = 1.5 mm d-1). Overall, the CB models provided smaller errors than the PB models. Larger errors in daily ET estimation were observed during low vegetation and drier conditions, especially for the PB models. Keywords: Flux tower, Landsat, Southern Great Plains, Water use.
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Campbell, Colin, and Shirley McIver. "Cultural Sources of Support for Contemporary Occultism." Social Compass 34, no. 1 (1987): 41–60. http://dx.doi.org/10.1177/003776868703400104.
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Certaines conceptions de l'occultisme le réduisent à n'être qu'une expression déviante et séparée du consensus culturel con ventionnel. Cette perception des choses a l'inconvénient de rendre particulièrement difficile la compréhension de la raison pour laquelle certaines personnes en viennent à adopter une vision occultiste du réel. Elle encourage aussi les sociologues à ne consi dérer ces personnes que comme des cas marginaux, expressifs d'un handicap socio-culturel. Pour rectifier cette conception, il est indispensable de com mencer par reconnaitre que ni la culture instituée ni l'occultisme ne constituent des systèmes culturels unitaires et que des zones d'interpénétration existent entre eux. En identifiant ce fait et en percevant que, par de multiples aspects, tant la culture populaire que la culture des élites opèrent des emprunts d l'occultisme, il peut être entrevu comment l'occultisme perdure et comment les individus peuvent entrer en contact avec ses enseignements.
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Ayello, Janet, Yaya Chu, Carolyn A. Keever-Taylor, et al. "Familial Haploidentical (FHI) Allogeneic Stem Cell Transplantation (AlloSCT) Utilizing CD34 Enrichment and PB MNC Addback in Children and Adolescents with High Risk Sickle Cell Disease (SCD): Rapid Engraftment, Immune Cell Reconstitution, and Sustained Donor Chimerism (IND 14359)." Blood 128, no. 22 (2016): 1245. http://dx.doi.org/10.1182/blood.v128.22.1245.1245.
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Abstract Background: SCD is characterized by chronic vaso-occlusive crises and multiorgan failure resulting in poor quality of life and early mortality (Bhatia/Cairo et al, BMT 2014). There is presently no curative therapy for patients with high risk SCD other than HLA-identical sibling AlloSCT. (Freed/Cairo et al BMT 2012). However, less than 15% of eligible SCD patients have an unaffected MSD with a 10-15% increase of graft failure and TRM (Talano/Cairo et al, EJH, 2015). Similarly, most patients lack a matched related donor and UCB is an inferior source in SCD recipients (Radhakrishman/Cairo et al, BBMT 2013). Haploidentical familial donors with SCD trait offers an opportunity for a new donor source for children with high risk SCD. To overcome HLA barriers, Geyer/Cairo et al (BJH, 2012) demonstrated that T cell depletion using CD34 enriched HPC products with PB MNC addback transplanted in pediatric recipients utilizing MUD was associated with sustained engraftment, low risk of aGVHD but limited by delayed immune reconstitution. Efforts to use FHI donors and T replete AlloSCT in patients with SCD were associated with high rates of graft failure (Bolanes-Meade J et al Blood 2012; Ruggieri et al BBMT 2011). We previously reported FHI CD34 enriched/PB MNC addback AlloSCT is feasible and well tolerated in patients with high risk SCD (Abikoff/Cairo, ASBMT 2015). Objective: To characterize immunological reconstitution following FHI AlloSCT with CD34 enriched grafts with PB MNC addback in children and adolescents with high risk SCD. Methods: 15 patients were evaluatedpretransplant at D+30, 60, 100 and 180 following FHI AlloSCT. GCSF mobilized HPC were collected by apheresis (Spectra OPTIA, Terumo BCT) and products underwent CD34 enrichment using the CliniMACS cell separation system (materials generously supplied by Miltenyi Biotec, Cambridge , MA) with a PB MNC addback dose of 2x10*5 CD3/kg. Immune cell and subset reconstitution was assessed by flow cytometry. NK function was determined by cytotoxic activity against K562 tumor targets at 10:1 E:T ratio by europium release assay and intracellular LAMP-1 (CD107a) and granzyme B expression by flow cytometry. Whole blood, T cell and RBC chimerism (CD71) determined by flow cytometry and by STR. Results: Patients achieved neutrophil and platelet engraftment in a median time of 10 and 16 days, respectively. By D+30, median whole blood donor chimerism was ≥93% and ≥95% at most recent followup (D+30-730). Median donor chimerism in the erythroid lineage was 95% by D+60, with 7 of 13 patients ≥99% at D+30. This was maintained at most recent followup (D+30-730). Median T cell chimerism was 90% (D+60-550) and median NK cell chimerism was 90% by D+30 and maintained at ≥95% through D+730. NK (CD3-/56+) and NKT (CD3+/56+) cell reconstitution following FHI AlloSCT was rapid and peaked at D+30 (35.5±8.6%, 271x10*3/ul; 14.2±4%, 179x10*3/ul, respectively). Moreover, there was robust NK cell receptor expression reconstitution with high levels of activating receptors, NKp46, NKG2D and KIR2DS and inhibitory receptors NKG2A, CD94 and KIR2DL2/3 at D+30 [Fig 1]. NK cytotoxicity against K562 at E;T 10:1 peaked at D+30 (26±3%) and D+180 (28±3%) compared to pretransplant (16±2%, p<0.01). NK activation marker, CD107a, peaked at D+30 (37±9%) and D+180 (41±6%) and there was robust granzyme B degranulation at D+30. CD3+, CD4+, CD8+ and CD19+ immune reconstitution occurred between D+180 and D+270. One year absolute (mean±SEM) cells/ul of CD3+, CD4+, CD8+, CD19+ and CD56+ was 795±168, 408±102, 375±90, 815±352 and 204±37, respectively. [Fig 2] Conclusion: Immune reconstitution and donor chimerism was relatively rapid after FHI AlloSCT with CD34 enriched grafts with PB MNC addback in high risk SCD patients. The donor MNC addback after CD34 selection may in part contribute to rapid engraftment and immune reconstitution along with sustained donor chimerism. This research was supported by FDA grant 5R01FD004090. Disclosures Cairo: Celgene: Research Funding.
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Gavini-Chevet, Christine. "Le rapport des inspections g�n�rales sur le statut de parent d�l�gu�: quelques enseignements sur la relation entre les parents et l��cole." Administration & �ducation N�153, no. 1 (2017): 93. http://dx.doi.org/10.3917/admed.153.0093.
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Lima, José Romualdo de Sousa, Antonio Celso Dantas Antonino, Willames De Albuquerque Soares, and Ivandro De França da Silva. "ESTIMATIVA DA EVAPOTRANSPIRAÇÃO DO FEIJÃO CAUPI UTILIZANDO O MODELO DE PENMAN-MONTEITH." IRRIGA 11, no. 4 (2006): 477–91. http://dx.doi.org/10.15809/irriga.2006v11n4p477-491.
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ESTIMATIVA DA EVAPOTRANSPIRAÇÃO DO FEIJÃO CAUPI UTILIZANDO O MODELO DE PENMAN-MONTEITH José Romualdo de Sousa Lima1; Antonio Celso Dantas Antonino2; Willames de Albuquerque Soares2; Ivandro de França da Silva11Departamento de Solos e Engenharia Rural, Centro de Ciências Agrárias, Universidade Federal da Paraíba, Areia, PB, romualdosolo@yahoo.com2Universidade Federal de Pernambuco, Recife, PE 1 RESUMO O modelo de Penman-Monteith (PM) com uma resistência do dossel (rc) variável foi usado para estimar a evapotranspiração (ET) do feijão caupi sob diferentes condições atmosféricas e de conteúdo de água do solo. A resistência rc é função da temperatura do ar, do déficit de pressão de vapor, do saldo de radiação e do conteúdo de água do solo. Esses parâmetros foram medidos, com sensores conectados a uma central de aquisição, numa área cultivada de 4,0 ha, localizada no CCA-UFPB, Areia, PB. A ET foi determinada experimentalmente por meio do método do Balanço de Energia-razão de Bowen. O conteúdo de água do solo foi monitorado com sensores do tipo TDR. O desempenho do modelo de PM foi avaliado comparando-se os valores horários e diários de ET calculados e os determinados experimentalmente. O valor do erro padrão (SE) para os valores horários da ET foi de 0,02 mm h-1, enquanto o índice d (Id) foi 0,99; para os valores diários, SE foi de 0,45 mm d-1 e o Id de 0,89. O modelo de PM pode ser usado para estimar com exatidão a ET do feijão caupi nas escalas horária e diária. UNITERMOS: razão de Bowen, calor latente, conteúdo de água no solo, irrigação, TDR LIMA, J. R. de S.; ANTONINO, A. C. D.; SOARES, W. de A.; SILVA, I. de F. da.COWPEA EVAPOTRANSPIRATION ESTIMATE USING THE PENMAN-MONTEITH MODEL 2 ABSTRACT The Penman-Monteith model with a variable surface canopy resistance (rc) was used to estimate cowpea crop evapotranspiration (ET) under different soil water content and atmospheric conditions. rc is a function of air temperature, vapor pressure deficit, net radiation and soil water content. These parameters were measured with sensors connected to a datalogger, in a 4.0-ha cultivated area situated at the CCA-UFPB, Areia, PB. ET was determined experimentally by the Bowen Ration Energy Balance method. Soil water content was monitored by TDR sensors. The Penman-Monteith model performance (ETPM) was evaluated using hourly and daily evapotranspiration values that were obtained from the energy balance – Bowen ratio (ETB). On an hourly basis, the overall standard estimate error (SEE) was 0.02 mm h‑1 and the d index (Id) was 0.99; while on a daily basis, the SEE was 0.45 mm d-1 and the Id, 0.89. Thus, the Penman-Monteith model may be used to estimate daily and hourly cowpea crop ET accurately.KEYWORDS: Bowen ratio, latent heat, soil water content, irrigation, TDR
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Song, K., J. Park, and E. Lee. "356 IMPROVED ENUCLEATION EFFICIENCY FOR PIG SOMATIC CELL NUCLEAR TRANSFER BY DENUDING OOCYTES AT 30 HOURS OF IN VITRO MATURATION." Reproduction, Fertility and Development 19, no. 1 (2007): 293. http://dx.doi.org/10.1071/rdv19n1ab356.
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Oocytes for somatic cell nuclear transfer (SCNT) have to be removed from their cumulus cells before enucleation. Denuding oocytes by vortexing or repeated pipetting makes the polar body (PB) deviate from the metaphase (MII) plate, which in turn makes it difficult to remove DNA materials completely during enucleation. We hypothesized that denuding oocytes at 30 h of IVM maintains the MII plate and PB in a closer position and therefore makes it easy to enucleate. To test this hypothesis, oocytes were matured in TCM-199 supplemented follicular fluid, hormones, EGF, cysteine, and insulin for first 22 h, and in a hormone-free medium for 18 h with three modifications: (1) cumulus cells were removed from oocytes just prior to enucleation at 40 h of IVM (control), (2) oocytes were denuded at 30 h of IVM and co-cultured with their detached cumulus cells for 10 h (D+), and (3) oocytes denuded at 30 h of IVM were cultured without cumulus cells (D-). After IVM, some oocytes were stained with Hoechst 33342 and photographed by a digital camera; the distance between the MII plate and the PB were measured using an image analysis program (ImageJ 1.36; http://rsb.info.nih.gov/ij). Also, the enucleation rate after blind enucleation and the in vitro development of SCNT embryos were determined. For SCNT, oocytes were enucleated, and nuclear material from donor cells (skin fibroblasts from a miniature pig) was inserted; oocytes were then electrically fused, and activated 1 h after fusion. SCNT embryos were cultured in a modified NCSU-23 (Park et al. 2005 Zygote 13, 269-275) for 6 days. Embryos were examined for their cleavage and blastocyst formation on Days 2 and 6, respectively (the day of SCNT was designated Day 0). Data were analyzed by the GLM procedure and the least significant difference test in SAS (SAS Institute, Cary, NC, USA). The distance between the MII plate and the PB was significantly (P &lt; 0.01) shorter in D+ and D- embryos (19.4 and 18.9 �m, respectively) than in the controls (25.5 �m). Enucleation rates after blind enucleation were significantly (P &lt; 0.01) higher in D+ and D- groups (77% and 72%, respectively) than in the controls (60%). Oocyte maturation (89–91%), SCNT embryo cleavage (71–77%), blastocyst formation (4–5%), and embryo cell number (39-45 cells/embryo) were not altered by different denuding methods. The perivitelline space (PVS) increases with time during maturation and denudation, after PB extrusion markedly enhances PB deviation. It is likely that increased PVS in control oocytes enhanced PB deviation during denudation and then resulted in lower enucleation rate. In conclusion, the results of this study indicated that denuding at 30 h of IVM maintained the MII plate and the PB in a closer position and improved enucleation efficiency without impairing developmental capacity of SCNT embryos. This work was supported by the Research Project on the Production of Bio-organs (No. 200506020601), Ministry of Agriculture and Forestry, Republic of Korea.
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Taylor, David M. "Current Psychotherapeutic Drugs. By F. M. Quitkin, D. C. Adams, C. L. Bowden, et al. Washington, DC: APA. 1998. 188 pp. $33.95 (pb). ISBN 0-98048-994-4." Psychiatric Bulletin 24, no. 9 (2000): 358. http://dx.doi.org/10.1192/pb.24.9.358-a.
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Savarese, J. L. "WARMING UP THE “CHILLING EFFECT”: A COMMENT ON THE MOTIVE CLAUSE DISCUSSIONS IN R V KHAWAJA (2010) AND R V KHAWAJA (2012)." Windsor Yearbook of Access to Justice 30, no. 2 (2012): 199. http://dx.doi.org/10.22329/wyaj.v30i2.4375.
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Following the attacks on September 11, 2001, biased surveillance and discriminatory law enforcement approaches gained momentum. In 2003, Reem Bahdi published “No Exit: Racial Profiling and Canada‟s War Against Terrorism.” She analyzed the influence that the declaration of a war against terrorism by Western nations, including Canada, was having on Arabs and Muslims. Other scholars critiqued aspects of Canada‟s anti-terrorism response, including the incorporation of a motive clause into the Criminal Code sections prohibiting terrorist offences. In R. v. Khawaja (2006), the Superior Court reviewed the constitutionality of the motive element in the definition of terrorism. It held that the motive clause facilitated the targeted law enforcement practices that Bahdi and others advocated against. This paper reports on a review of the appellate decisions, R. v. Khawaja (2010) and (2012), which held that the motive clause was consistent with the Canadian Charter of Rights and Freedoms. The appellate decisions are critiqued for their failure to adequately promote human dignity and equality in keeping with the Charter‘s spirit. As a result, the paper concludes by arguing for a return to the insights of Bahdi and others who encourage a rethinking of Canadian social policy after 9/11 to ensure commitment to human rights doctrines, particularly in regard to the racial profiling that the motive clause seemed to animate.Dans la foulée des attaques du 11 septembre 2001, des chercheurs ont observé que les activités de surveillance biaisées et les mesures discriminatoires d‟application de la loi se sont intensifiées. En 2003, Reem Bahdi a publié “No Exit: Racial Profiling and Canada‟s War Against Terrorism.” [« Sans issue : Profilage racial et guerre du Canada contre le terrorisme »]. Elle y analysait les répercussions de la déclaration de guerre contre le terrorisme par les pays occidentaux, y compris le Canada, sur les Arabes et les Musulmans. D‟autres chercheurs ont critiqué des aspects de la réponse antiterroriste du Canada, dont l‟incorporation d‟une disposition relative au mobile dans des articles du Code criminel portant sur des infractions de terrorisme. Dans l‟affaire R. v. Khawaja (2006), la Cour supérieure a accepté le point de vue selon lequel la disposition relative au mobile facilitait les mesures d‟application de la loi contestées par Reem Bahdi et les autres chercheurs. Le présent document fait état d‟une analyse de la décision rendue par la cour d‟appel dans l‟affaire R. v. Khawaja (2010) et portant que la disposition relative au mobile était conforme à la Charte canadienne des droits et libertés. La décision de la cour d‟appel est critiquée parce qu‟elle a négligé de promouvoir suffisamment la dignité et l‟égalité des personnes en respectant l‟esprit de la Charte. Finalement, le document conclut en plaidant un retour aux enseignements de Mme Bahdi et des autres chercheurs qui invitent à repenser la politique sociale canadienne après le 9/11 pour s‟assurer du respect des théories sur les droits de la personne, tout particulièrement en ce qui concerne le profilage racial auquel la disposition relative au mobile semble avoir donné vie.
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Pereira, Bruna Karla. "Nump e silent nouns: Fronteiras sintáticas na marcação de plural no PB." Revista da Anpoll 1, no. 46 (2018): 18–39. http://dx.doi.org/10.18309/anp.v1i46.1082.
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Neste artigo, investiga-se a distribuição do morfema de plural, na estrutura interna do DP, em português brasileiro não padrão (PB). Argumenta-se que essa distribuição é determinada pela posição de cardinais (DANON, 2011; NORRIS, 2014) ou de silent nouns (KAYNE, 2005). Assim, propõe-se que: (I) a posição dos cardinais divide o DP em dois domínios nos quais sintagmas à esquerda de NumP são marcados com o morfema ‘-s’ de plural, enquanto sintagmas à direita de NumP não são; (II) a posição de silent nouns exerce basicamente essa mesma função, em estruturas nas quais os cardinais não podem aparecer; e (III) os traços de número são valorados e interpretáveis em Num (AUGUSTO et al., 2006) e se tornam valorados em D e N após checagem via concordância (PESETSKY; TORREGO, 2006).
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Silva, Juliano Quarteroli, Erivaldo José Scaloppi Júnior, Rogério Manoel Biagi Moreno, Gilberto Batista de Souza, Paulo de Souza Gonçalves, and João Alexio Scarpare Filho. "Producción y propiedades químicas del caucho en clones de Hevea según los estados fenológicos." Pesquisa Agropecuária Brasileira 47, no. 8 (2012): 1066–76. http://dx.doi.org/10.1590/s0100-204x2012000800006.
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El objetivo de este trabajo fue evaluar el desempeño productivo y el contenido de macronutrientes del caucho extraído de cuatro clones de Hevea brasiliensis, en diferentes sistemas de sangría y estados fenológicos de las plantas. El experimento fue realizado en los años agrícolas de 2010 y 2011, en diseño experimental de bloques completos al azar, en parcelas subdivididas, con cuatro repeticiones. Los tratamientos principales - clones GT 1, PB 235, IAN 873 e RRIM 600 - fueron ubicados en las parcelas, y los subtratamientos, que fueron los sistemas de sangría ½S d/2, ½S d/4 ET 2,5% y ½S d/7 ET 2,5%, se ubicaron en las subparcelas. Las variables analizadas fueron producción y contenido de macronutrientes. Las muestras fueron obtenidas en los estados fenológicos de brotación foliar, hojas maduras y senescencia foliar. La producción y los contenidos de macronutrientes del caucho son más influenciados por la práctica de sangría que por el material genético en los estados fenológicos más restrictivos para el follaje de caucho.
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Moczydłowska, Małgorzata. "Comments on ‘Evidence for a Caledonian orogeny in Poland’ by J. D. Johnston, J. A. Tait, J. H. Oliver and F. G. Murphy." Transactions of the Royal Society of Edinburgh: Earth Sciences 86, no. 3 (1995): 227–30. http://dx.doi.org/10.1017/s0263593300002236.
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In a recent paper Johnston et al. (1994) have provided an innovative interpretation of the tectonostratigraphic relationships between distinct terranes juxtaposed along the Intra–Sudetic Fault in the Sudetes Mountainsof the Polish Variscides. They identified this fault as a major crustal fracture between Gondwana and Baltica, rramed the Tornquist Suture, resulting from the closure of the Tornquist Sea during the Caledonian orogeny. This interpretation is based on new U/Pb ages on zircon and titanite from igneous and metamorphic rocks (Oliver et al. 1993), field observations and reassessment of pre–existing data. Previously, the Sudetes were generally thought to haveformed during the Hercynian orogeny, although Caledonian age deformation was also inferred (Oberc 1977, 1986; Don 1984, 1986, 1990).
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Dick, EA, MS Traore, AEA Elabo, et al. "Effets de différentes fréquences annuelles de stimulation éthylénique sur les paramètres agrophysiologiques et de sensibilité à l’encoche sèche d’Hevea brasiliensis au sud-est de la Côte d’Ivoire:Cas des clones PB 235 et PB 260 de la classe .." International Journal of Biological and Chemical Sciences 8, no. 3 (2014): 956. http://dx.doi.org/10.4314/ijbcs.v8i3.12.
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Mesquita NETO, José Rodrigues de, and Clerton Luiz Felix BARBOZA. "O EFEITO DA PALAVRA NA CONSTRUÇÃO DA INTERFONOLOGIA RÓTICA PB-ELE." Trama 15, no. 34 (2019): 52–67. http://dx.doi.org/10.48075/rt.v15i34.20476.
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Este trabalho tem como objetivo geral analisar o efeito da palavra na construção da interfonologia rótica envolvendo o PB e o ELE de professores de espanhol no Brasil. Temos como pergunta-problema: como a palavra influencia na construção da interfonologia rótica entre o português e o espanhol? Nossa hipótese básica afirma que a interfonologia será construída de modo diferente segundo as palavras, os sujeitos e os experimentos. Para a realização da pesquisa temos como base teórica a língua como SAC (BECKNER et al., 2009) e os modelos fonológicos multirepresentacionais: FU (BYBBE, 2001) e ME (PIERREHUMBERT, 2001). A metodologia é de cunho quali-quantitativo e corte transversal, traz como corpus o áudio de 770 tokens em que os róticos aparecem em diferentes contextos fonotáticos e em dois experimentos. Desse modo, verificamos que uma palavra com alto Índice de Realização Não-Padrão no experimento 1, pode aparecer com um baixo Índice no experimento 2. Assim, comprovando o comportamento dinâmico da língua. REFERÊNCIASALVARENGA, E. Metodología de la investigación cuantitativa y cualitativa. 5 ed. Asunción: Diseños. 2014. BAICCHI, A. Construction learning as a complex adaptive system: psycholinguistic evidence from L2 learners of English.BARBOZA, C. L.. Efeitos da palatalização das oclusivas alveolares do português brasileiro no percurso de construção da fonologia do inglês língua estrangeira. 2013. 165f. Tese (Doutorado em Linguística) – Curso de Pós-Graduação em Linguística, Universidade Federal do Ceará, Fortaleza, 2013. BECKNER, et al. Language is a complex adaptive system: position paper. Language Learning, Michigan, v. 51, n. 1, p.1-26, Dec. 2009. BOERSMA, P., WEENIK, D. Praat: doing phonetics by computer. Version 5.1.43. Disponível em: http://www.praat.org. 2012.BRISOLARA, L.; SEMINO, M. ¿Cómo pronunciar el español? La enseñanza de la fonética y la fonología para brasileños: Ejercicios prácticos. Campinas: Pontes Editores. 2014.BYBEE, J. Phonology and language use. Cambridge: Cambridge University Press, 2001.______. Usage-based grammar and second language acquisition. In: ROBINSON, Peter; ELLIS, Nick C. Handbook of cognitive linguistics and second language acquisition. New York: Routledge, 2008. p. 216-236.______, Joan. Language, usage and cognition. Nova York: Cambridge. 2010.CARVALHO, K. C. Descrição fonético-acústica das vibrantes no português e no espanhol. 2004. 213f. Tese (Doutorado em Letras) – Curso de Pós-Graduação em Letras, Universidade Estadual Paulista, Assis, 2004.CRISTÓFARO-SILVA, T. Descartando fonemas: a representação mental na fonologia de uso. In: HORA, D. da; COLLISCHON, G. Teoria linguística: fonologia e outros temas. João Pessoa: Editora Universitária/UFPB, 2003. p. 200-231.______. Fonologia probabilística: estudos de caso do português brasileiro. Lingua(gem), Macapá, v. 2, n. 2, p.223-248, 2005.______. Fonética e fonologia do português: roteiro de estudos e guia de exercícios. São Paulo: Contexto. 2013.FERNÁNDEZ, J. Fonética para profesores de español: de la teoría a la práctica. Madrid: Arco/libros. 2007.GOMES, A. S.. A vibrante múltipla espanhola em aprendentes de Espanhol como língua estrangeira na Bahia e em São Paulo: uma abordagem sociolinguística. 2013. 125f. Dissertação (Mestrado em Estudo de Linguagens) – Curso de Pós-Graduação em Estudo de Linguagens, Universidade do Estado da Bahia, Salvador, 2013.LARSEN-FREEMAN, D.; CAMERON, L. Complex systems and applied linguistics. Oxford: Oxford Universuty Press, 2008.LEFFA, V. J. ReVEL na Escola: Ensinando a língua como um sistema adaptativo complexo. ReVEL, v. 14, n. 27, 2016 [www.revel.inf.br].NAVARRO, T. Manual de pronunciación española. Madrid: CSIC, 1991.PIERREHUMBERT, J. B. Exemplar dynamics: word frequency, lenition and contrast. In: BYBEE, Joan; HOPPER, P. (Comp.). Frequency and the emergence of linguistic structure. Amsterdam: John Benjamins, 2001. p. 137-158.SILVA, K. C. Ensino-Aprendizagem do espanhol: O uso interlinguístico das vibrantes. 2007. 161f. Dissertação (Mestrado em Linguística) – Curso de Pós-Graduação em Linguística, Universidade Federal do Ceará, Fortaleza, 2007. Recebido em 06-09-2018.Aceito em 22-02-2019.
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Bommannan, Karthik B. K., Man Updesh Singh Sachdeva, Parveen Bose, Deepak Bansal, Ram Kumar Marwaha, and Neelam Varma. "Role Of Day-15 Peripheral Blood MRD Assessment In Pediatric B-ALL Patients." Blood 122, no. 21 (2013): 1384. http://dx.doi.org/10.1182/blood.v122.21.1384.1384.
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Abstract Introduction Minimal residual disease (MRD) has emerged as an independent prognostic factor for patients of acute lymphoblastic leukemia (ALL). There is a strong correlation between MRD levels in bone marrow and the risk of relapse in childhood & adult leukemias 1, 2. Bone marrow MRD (BM-MRD) level of ≥ 0.01% is considered as positive and a mid-induction MRD of ≥ 1% is associated with high risk of relapse 3. Recently, the concept of peripheral blood MRD (PB-MRD), as a replacement for BM-MRD, has hit the lime light. In pediatric B-ALL, presence of PB-MRD is associated with a high relapse rate in comparison to cases which are PB-MRD negative 4, 5. This study was aimed to compare the levels of mid-induction (day 15) MRD levels in bone marrow and peripheral blood of pediatric B-ALL patients with a hypothesis that PB-MRD levels correlate with BM-MRD levels, and thus can predict BM-MRD levels for further management of the patient. Methods Forty newly diagnosed CD19+CD10+CD34+/- pediatric B-ALL patients under Vincristine, L-Asparaginase and Dexamethasone, were assessed for MRD levels on their paired day 15 PB & BM samples using six colour flow cytometry. With informed consent, both the samples were collected in EDTA vacutainers and lyse-stain-wash technique was used to prepare a single six colour tube comprising of SYTO 13/ CD34PE/ CD20PerCP/ CD19 PECy7/ CD10APC/ CD45APCH7 for each sample. The processed samples were run on BD FACS Canto II with acquisition of 1 million events or till the tubes were empty. Analysis was done using BD FACS Diva software and MRD of ≥ 0.01% was considered positive. Results Among 40 pairs of day 15 PB and BM samples, 25 (62.5%) were BM-MRD positive. Sixteen pairs (40%) had PB-MRD and BM-MRD co-positivity, 9 pairs (22.5%) had isolated BM-MRD positivity and 15 pairs (37.5%) were MRD negative in both PB and BM samples. In other words, among the 25 BM-MRD positive cases, simultaneous PB-MRD was positive in 16 patients (64%) and none of the samples had isolated PB-MRD positivity. Overall analysis of MRD positive cases showed a direct correlation between PB-MRD and BM-MRD (ρ = +0.684, p < 0.000) and BM-MRD levels were 7 times higher than the PB-MRD. In addition, ROC analysis with PB-MRD of ≥ 0.01% as a cut-off, revealed that, the most likelihood of PB-MRD being positive was when BM-MRD was ≥ 0.31%. Conclusions In contrast to the sparsely available literature, our study shows a significant correlation between PB & BM-MRD levels in day 15 paired samples of B-ALL cases. The MRD levels were 7 times higher in BM as compared to PB and PB-MRD was mostly positive with BM-MRD of ≥0.31%. In other words, day 15 PB-MRD positivity indirectly indicates that there is a minimum BM-MRD of 0.31%. Since literature reports prognostic significance of mid-induction BM-MRD at levels ≥1%, on day 15, an assessment of peripheral blood MRD alone, might yield clinically relevant prognostic information. A paired analysis at different time points might also establish a similar correlation as seen in the present study, eliminating the need of BM-MRD during further follow ups of the patient. This will help in avoiding an invasive procedure and improve patient compliance. References 1. Irving J, Jesson J, Virgo P, Case M, Minto L, Eyre L, et al. Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting. haematologica. 2009;94(6):870-4. 2. Coustan-Smith E, Sancho J, Behm FG, Hancock ML, Razzouk BI, Ribeiro RC, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood. 2002;100(1):52-8. 3. Basso G, Veltroni M, Valsecchi MG, Dworzak MN, Ratei R, Silvestri D, et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. Journal of Clinical Oncology. 2009;27(31):5168-74. 4. Elain CS, Sancho J, Michael LH, Bassem. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood. 2002;100 (7):2399-402. 5. Brisco MJ, Sykes PJ, Hughes E, Dolman G, Neoh SH, Peng LM, et al. Monitoring minimal residual disease in peripheral blood in B lineage acute lymphoblastic leukaemia. British journal of haematology. 1997;99(2):314-9. Disclosures: No relevant conflicts of interest to declare.
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Jones, R. D. "Core Memory for Clinicians." Journal of the International Neuropsychological Society 11, no. 3 (2005): 339–40. http://dx.doi.org/10.1017/s1355617705210391.
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The Essential Handbook of Memory Disorders for Clinicians. Alan D. Baddeley, Michael D. Kopelman, and Barbara A. Wilson (Eds.). (2004). Chichester: John Wiley & Sons. 381 pp., $45.00, £26.99/€40.50 (PB).In the preface to this book, the editors reflect that the original Handbook of Memory Disorders (Baddeley et al., 1995) was aimed at a clinically oriented readership. Following publication of the original text, it was noted that neuroscientists expressed enthusiasm for the work, thus the second edition of the handbook (Baddeley et al., 2002) expanded significantly on scientific issues that were perhaps of less immediate clinical relevance. The current text, which the editors have titled The Essential Handbook of Memory Disorders for Clinicians is composed of a series of chapters from the 2002 text. Similar to the 1995 first edition, the goal of this new book is to provide an accessible text aimed at clinicians. Core clinical issues of assessment, nomenclature, phenomenology, etiology, and management are examined as they relate to disorders of memory and associated underlying diseases.
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Lien, Nguyen Thi, and Nguyen Van Pho. "Formation of secondary nonsulfide zinc ore in Cho Dien Pb-Zn deposits." VIETNAM JOURNAL OF EARTH SCIENCES 40, no. 3 (2018): 228–39. http://dx.doi.org/10.15625/0866-7187/40/3/12615.
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In Viet Nam, non-sulfide zinc ore in the Cho Dien deposit has been exploited for a long time. Up to the present, zinc ore remains the major exploited ore in Cho Dien. There are numerous studies of Pb-Zn ore in Cho Dien. However, most of the studies have dedicated only to description of mineralogical and chemical composition of Pb-Zn ore. There has been no publication on this non-sulfide zinc ore. Based on the mineralogical studies, the content of Pb and Zn in groundwater determined by reflective microscope, SEM, EPMA and ICP-MS methods, the study explained the formation of secondary non-sulfide zinc ore in the Cho Dien deposit. Strong weathering process makes the upper part of ore bodies completely oxidized. Difference in geochemical behavior of lead (Pb) and zinc (Zn) in the oxidation process of Pb-Zn ore is the reason to form non-sulfide zinc ore in the Cho Dien deposit. Oxidation of primary Pb-Zn ore is mainly sphalerite, pyrite, galena minerals which creates a low pH environment and transforms of zinc from immobile (sphalerite - ZnS) to mobile (Zn2+) and retained in solution under acid pH conditions whereas lead has the tendency to form soluble minerals (anglesite, cerussite). The acid neutralization actions of the surrounding rocks make zinc precipitate, to form secondary non-sulfide zinc minerals.ReferencesAndreas Nuspl, 2009. Genesis of nonsulfide zinc deposits and their future utilization (www.geo.tu-frei berg.de/oberseminar/OS_09/Andreas_Nuspl.pdf.Boland M.B., et al., 2003. The Shaimerden supergene zinc deposit, Kazakhstan: Economic Geology, 98(4), 787-795.Chau N.D., Jadwiga P., Adam P., D.V. Hao, L.K. Phon, J. Paweł, 2017. General characteristics of rare earth and radioactive elements in Dong Pao deposit, Lai Chau, Vietnam, Vietnam J. Earth Sci., 39(1), 14-26.Dao Thai Bac, 2012. Characteristics and distribution law of lead-zinc metallogenic fomations in Viet Bac region. Doctoral thesis.Heyl A.V., Bozion C.N., 1962. Oxidized zinc deposits of the United States, Part 1. General Geology: U.S. Geological Survey Bulletin 1135-A.Hoa T.T., et al., 2010. By-products in lead-zinc and copper ores of Northeast Vietnam. J. Sci. of the Earth, 289-298 (in Vietnamese).Hoang Minh Thao, Tran Thi Hien, Dao Duy Anh, Pham Thi Nga, 2017. Mineralogical characteristics of graphite ore from Bao Ha deposit, Lao Cai Province and proposing a wise use. Vietnam J. Earth Sci., 39(4), 324-336.Jurjovec J., et al., 2002. Acid neutralization mechanisms and metal release in mine tailings: A laboratory column experiment: Geochimica et Cosmochimica Acta, 66, 1511-1523.Large D., 2001. The geology of non-sulphide zinc Deposits - an Overview: Erzmetall, 54(5), 264-276.Maria Boni, 2003. Nonsulfide Zinc Deposits: a new - (old) type of economic mineralization. Society for geology applied to mineral deposits (SGA) News, Number 15. https://www.e-sga.org/fileadmin/sga/newsletter/news15/art01.html.McPhail D.C., et al., 2003, The geochemistry and mobility of zinc in the regolith: in Roach, I.C., ed., Advances in Regolith, 287-291.Murray W. Hitzman, et al., 2003. Classification, genesis, and exploration guides for non-sulfide zinc deposits: Economic Geology, 98(4), 685-714.Nguyen V.P., 2013. Wet tropical wethering in Viet Nam. Natural Science and Technology Publisher.Nicola Mondillo, 2013. Supergene Nonsulfide Zinc-Lead Deposits: The Examples of Jabali (Yemen) and Yanque (Peru). Doctoral thesis.Nordstrom D.K., Alpers C.N., 1999. Geochemistry of acid mine waste. Review in Economic Geology, the environmental geochemistry of ore deposits/Eds. G.S.Plumlee, M.J. Logsdon. Part A: Processes, techniques, and health issues, 6A, 133-160.Reynolds N.A., et al., 2003. The Padaeng Supergene Nonsulfide Zinc Deposit, Mae Sod, Thailand. Economic Geology, 98(4), 773-785.Sangameshwar S.R., Barnes H.L., 1983. Supergene Processes in Zinc-Lead-Silver Sulfide Ores in Carbonates: Economic Geology, 78, 1379-1397.Stumm W., Morgan J.J., 1996. Aquatic Chemistry, Third Edition. John Wiley & Sons, New York, NY.Takahashi T., 1960. Supergene alteration of zinc and lead deposits in limestone: Economic Geology, 55, 1083-1115.Thornber M.R. and Taylor G.F., 1992. The mechanisms of sulphide oxidation and gossan formation, in: Butt, C.R.M., and Zeegers H., (Eds.)., Regolith exploration geochemistry in tropical and subtropical terrains, in Govett G.J.S., ed., Handbook of exploration geochemistry: Amsterdam, Elsevier, 4, 119-138.Tran Trong Hoa, 2005. Potential assessment of By- products in lead-zinc and copper deposits of Northeast Vietnam. Final report.Tran Tuan Anh, 2010. Studying accompanying component in the types of potential deposits of basic metals and precious - rare metals of north Viet Nam to improve the efficiency of mining and environmental protection. Final report. KC.08.24/06-10.Tran Tuan Anh, et al., 2011. Mineralogical and geochemical characteristics and forming conditions of lead - zinc deposits in Lo Gam structure, northern Vietnam. J. Sci. of the Earth, 33(3DB), 393-408 ( in Vietnamese).Vito Coppola et al., 2009. Nonsulfide zinc deposits in the Silesia - Cracow district, Southern Poland. Springer Link, 44, 559-580.Vito Coppola, et al., 2007. Non-sulfide zinc deposits in Upper Silesia, Southern Poland. Proceeding of the Ninth Biennial SGA Meeting, Dublin, 1401-1404.Williams P.A., 1990. Oxide zone geochemistry: Ellis Horwood Ltd., Chichester, UK, 286p.
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Asprem, Egil. "Magic Naturalized? Negotiating Science and Occult Experience in Aleister Crowley's Scientific Illuminism La Magie “naturalisée”? De la négociation entre science et expérience occulte dans l'illuminisme scientifique d'Aleister Crowley." Aries 8, no. 2 (2008): 139–65. http://dx.doi.org/10.1163/156798908x327311.
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AbstractL'une des questions centrales qui se posent en matière d'ésotérisme occidental moderne porte sur l'attrait persistant de la magie; comment la magie a-t-elle survécu au “désenchantement du monde”? Une explication tentante a été que l'émergence de la “magie occultiste”, fondée sur les écrits d'Eliphas Lévi (1810-1875) et les enseignements de l'Ordre Hermétique de la Golden Dawn (créé en 1888) en particulier, ont eu pour effet une “psychologisation” de la magie. Le fait d'interpréter les pratiques magiques comme des techniques psychologiques, et le commerce avec des entités ésotériques comme une manipulation d'états intérieurs, psychologiques, plutôt que comme un commerce avec des êtres spirituels existant réellement, a permis à des modernes possédant une bonne culture et appartenant à une classe supérieure à la classe moyenne, de maintenir à la fois leur croyance à la magie, et leur intégrité rationnelle. En présentant une étude de cas, celui d'un des occultistes modernes ayant exercé le plus d'influence, à savoir Aleister Crowley (1875-1947), cet article cherche à montrer que “la thèse de la psychologisation” ne résiste pas entièrement à l'examen. Feront l'objet d'une mention particulière le système magique de Crowley, présenté comme un “Illuminisme scientifique”, ainsi que le rôle et à l'attrait de la science dans ce système. Contrairement à la thèse de la psychologisation, laquelle, comme on en traitera, représente une sorte d' “escapisme psychologique”, Crowley ne cherchait pas à dissocier ses croyances magiques de ses croyances rationnelles en les faisant passer dans le champ de la psychologie et des états intérieurs; au lieu de cela, influencé qu'il était par les idéaux du naturalisme scientifique il a cherché à concevoir une méthode naturaliste permettant de critiquer, de tester et de raffiner rationnellement la pratique magique. En somme, on s'attachera à montrer que le système de Crowley représente un pas en direction de la naturalisation plutôt que vers la psychologisation de la magie. On présentera une lecture serrée de certaines des idées de Crowley portant sur le rapport entre science et magie, et on procédera aussi à une contextualisation historique dans laquelle on s'attachera spécialement à traiter des rapports entretenus par Crowley avec des courants intellectuels marquants au sein desquels on s'intéressait à cette question (notamment, la Society for Psychical Research, Sir James Frazer, ainsi que des philosophes naturalistes—de T.H. Huxley à Henry Maudsley).
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Jenkins, Rosie, and David Jolley. "Care Management and Health Care of Older People. By D. Challis, R. Darton, L. Johnson, et al. Aldershot: Ashgate Publishing. 1995. 370 pp. £18.95 (pb)." British Journal of Psychiatry 167, no. 4 (1995): 558–59. http://dx.doi.org/10.1192/s0007125000065880.
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Karp, Rebecca, Jon E. Arnason, Jacalyn Rosenblatt, et al. "Pure Red Cell Aplasia after ABO-Mismatched Allogeneic Stem Cell Transplantation Treated with Therapeutic Plasma Exchange and Rituximab." Blood 126, no. 23 (2015): 5453. http://dx.doi.org/10.1182/blood.v126.23.5453.5453.
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Abstract Introduction Pure red cell aplasia (PRCA) is a severe consequence of major and bi-directional ABO-mismatched allogeneic stem cell transplantation (allo-SCT), likely the result of persistent isoagglutinin-producing host plasma cells that have escaped pre-transplant conditioning or graft vs. plasma cell effect (Aung et. al. 2013). PRCA, defined as anemia with reduced reticuloytosis and absence of red cell precursors in the bone marrow at 60 days after transplantation, complicates about 10-20% of all ABO-mismatched allo-SCTs; however, optimal treatment remains unknown. We report 5 cases from our institution of ABO mismatched allo-SCT complicated by PRCA treated with therapeutic plasma exchange (PEX) with or without the anti-CD20 monoclonal antibody rituximab. Report Patient characteristics are shown in Table 1. Indications for transplantation included refractory multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome (table 1); four of five patients underwent myeloablative conditioning, and the fifth received a reduced-intensity regimen due to age and co-morbidities. Prophylaxis for graft-versus-host disease consisted of cyclosporine alone, cyclosporine and prednisone, or tacrolimus and prednisone. ABO mismatching was major in four patients and bi-directional in one patient; all donors and recipients were Rh(D) positive. In all five patients, neutrophil engraftment occurred between days 11-15 after transplantation, with failure of red cell engraftment by day 60. Response Intervention included PEX in all patients, performed every-other-day (table 1). Three patients also received adjuvant rituximab in addition to PEX. Resolution of PRCA, which we defined as transfusion independence, presence of erythroid precursors on bone marrow biopsy, and Òmixed fieldÓ on blood type crossing, occurred in four out of five patients (mean 95 days). In two patients (patients 3 and 5) PEX and rituximab led to transfusion independence in less than 30 days after initiation of PEX. In one patient (patient 2), red cell engraftment occurred 87 days after initiation of PEX; another patient (patient 4) required 10 sessions of PEX and 2 cycles of rituximab (4 weekly doses separated by 6 months) to achieve transfusion independence 253 days after initiation of PEX. One patient (patient 1) had persistent PRCA despite 10 sessions of PEX and died of disease relapse 398 days after transplantation. In one patient (patient 2), tapering of immunosuppression was attempted in conjunction with PEX and led to resolution of PRCA; in the other four, withdrawal of immunosuppression was either not clinically indicated or unsuccessful in resolving PRCA. Conclusion We report five cases of PRCA after ABO-mismatched allo-SCT in the setting of major or bi-directional ABO incompatibility treated with PEX with or without rituximab, with four out of five patients responding to this intervention. This case series demonstrates the potential efficacy of PEX and rituximab for the treatment of PRCA. However, the optimal number of sessions of PEX, timing of this intervention, dosing and schedule of rituximab, and appropriate patient selection still remain unknown. A prospective study is planned. Table 1. Patient characteristics and treatment outcomes Patient Age Disease Graft Conditioning Recipient/Donor ANC>500 Treatment Outcome/TTE 1 48M IgG MM PB MURD MyeloablativeBu/Cy O+/A+ F D+15 PEX 10 sessions PRCA unresolved Died 398 days after transplant of recurrent disease 2 56 M MDS PB MURD MyeloablativeFlu/Bu/ATG O+/B+ M D+11 PEX 10 sessions Withdrawal of immunosuppression Resolution of PRCA 87 days 3 58 M AML PB MRD MyeloablativeFlu/Bu O+/A+ M D+13 PEX 10 sessions Rituximab 2 doses Resolution of PRCA 13 days 4 49 M AML PB MRD MyeloablativeBu/Cy B+/A+ F D+11 PEX 10 sessions Rituximab 8 doses (2 cycles of 4 weekly doses separated by 6 months) Resolution of PRCA 253 days 5 70 M MDS PB MRD RIC Flu/Bu O+/A+ M D+15 PEX 7 sessions Rituximab 4 doses Resolution of PRCA 15 days M: male; MM: multiple myeloma; MDS: myelodysplastic syndrome; AML: acute myelogenous leukemia PB: peripheral blood; MRD: matched related donor; MURD: matched unrelated donor; Bu: busulfan; Cy: cyclophosphamide; Flu: fludarabine; RIC: reduced intensity conditioning regimen; F: female; ANC: absolute neutrophil count; PEX: plasma exchange; TTE: time to red cell engraftment after PEX. Disclosures No relevant conflicts of interest to declare.
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Matos, Gabriela, and Inês Catarino. "Sluicing e Pseudosluicing em português europeu e brasileiro." Revista da Associação Portuguesa de Linguística, no. 3 (September 29, 2017): 191–211. http://dx.doi.org/10.26334/2183-9077/rapln3ano2017a12.
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Sluicing and Pseudosluicing are elliptical constructions that differ in Portuguese regarding the (im)possibility of preposition omission. Rodrigues et al. (2009) and Rodrigues (2016) claim that in Brazilian Portuguese (BP), and Spanish, this omission is apparent in Pseudosluicing, because the prepositional phrase occurs inside the elided cleft sentence that affects the overt wh-phrase (whP). European Portuguese (EP) shows that this apparent omission only occurs with whPs that are D-linked and the linguistic context permits the recovering of the nominal that expresses the kind of entities that are under inquire. When free relatives are involved in the cleft sentences, the omission of preposition is required, and the differences in acceptability between PE and PB are due to the narrow extension of the Preposition Drop phenomenon in EP.
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DJADE, Péhégninon Junior Ophélie, Abou TRAORE, Koffi Jean Thiérry KOFFI, Keiba Noël KEUMEAN, Gbombélé SORO, and Nagnin SORO. "Evaluation du niveau de contamination des eaux souterraines par les éléments traces métalliques dans le département de Zouan-Hounien (Ouest de la Côte d’Ivoire)." Journal of Applied Biosciences 150 (June 30, 2020): 15457–68. http://dx.doi.org/10.35759/jabs.150.6.
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Objectif : Evaluer le niveau de contamination des eaux souterraines de Zouan-Hounien en élément traces métalliques (ETM). Méthodologie et résultats : Un total de soixante-douze (72) échantillons d’eaux souterraines ont été prélevés en raison de quarante-six échantillons d’eaux de puits (23 puits) et vingt-six échantillons d’eaux de forages (13 forages). Dans ces échantillons, des ETM tels que : Hg, Pb, Cd, As et Fe ont été dosés par spectrométrie d’absorption atomique. Les concentrations moyennes respectives de Fe, Pb, Hg, As et Cd sont de 2233,48 > 3,10 > 1,67 > 1,18 > 0,08 µg.L-1 dans les puits et de 2427,94 > 4,08 > , 2,36 > 1,76 > 0,08 µg.L-1 dans les forages. La valeur moyenne du degré de contamination (Dc) dans les puits et les forages est supérieure à 3, indiquant ainsi une forte contamination des eaux souterraines. Avec des valeurs moyennes de l’indice de pollution par les ETM (HPI) inférieures à la valeur seuil de 100, ces eaux restent faiblement polluées dans l’ensemble. Pourtant, deux puits et deux forages ont enregistré une forte pollution des eaux, avec des valeurs supérieures à 100. Conclusion : L’indice de pollution des eaux souterraines par les ETM appliqué aux eaux souterraines révèle que les eaux de puits et de forages sont de bonne qualité, à l’exception de deux puits et deux forages. Le mercure reste le principal élément qui contribue à la toxicité des eaux. Sa présence dans les eaux est due à l’effet des activités d’orpaillage ancien et actuel dans la zone. Une sensibilisation sur les impacts de l’orpaillage sur les ressources en eau est à mener au sein des orpailleurs afin de réduire l’utilisation du mercure. Une consommation prolongée de ces eaux peut entrainer des problèmes graves de santé publique. Mots clés : indices de pollution, eaux souterraines, ETM, orpaillage, Zouan-Hounien Assessment of pollution indices by metallic trace elements of groundwater resources in the mining area of the department of Zouan-Hounien, Côte d´Ivoire. Objective : Assess the level of contamination of Zouan-Hounien groundwater with metallic trace elements (ETM). Methodology and results: A total of seventy-two (72) groundwater samples were taken that is forty-six well water samples (23 wells) and twenty-six borehole water samples (13 wells). In these samples, ETMs such as: Hg, Pb, Cd, As and Fe were determined by atomic absorption spectrometry. The respective average concentrations of Fe, Pb, Hg, As and Cd are 2233.48> 3.10> 1.67> 1.18> 0.08 µg.L-1 in the wells and 2427.94> 4 , 08>, 2.36> 1.76> 0.08 µg.L-1 in boreholes. The average value of the degree of contamination (Dc) in wells and boreholes is greater than 3, thus indicating a strong contamination of groundwater. With average values of the ETM pollution index (HPI) below the threshold value of 100, these waters remain slightly polluted. However, two wells and two boreholes recorded heavy water pollution, with values greater than 100. The correlation matrix carried out between the ETM and the HPI reveals that Hg is the main element, which contributes to the toxicity of the water. Conclusion: The ETM pollution indices for groundwater applied to waters revealed that well and borehole water are of good quality, with the exception of two wells and two boreholes. However, mercury remains the main element that contributes to the toxicity of water. Its presence in the waters is due to the effect of old and current gold panning activities in the area. Thus, raising awareness of the impacts of gold panning on water resources is to be carried out among gold panners in order to reduce the use of mercury. Prolonged consumption of these waters can lead to serious public health problems. Keywords: pollution indices, groundwater, ETM, gold panning, Zouan-Hounien
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Gulukun, E. Z., M. M. Ari, and S. E. Alu. "Proximate composition and antinutritional factors of differently processed kidney bean (Phaseolus vulgaris) seeds." Nigerian Journal of Animal Production 47, no. 5 (2020): 169–75. http://dx.doi.org/10.51791/njap.v47i5.1274.
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Kidney bean is an important source of high quality protein, as well as other nutritious substances. The higher the content of these nutritious substances in a given kidney bean, the higher it's quality. Proximate composition and anti-nutritional factors of raw and processed kidney bean seed were investigated with a view to finding alternative and cheaper source of protein. The study was conducted at plateau state college of agriculture livestock farm, Garkawa to investigate the proximate composition and anti – nutritional factors of differently processed kidney bean (Phaseolus vulgaris) seeds. The Processing methods investigated were raw, cooked, soaked, fermented and sprouted in (T1, T2, T3, T4 and T5) respectively. The results obtained indicates that Ether Extract (EE), Ash, Moisture contents and calculated Metabolizable Energy (ME) showed no significant difference (P > 0.05) between the processed and the raw sample. However, there were significant differences (P < 0.05) in the crude protein (CP) and crude fibre (CF) contents for both raw and processed samples. Fermented kidney bean seeds had the highest CP level of 25.00%, compared to sprouted, raw, soaked and cooked with CP % of 22.94, 20.70, 20.31 and 20.13%, respectively. The fermented kidney bean seeds had the highest CF of 10.55% while others did not differ with value of the raw. Anti – nutrients composition showed that fermented seeds had significant reduction in the levels of oxalate, saponin, tannin, cyanide, and trypsin inhibitor, compared to the raw sample. These results suggest that fermentation of kidney bean seeds enhances its usage as proteins source in animal feed due to its increased protein content and reduction in some anti – nutritional factors. Le haricot rouge est une source importante de protéines de haute qualité, ainsi que d'autres substances nutritives. Plus la teneur en ces substances nutritives d'un haricot est élevée, plus sa qualité est élevée. La composition immédiate et les facteurs anti-nutritionnels des grains de haricots rouges crus et transformés ont été étudiés en vue de trouver une autre source de protein qui seramoins chère. L 'étude a été menée à la ferme d'élevage de College d'Agriculture, dans l'etat de Plateau, à Garkawa, au Nigeria, pour étudier la composition immédiate et les facteurs anti - nutritionnels des graines de haricot rouge (Phaseolusvulgaris) traitées différemment. Les méthodes de traitement étudiées étaient crues, cuites, trempées, fermentées et germées en (T1, T2, T3, T4 et T5) respectivement. Les résultats obtenus indiquent que l'extrait d'éther (EE), les cendres, les teneurs en humidité et l'énergie métabolisable (EM) calculée n'ont montré aucune différence significative (P> 0.05) entre l'échantillon traité et l'échantillon brut. Cependant, il y avait des differences significatives (P <0.05) dans les teneurs en protéines brutes (PB) et en fibres brutes (FB) pour les échantillons bruts et traités. Les graines de haricots rouges fermentés avaient le niveau de PB le plus élevé de 25.00%, comparativement aux graines germées, crues, trempées et cuites avec des PB% de 22.94, 20.70, 20.31 et 20.13%, respectivement. Les graines de haricots rouges fermentés avaient le FB le plus élevé de 10.55% tandis que d'autres ne différaient pas avec la valeur de la matière première. La composition anti - nutriments a montré que les graines fermentées avaient une réduction significative des niveaux d 'oxalate, de saponine, de tanin, de cyanure et d'inhibiteur de trypsine, par rapport à l 'échantillon brut. Ces résultats suggèrent que la fermentation des graines de haricots rouges améliore son utilisation comme source de protéines dans l'alimentation animale en raison de sa teneur accrue en protéines et de la réduction de certains facteurs antinutritionnels.
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Costa-Borges, N., J. Santaló, and E. Ibàñez. "33 ENUCLEATION OF PRE-ACTIVATED MOUSE OOCYTES INDUCED BY DEMECOLCINE, NOCODAZOLE, AND VINBLASTINE." Reproduction, Fertility and Development 19, no. 1 (2007): 135. http://dx.doi.org/10.1071/rdv19n1ab33.
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Demecolcine-induced enucleation has been previously used to prepare developmentally competent enucleated mouse and bovine cytoplasts for nuclear transfer (Gasparrini et al. 2003 Biol. Reprod. 68, 1259–1266; Fischer-Russell et al. 2005 Mol. Reprod. Dev. 72, 161–170). The approach is technically simple, but the proportion of pre-activated oocytes that extrude all of the chromatin within the second polar body (PB) after exposure to demecolcine is relatively low, especially in the mouse (20%). This study was designed to explore the potential of other antimitotic drugs (nocodazole and vinblastine), besides demecolcine, to induce enucleation of mouse oocytes and to characterize the morphological progression of the treated oocytes after drug removal. Metaphase II (MII) oocytes were collected from cytochalasin D-1 (CD-1) females (6–12 weeks old) at 16 h post-hCG, activated in 7% ethanol (for a fast release from MII arrest) for 5 min and immediately treated for 15, 30, or 60 min with demecolcine (DEM, 0.4 �g mL-1), nocodazole (NOC, 0.3 �g mL-1), or vinblastine (VIN, 0.1 �g mL-1), prepared in calcium-free KSOM containing 10 mM strontium. Then, the oocytes were cultured in drug-free medium for up to 2 h, 6 h, or 20 h post-activation (p.a.) and fixed in a microtubule stabilization buffer-extraction fixative. A triple-labelling protocol for microtubules, microfilaments, and chromatin was used to analyze oocytes (approximately 60 per treatment) by fluorescence microscopy. Results were statistically analyzed by chi-square. At 2 h p.a., the highest rates of enucleation were achieved when pre-activated oocytes were treated with VIN (63.8%) or NOC (41.9%) for 15 min or with DEM (66.1%) for 30 min. Although antimitotic treatments did not affect activation rates (91.8–100%), a significant proportion of DEM- (19.6%) and of VIN-treated (15.5%) oocytes failed to complete second PB extrusion when compared to control (0%) or NOC-treated (4.8%) oocytes. From the total of the enucleated oocytes, 11.5%, 24.3%, and 29.7% had an incomplete second PB extrusion in NOC, VIN, and DEM groups, respectively, and therefore were classified as partially enucleated. Further culture of oocytes after drug withdrawal resulted in 100% of activated oocytes having a completely extruded second PB in all groups by 6 h p.a. and resulted in a significant and similar decrease in enucleation rates for all treatments by 6 h (20.3–34.9%) and 20 h p.a. (10.2–16.1%). This decrease might be caused by the reintegration of the chromosomes into the oocyte after incomplete second PB extrusion, or by re-fusion of second PBs to enucleated oocytes. Thus, our results show that both VIN and NOC, in addition to DEM, can be successfully applied to produce enucleated mouse cytoplasts, omitting the potentially harmful step (staining and ultraviolet illumination) of the traditional enucleation method. However, removal of the second PB at 2 h p.a. is recommended in order to achieve an irreversible oocyte enucleation. It remains to be demonstrated if the cytoplasts prepared with VIN or NOC are as competent as those prepared by DEM to support embryo development to term after being reconstructed by nuclear transfer.
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Wolf, Jeffrey L., Katherine A. Kong, Jenai Wilmoth, et al. "Next-Generation Sequencing Based Minimal Residual Disease Assessment in Peripheral Blood RNA from Multiple Myeloma Patients." Blood 128, no. 22 (2016): 3286. http://dx.doi.org/10.1182/blood.v128.22.3286.3286.
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Abstract Introduction: Multiple myeloma (MM) is characterized by the presence of monoclonal protein (M-protein) in serum and/or urine, clonal plasma cell accumulation in bone marrow, and related organ or tissue impairment. MM patients are monitored during and after therapy using immunoglobulin, M-protein and free light chain assays. Minimal residual disease (MRD) assessment of bone marrow samples from MM patients in complete remission (CR) using next-generation sequencing (NGS)-based technology has been shown to have prognostic value, and previous studies have demonstrated evidence of circulating myeloma cells in peripheral blood. In this prospective study, we compared the sensitivity of RNA- and DNA-based MRD assays in peripheral blood (PB) and bone marrow (BM) samples collected from MM patients. Methods: Matched BM and PB samples were obtained from 50 MM patients in various stages of their disease. Diagnostic BM samples were used to identify clonal immunoglobulin sequences (i.e. clonotypes) unique to each MM patient. Matched BM and PB samples were then assessed for the presence of the MM clonotype. Using universal primer sets, we amplified immunoglobulin (IgH) variable (V), diversity (D), and joining (J) gene segments, the incomplete IgH-DJ rearrangement, and IgK receptors. Genomic DNA samples were assessed for all 3 receptors, while RNA samples were only assessed for the functional IgH-VDJ and IgK receptors. Amplified products were sequenced to obtain >1 million reads and analyzed using standardized algorithms for clonotype quantification. Myeloma-specific IgH, IgK, and IgH-DJ clonotypes were identified for each patient based on their high frequency at diagnosis. The presence of the myeloma clonotype was then assessed in BM cells (DNA), PB cells (DNA and RNA), and PB plasma (DNA) samples. Myeloma clonotype levels were calculated as previously described (Martinez-Lopez et al. 2014). Results: High-frequency myeloma clonotypes were identified in the BM of all 50 patients. We performed a sequence-level assessment of each clonotype to determine whether it was also evaluable in RNA. Non-functional clonotypes (e.g. IgH-DJ and kappa deleting element clones, frameshift/nonsense mutations, nonfunctional V or J segments, loss of cysteine in CDR3) were excluded from the analysis. 37 evaluable RNA clonotypes were identified in 28 of the 50 patients (56%). We compared the sensitivity of MRD assessment using DNA and RNA extracted from PB mononuclear cells. 20 clonotypes were qualitatively concordant in both DNA and RNA. 17 clonotypes were discordant, with all 17 clonotypes being detectable in RNA but not in DNA (Figure 1A). Only 4 of 21 (19%) clonotypes detectable in RNA were also detectable in DNA in the PB. Thus, RNA provides a clear sensitivity advantage over DNA analysis in PB cellular samples. We then investigated whether the sensitivity advantage conferred by RNA in PB cells was equivalent or superior to the sensitivity of DNA analysis in BM cells. On a patient level, 23 patients were qualitatively concordant in the PB and BM assays. 5 patients were discordant, with all patients being positive in BM and negative in PB. 4 of the discordant patients were positive at low levels in the BM (1-10 MM clonotype molecules per 1 million cells). On a clonotype level, 28 clonotypes were qualitatively concordant in BM DNA and PB RNA. 9 clonotypes were discordant, with all 9 clonotypes being positive in BM DNA and negative in PB RNA (Figure 1B). Nevertheless, PB RNA detected MRD in 21 of 30 with measurable disease in the BM DNA (ie, 70% sensitivity). These results demonstrate that MRD assessment using PB RNA is more informative than PB DNA in MM; however, despite the sensitivity improvement provided by RNA, MRD assessment in the BM DNA remains the superior sample source for MRD assessment, particularly when achievement of MRD negativity is the goal of therapy. Conclusions: NGS-based MRD assessment of BM in myeloma patients has been shown to have prognostic value. PB-based MRD assessment would improve clinical MRD assessment and monitoring paradigms. Our results demonstrate that RNA provides increased sensitivity for blood-based MRD assessment. Additional assay optimization to improve the fraction of clonotypes evaluable in RNA and to enhance sensitivity compared with BM is necessary before PB MRD monitoring in MM patients can be incorporated into routine clinical practice. Figure Figure. Disclosures Wolf: Telomere Diagnostics: Consultancy; Pharmacyclics: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Kong:Adaptive Biotechnologies Corp: Employment, Equity Ownership. Bayes:Adaptive Biotechnologies Corp: Equity Ownership. Carlton:Adaptive Biotechnologies: Employment, Equity Ownership. Martin:Sanofi: Research Funding; Amgen: Research Funding.
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Shan, Xiaochuan, Cedric Dos Santos, Chenghui Zhou, et al. "Improved Patient-Derived Xenograft Model for Acute Myeloid Leukemia." Blood 124, no. 21 (2014): 3491. http://dx.doi.org/10.1182/blood.v124.21.3491.3491.
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Abstract We previously demonstrated that the NSG (NOD-Scid-IL2Rgcnull) xenotransplantation is an improved model for human AML samples, allowing us to better understand and characterize AML biology, especially in the context of drug therapy studies (Sanchez et al., Leukemia 2009). However, we observed that approximately half of AML patients’ samples either did not engraft in NSG mice (based on <0.1% human blasts in mouse bone marrow) or showed low (0.1 to 1% blasts) and highly variable engraftment. Recently, NSG mice expressing human SCF, GM-CSF and IL-3 transgenes (NSG-S) have been reported to enhance the engraftment of normal hematopoietic stem cells and primary AML cells, although only a few AML patients were evaluated (Wunderlich M et al, Leukemia 2010). This report describes a comprehensive paired analysis of engraftment of AML samples in NSG and NSG-S mice. T-cell depleted AML cells (5 -10 x 106 per mouse) were injected intravenously in sub-lethally irradiated mice (n=5/AML sample). Leukemia engraftment was assessed up to 16 weeks after injection in peripheral blood (PB), spleen (SPL) and bone marrow (BM) based on the percentage and absolute number of human leukemic blasts (huCD45+CD33+/-CD3-) in each tissue. Samples from 71 AML patients, representing all FAB and prognosis groups, were injected in NSG mice and only 35 samples (49%) engrafted based on human blasts >0.5% in mouse BM. From these 35 NSG-engrafting samples, 14 were also injected in NSG-S mice and all of them engrafted. Leukemic burden was significantly (p ≤ 0.05) increased in NSG-S versus NSG mice: 39±21% vs 22±23% BM blasts, 21±15% vs 7±10% SPL blasts, 2,732±6,488 vs 141±221 blasts/ml PB. Interestingly, the dramatic increase in peripheral blast count observed in NSG-S mice provides new opportunities to use PB to monitor drug response for the many patient samples that show no or very low peripheral engraftment in NSG mice. However, for 7 of these 14 NSG-engrafting AML samples, the use of NSG-S mice as recipients was associated with rapid engraftment, excessive leukemic burden, anemia, weight loss and lethargy requiring early sacrifice and leading to shorter overall survival (54±26 days in NSG-S vs >90 days in NSG). Out of the 36 patients’ samples that failed to engraft in NSG mice, 19 were tested for engraftment in NSG-S mice. Remarkably, 14 out 19 (74%) samples engrafted (17±16% BM blasts, 8±12% SPL, and 1,418±4,609/ml PB blasts at Day 77 post-transplant) and the kinetics of engraftment were slower compared to AML samples that can engraft in both mouse strains. These results suggest that the presence of human SCF, GM-CSF and IL-3 in NSG-S is sufficient to rescue leukemia-initiating cells for most AML samples that fail to engraft in NSG mice. Only 5 out of 33 samples (15%) failed to engraft in NSG and NSG-S mice, indicating that the NSG-S BM microenvironment remains suboptimal for a small minority of AML samples. We are investigating if NSG-S engraftment is correlated to CD116, CD117, CD123 expression, cytogenetics, mutations, and prognosis. Overall, our results show that NSG-S mice represent a significant improvement over previous patient-derived xenograft models since they can (1) accelerate and enhance leukemic engraftment compared to NSG mice, and (2) support engraftment for 85% of our AML patients, making this model particularly useful for pre-clinical studies. Disclosures Dos Santos: Janssen R&D: Research Funding. Danet-Desnoyers:Janssen R&D: Research Funding.
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Argyriou, A., M. H. Wadsworth, A. Lendvai, et al. "OP0072 SINGLE CELL SEQUENCING REVEALS CLONALLY EXPANDED CYTOTOXIC CD4+ T CELLS IN THE JOINTS OF ACPA+ RA PATIENTS." Annals of the Rheumatic Diseases 80, Suppl 1 (2021): 38.1–39. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1403.
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Background:CD4+ T cells with cytotoxic functions (CD4+ CTL) have gained attention in recent years. Accumulating evidence supports their importance in defense against human viral infections such as CMV1, EBV2, dengue3, HIV4, 5 and SARS-CoV-26. Moreover, expansion of so called CD28null cytotoxic CD4+ T cells have been reported in the blood of patients with rheumatic diseases such as rheumatoid arthritis (RA)7, myositis8 and vasculitis9 as well as in cardiovascular diseases10.Objectives:Here, we aimed to investigate the presence and clonal expansion of CD4+ CTL in the peripheral blood (PB) and synovial fluid (SF) of RA patients using single cell technologies.Methods:We assessed the expression of cytotoxic effector molecules and transcription factors in CD4+ T cells in synovial fluid (n=21) and paired peripheral blood (n=16) from ACPA- and APCA+ RA patients by multi-parameter flow cytometry. We performed single cell sequencing, in combination with 5´ TCRab sequencing, on purified CD4+ T cells from the peripheral blood (PB) and synovial fluid (SF) of ACPA+ RA patients (n=7).Results:Flow cytometry experiments show that Granzyme-B+ Perforin-1+ CD4+ CTL are significantly increased in the SF of ACPA+ RA patients as compared to ACPA- RA patients (p=0.0072). The presence of CD4+ CTL could be confirmed by single cell sequencing in SF of each ACPA+ RA patient tested (n=7). Moreover, we found that the adhesion G-protein coupled receptor GPR56 is selectively expressed on the recently described peripheral helper (TPH) T-cell subset11 and associates with the expression of tissue resident memory markers LAG-3, CXCR6 and CD69. In blood, we confirmed a previous report12 showing that GPR56 delineates cytotoxic CD4+ T cells. Finally, expanded TCR clones expressing cytotoxic effector molecules were identified in synovial fluid of ACPA+ RA patients and, for some patients, in their corresponding peripheral blood.Conclusion:We identified GPR56 as a marker of TPH cells in SF of ACPA+ RA patients that associates with tissue residency receptors. The combination of single cell sequencing and multi-parameter flow cytometry highlights the importance of CD4+ CTL in ACPA+ RA and suggests a potential therapeutic target (Figure 1).References:[1]Casazza J. P. et al., J Exp Med2006,203 (13), 2865-77.[2]Landais E. et al., Blood2004,103 (4), 1408-16.[3]Kurane I. et al. J Exp Med1989,170 (3), 763-75.[4]Appay V. et al. J Immunol2002,168 (11), 5954-8.[5]Juno J. A. et al. Front Immunol2017,8, 19.[6]Meckiff B. J. et al. Cell2020,183 (5), 1340-1353 e16.[7]Schmidt D. et al. J Clin Invest1996,97 (9), 2027-37.[8]Fasth A. E. et al. J Immunol2009,183 (7), 4792-9.[9]Moosig F. et al. Clin Exp Immunol1998,114 (1), 113-8.[10]Sato K. et al. J Exp Med2006,203 (1), 239-50.[11]Rao D. A., et al. Nature2017,542 (7639), 110-114.[12]Peng Y. M. et al. J Leukoc Biol2011,90 (4), 735-40.Acknowledgements:We thank the patients who donated samples and the medical staff at the Rheumatology Clinic of Karolinska University Hospital. Julia Boström, Gloria Rostvall, and Susana Hernandez Machado are acknowledged for organizing the sampling, storage, and administration of biomaterial. This study is supported by grants from Dr. Margaretha Nilssons, the Nanna Svartz, the Ulla and Gustaf af Ugglas foundations and the Swedish association against rheumatism.Disclosure of Interests:Alexandra Argyriou: None declared, Marc H Wadsworth II Employee of: Pfizer, Inc, Cambridge, MA 02139, United States, Adrian Lendvai: None declared, Stephen Christensen Employee of: Pfizer, Inc, Cambridge, MA 02139, United States, Aase Hensvold: None declared, Christina Gerstner: None declared, Kellie Kravarik Employee of: Pfizer, Inc, Cambridge, MA 02139, United States, Aaron Winkler Employee of: Pfizer, Inc, Cambridge, MA 02139, United States, Vivianne Malmström: None declared, Karine Chemin: None declared
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GROSCLAUDE, F., Y. GEAY, and M. H. FARCE. "Avant-propos." INRAE Productions Animales 9, HS (1996): 3. http://dx.doi.org/10.20870/productions-animales.1996.9.hs.4078.
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Je pense, écrivait Auguste Comte, qu’on ne connaît pas complètement une science tant qu’on n’en connaît pas l’histoire. N’y a-t-il pas là, sur l’intérêt de la connaissance historique, une remarque de portée très générale ? En vérité peut-on réellement comprendre et aimer un institut de recherches comme le nôtre sans s’être tant soit peu penché sur son passé ?
 Cette attention à l’histoire ne présente pas qu’un simple intérêt culturel. Tirer les enseignements des succès et des échecs, comprendre le sens des évolutions, doit permettre de poser en termes plus pertinents et plus précis les problèmes d’actualité et les questions pour demain. Le rôle de l’INRA dans la prise en compte par les producteurs des critères de qualité des produits en fournit un parfait exemple.
 On reproche en effet parfois à l’INRA d’avoir surtout œvré, dans le passé, pour accroître les quantités produites au détriment de "la" qualité. Cette affirmation mérite d’être confrontée aux faits. Dès les débuts des recherches zootechniques, dans les années cinquante, le généticien Paul Auriol et le technologue Germain Mocquot lanaient, dans le Jura, un programme de testage des taureaux montbéliards sur les qualités fromagères des laits de leurs filles. Ds 1951, un des tout premiers chercheurs du Centre de recherches zootechniques de Jouy-en-Josas, Bernard-Louis Dumont, publiait, dans le premier numéro des Annales de Zootechnie, une synthèse détaillée sur la tendreté de la viande et ses facteurs de variation. En 1961, Fernand Ricard publiait, dans le même Journal, les résultats d’un travail sur les qualités organoleptiques de la viande de poulet... L’observateur attentif comprendra vite que s’il y a eu prise en compte insuffisante par les filières des critères de qualité, les raisons pourraient en être recherchées ailleurs que dans les orientations de l’INRA. Il se trouvera renvoyé à des problèmes tels que celui du niveau de rémunération des efforts d’amélioration de la composition du lait consentis par les éleveurs, ou celui du manque de prédicteurs simples, in vivo, de la qualité des viandes. Or ce type de questions est toujours d’actualité. On voit donc à quel point il est important d’analyser l’évolution historique des problèmes dans leur contexte ainsi que la nature et la pertinence des réponses qui ont pu être apportées à chaque époque.
 Ainsi, c’est non seulement pour commémorer, témoigner ou laisser des traces, mais aussi pour éclairer les réflexions actuelles qu’il a paru inté.ressant et utile de rassembler en un document anniversaire, des analyses historiques de l’évolution de nos travaux dans un certain nombre de domaines. Ce document n’a pas la prétention d’être exhaustif. Il présente, pour chacun des cinq départements de recherches constituant le secteur des productions animales, quelques exemples représentatifs de ses axes de recherche. Par-delà la diversité des thèmes et de leur mode de traitement, on sentira sans doute une grande communauté de pensée, liée au souci de toutes les équipes, permanent depuis les origines, de répondre aussi efficacement que possible aux objectifs de l’Institut. Ces textes mettent aussi très bien en évidence le rôle joué par les progrès - parfois décisifs - des techniques, par le hasard ou la chance, et surtout par la qualité et la ténacité des équipes. Ils sont autant de sources de réflexion stimulantes.
 Je remercie très sincèrement tous ceux qui, malgré leurs charges, ont contribué à la réalisation de cet ouvrage. Il aura, j’en suis certain, une place à part dans nos bibliothèques.
 F. GROSCLAUDE Directeur scientifique des Productions Animales
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Yong, Agnes S. M., Keyvan Keyvanfar, Rhoda Eniafe, et al. "The Level of Minimal Residual Disease in Primitive Progenitor Cells from CML Patients after Allogeneic Stem Cell Transplantation Is Higher Than after Treatment with Tyrosine Kinase Inhibitors." Blood 112, no. 11 (2008): 1107. http://dx.doi.org/10.1182/blood.v112.11.1107.1107.
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Abstract The advent of imatinib, and subsequently, other tyrosine kinase inhibitors (TKIs) has relegated allogeneic stem cell transplantation (SCT) to second-or third-line therapy for chronic phase-chronic myeloid leukemia (CML). A significant shortcoming of TKIs in the large majority of good-responder patients is the persistent detection of BCR-ABL transcripts despite achievement of complete cytogenetic response (CCyR) or major molecular response (greater than 3-log reduction of BCR-ABL levels below a standardized baseline in minimal residual disease (MRD) measurements from total mononuclear cells). The presence of this MRD, and the demonstration that primitive CD34+ cells from patients in CCyR still harbor BCR-ABL (Bhatia, et al, Blood 2003) strengthens the opinion that TKIs do not eradicate all CML cells. Conversely, SCT has apparently cured some CML patients with more than 20 years follow-up. Of note, MRD is also quite frequently found in CML patients more than 5 years post-SCT, and donor lymphocyte infusions (DLI) are usually given to patients who satisfy criteria for molecular relapse. We compared the level of BCR-ABL transcripts in primitive hematopoietic cells from patients who were treated with T-depleted SCT with scheduled T-cell addback from D+45 to D+100 post-SCT (n=34) with levels in those taking TKIs (n=4). CD34+ progenitor cells were isolated from leukapheresis collections at D+120 post-SCT (n=13), peripheral blood from D+60 – 66 months post-SCT (n=19), bone marrow aspirates in patients on long-term follow-up (4–10 years) post-SCT (n=8) or 15 – 18 months post-TKI treatment alone (n=4); serial post-SCT samples were available in 6 patients. Using fluorescence activated cell sorting, hematopoietic stem cells (HSC, CD34+CD38-Lin-CD90+), common myeloid progenitors (CMP, CD34+CD38+Lin-IL3Rα+CD45RA-) and granulocyte-macrophage progenitors (GMP, CD34+CD38+Lin-IL3Rα+CD45RA+) were collected. BCR-ABL expression in primitive CD34+ subpopulations and total leukocytes from peripheral blood (PB) was measured using real-time quantitative polymerase chain reaction, with the sensitivity to detect one BCR-ABL-positive cell in 106 normal cells. A median of 112 x 106 mononuclear cells (range 16 – 582 x 106) were available per patient sample, with a median of 3 x 106 CD34+ cells (range 1 – 90 x 106) sorted. There was no difference between the number of HSC, CMP or GMP CD34+ cells collected between MRD negative or MRD positive-post-SCT patients, or TKI-treated patients. All patients with negative MRD in PB (n=12 post-SCT, n=1 post-TKI) did not have detectable BCR-ABL transcripts in primitive CD34+ subpopulations. Furthermore, in PB MRD-positive patients, 3/21 (14%) post-SCT and 2/2 (100%) post-TKI did not have detectable BCR-ABL transcripts in HSC, CMP or GMP populations. 18/21 (86%) PB MRD-positive patients who were post-SCT had detectable BCR-ABL transcripts in at least one primitive CD34+ subpopulation. A rise in BCR-ABL levels in GMP populations tended to herald impending relapse. In post-SCT patients on long-term follow-up with persistent PB MRD positivity not fulfilling criteria for molecular relapse, the highest BCR-ABL levels were in HSC populations. In comparable patients with a major molecular response, post-SCT patients appeared to harbor a greater amount of residual leukemia cells in CD34+ subpopulations than TKI-treated patients. Our observations suggest that although SCT is a curative treatment for CML, the graft-versus-leukemia effect may eliminate only more mature leukemic CD34+ subpopulations in some patients who have enduring positive MRD post-SCT, with persistence of the most primitive leukemic HSCs, which are presumably constrained in patients who do not fulfill criteria for relapse. Conversely, TKI appears to reduce the number of BCR-ABL-positive primitive CD34+ subpopulations, especially GMPs and CMPs, more efficiently. Our data support TKI-treatment as an adjunct to DLI to treat CML relapse post-SCT, and concurrent vaccination strategies which are able to target surface proteins on HSC to eradicate disease.
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Henrique, Pedro Felipe de Lima, Ingrid Cruz Nascimento, and Lucas Possatti. "A mudança na produção de fricativas em coda medial por uma criança recifense residente em João Pessoa." Domínios de Lingu@gem 13, no. 4 (2019): 1526–56. http://dx.doi.org/10.14393/dl40-v13n4a2019-8.
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Este estudo compara a produção de fricativas em coda medial de uma informante recifense de 10 anos, residente em João Pessoa-PB, com a produção de duas crianças pessoenses e duas recifenses de mesma idade, que nunca saíram de sua comunidade de fala, averiguando em que medida a criança que mudou de cidade assimilou o dialeto pessoense. A diferença entre o comportamento da fricativa em Recife-PE, onde predomina a forma palatalizada (MACEDO, 2004), e em João Pessoa-PB, onde predomina a forma alveolar (HORA, 2003), suscitou a seleção da variável. Coletaram-se amostras de fala mediante inquérito fonético, leitura monitorada e entrevista semiestruturada. As palavras dos primeiros instrumentos foram escolhidas pensando-se no contexto fonológico anterior e seguinte, considerados como variáveis independentes para a aplicação da regra de palatalização. Analisaram-se as fricativas no Praat (BOERSMA; WEENINK, 2009) atentando para o pico espectral, que indicou o grau de palatalização (HENRIQUE et al., 2015), considerado como variável dependente. Como resultados, constatou-se que as fricativas produzidas pela informante recifense, residente em João Pessoa, não apresentaram diferença significativa com relação às crianças pessoenses, diferentemente das produzidas pelas crianças recifenses. Inferiu-se, portanto, que a criança assimilou o dialeto da comunidade onde vive atualmente, que tem apenas o contexto coronal /t/ e /d/ como gatilho para a palatalização. Analisam-se esses resultados à luz do processo de aquisição do segmento fricativo em coda por crianças (OLIVEIRA, 2002; MEZZOMO, 2003; BERTI, 2006) e de novas perspectivas inerentes à Sociolinguística e à comunidade de fala (LABOV, 2008; GUY, 2000).
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Jain, Nitin, Sreyashi Basu, Beenu Thakral, et al. "Defining the Immune Checkpoint Landscape in the Bone Marrow and Peripheral Blood of Patients with Chronic Lymphocytic Leukemia (CLL)." Blood 128, no. 22 (2016): 2012. http://dx.doi.org/10.1182/blood.v128.22.2012.2012.
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Abstract Background: Limited data is available on expression levels of checkpoint receptors, respective ligands, and other immune markers in patients with CLL (Ramsay et al. Blood 2012). Checkpoint blockade has been a successful therapy of many cancers including melanoma, and more recently, Hodgkin's lymphoma. Understanding expression patterns of checkpoint receptors and ligands may help in the clinical development of checkpoint blockade as a therapy for patients with CLL. Methods: Between September 2015 and April 2016, we performed 17-color multi-parameter flow-cytometry (MFC) in paired peripheral blood (PB) and bone marrow (BM) samples from 30 patients with CLL who presented as new patients for evaluation at MDACC. Patients may have received prior CLL therapy. We evaluated expression of immune receptors (inhibitory receptors: PD1, CTLA4, LAG3, TIM3; activating receptors: GITR, OX40, 41BB, ICOS) on T cell subsets: CD4 T effector cells [Teff]: CD3+CD4+CD127lo/+Foxp3-, CD4 T regulatory cells [Treg]: CD3+CD4+CD127-Foxp3+, and CD8 T cells. CLL cells were assessed for both immune receptors (as above), and ligands (4-1BBL, B7-1, B7-2, ICOSL, PDL-1, PDL-2, OX40L). These analyses were performed on freshly collected PB and BM samples by the M. D. Anderson Cancer Center Immunotherapy Platform. Results: A total of 30 patients with CLL were enrolled. The median age was 66 years (range, 35-83). Nine were women. Nineteen were treatment-naive. Prognostic markers included FISH [del(17p) = 6; del(13q) = 9, del(11q) = 4, trisomy 12 = 3, negative = 8]. IGHV mutation status was available for 19 patients (13 unmutated IGHV, 6 mutated IGHV). B2M was ≥3.5 in 11 pts. Baseline expression of costimulatory receptors in CD8 T cells in the marrow, and of the ligands in CLL cells in the marrow is shown in Figure 1. In paired PB and BM sample analysis, there was a high correlation between expression level of PD1 on Treg (Pearson correlation, r = 0.90, p<0.00001), Teff (r = 0.87, p<0.00001), CD8+ cells (r = 0.80, p<0.00001), and CLL cells (r = 0.75, p<0.00001). PD-L1 expression on CLL cells was moderately correlated between PB and BM (r = 0.57, p<0.001). Patients with prior therapy had significantly higher expression of PDL1 on the CLL cells in both PB and BM (p=0.01 and p=0.002, respectively) compared to previously untreated patients. OX40 expression on CD8 cells was significantly higher in both PB and BM in previously treated patients (compared to previously untreated patients). Patients with unmutated IGHV (p = 0.003) and del17p (p = .03) had higher PDL1 expression on CLL cells in the marrow. Conclusions: There is a strong correlation in the expression levels of PD1 on various T cell subsets between PB and BM. Clinically targetable checkpoint receptors including PD1, OX40, CTLA4, and ICOS are consistently expressed across patients with CLL, and present on cells in both PB and BM. Disclosures Jain: BMS: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Infinity: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Gilead: Research Funding. Thompson:Pharmacyclics: Consultancy, Honoraria. Daver:Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding. Wierda:Acerta: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Abbvie: Research Funding.
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Shang, L., T. Zhang, J. Luo, et al. "FRI0261 DIFFERENTIAL EXPRESSION OF PERIPHERAL CD4+ T CELLS IN PATIENTS WITH SYSTEMIC SCLEROSIS AND MIXED CONNECTIVE TISSUE DISEASE." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 714.1–715. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1671.
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Background:The CD4+T cell subsets plays an important role in its pathogenesis, and its new research are constantly being published, but its specific changes between SSc and MCTD are still unclear.Objectives:The aim of the present study was to explore the absolute numbers of CD4+T subsets in peripheral blood(PB) of patients with SSc and MCTD using our modified flow cryometric method and investigate the role in the pathogenesis of both.Methods:The PB samples from 54 patients with SSc, 51 patients with MCTD as well as 30 healthy control subjects were analyzed for lymphocyte subsets using flow cytometry. Of these patients, 19 had pulmonary involvement, including 9 patients with SSc and 10 patients with MCTD. Using directly the percentages from flow cytometry combined with internal standard beads calculated absolute number of peripheral lymphocyte subsets from the subjects in each group.Results:Although there were some changes among CD4+T cell subsets in PB from these SSc patients and MCTD patients, the major alteration was the reductions of Treg cells. Compared with the normal controls, the absolute number of CD4+CD25+FOXP3+Treg cells were significantly decreased in SSc patients and MCTD patients, and the absolute number of Th1 cells in MCTD patients is also significantly reduced. Notably, the absolute numbers of Th17 and Th2 cells were not different from those of normal controls, but the ratios of Th17/Treg in SSc patients and MCTD patients were significantly higher, causing by insufficient number of Treg cells (Fig 1). In addition, in patients with pulmonary involvement, we found that the absolute number of Treg cells was significantly reduced in patients with MCTD, while the absolute number of Th2 cells and Th17 cells was significantly reduced in patients with SSc(Fig 2).Fig 1.Comparison of the levels of CD4+T lymphocyte subsets in SSc patients, MCTD patients and healthy controls: (A) The absolute number of peripheral Th1 cells in patients with MCTD was significantly reduced; (B and C) There was no significant difference in the absolute number of Th2 cells in peripheral blood of different subjects; (D and E) The ratio of Th17/Treg cells in PB of patients with SSc and MCTD were significantly higher.*P< 0.05; **P< 0.01; ***P< 0.001.Conclusion:The number of peripheral Treg cells in patients with SSc and MCTD was significantly reduced, suggesting that that SSc and MCTD progression is associated with the imbalances between pro-inflammation cells to anti-inflammation Treg cells. In addition, we also found that the decrease in peripheral numbers of Treg cells may contribute to the development of MCTD-associated lung disease, whereas in SSc patients who had lung involvement, the reduce in peripheral number of Th17 cells may result in a severe imbalance of Th17/Treg cells, thereby promoting disease progression.Fig 2.Comparison of the levels of CD4+T lymphocyte subsets in patients who had pulmonary involvement and healthy controls: (A) There was no significant difference in the absolute number of Th1 cells in peripheral blood of different subjects; (B and C) The absolute number of peripheral Th2 cells and Th17 cells in patients with SSc were significantly reduced; (D and E) The ratio of Th17/Treg cells in PB of patients with MCTD were higher.*P< 0.05; **P< 0.01; ***P< 0.001.References:[1]Liu M, Wu W, Sun X, et al. New insights into CD4(+) T cell abnormalities in systemic sclerosis. Cytokine Growth Factor Rev. 2016 Apr; 28:31-6. doi: 10.1016/j.cytogfr.2015.12.002.Acknowledgments:NoneDisclosure of Interests:None declared
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Du, Zhao Fu, Sam Zhang, Hui Ding, Lei Wang, Hong Ping Zhang, and Dong Liang Zhao. "Variation of Magnetoelectric Coefficient with Volume Fraction of Piezoelectric Phase in Pb(Mg1/3Nb2/3)O3-PbTiO3/FeCoV Laminate Composite." Materials Science Forum 848 (March 2016): 23–27. http://dx.doi.org/10.4028/www.scientific.net/msf.848.23.
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Soft magnetic material FeCoV is sensitive to magnetic field and its cost is lower than giant magnetostriction materials (Terfenol-D et al.). In the present investigation Pb (Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) with different thickness and FeCoV laminate with 0.8mm thickness were assembled into layer structure to study the effect of the PMN-PT volume fraction on the magnetoelectric coefficient of PMN-PT/FeCoV laminate composites. The ME coefficients and voltages have been characterized in the longitudinally magnetized and transversely polarized mode. The measurement was conducted under a static magnetic field superimposed with an alternating magnetic field. The influences of the static and the alternating field strength were discussed. The peak ME coefficient was obtained at 430 Oe. With the volume fraction of PMN-PT increased, the ME coefficient decreased within the experiment fraction. It can be explained by the module of M.I.Bichurin. A linear relationship was observed between the magnetoelectric voltage and the alternating field strength under a static field of 400 Oe. The ME voltage decreased when the PMN-PT volume fraction increased in the experiment fraction.
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Gagnevin, Damien. "Erratum to D. Gagnevin, J. S. Daly, T. E. Waight, D. Morgan, and G. Poli (2005) “Pb isotopic zoning of K-feldspar megacrysts determined by Laser Ablation Multi-Collector ICP-MS: Insights into granite petrogenesis”, Geochimica et Cosmochimica Acta 69, 1899–1915." Geochimica et Cosmochimica Acta 69, no. 21 (2005): 5171. http://dx.doi.org/10.1016/j.gca.2005.05.001.
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Alem, Hernandes Martins, Lígia Regina Lima Gouvêa, Guilherme Augusto Peres Silva, Andre Luíz Bombonato de Oliveira, and Paulo de Souza Gonçalves. "Avaliação de clones de seringueira para a região noroeste do Estado de São Paulo." Revista Ceres 62, no. 5 (2015): 430–37. http://dx.doi.org/10.1590/0034-737x201562050002.
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RESUMOSão Paulo é o Estado no qual clones de seringueira (Hevea brasiliensisWilld. ex Adr. de Juss.) Muell. Arg. têm apresentado maior produtividade de borracha, no Brasil. O objetivo deste estudo foi avaliar a produção de borracha e o vigor de 14 clones de seringueira, implantados na região de Votuporanga, além de averiguar mudanças na tendência da correlação anual, para analisar a possibilidade de uma seleção precoce, com base nos caracteres estudados. Para isso, a produção de borracha, em gramas árvore-1sangria-1, foi avaliada, utilizando-se o sistema de sangria 1/2S d/4 5d/7 11m/y ET 2,5%. O período de avaliação da produção de borracha foi de oito anos. O vigor, também, foi analisado, medindo-se o perímetro do caule por 16 anos. Os clones IRCA 111 e PB 235 tiveram os melhores desempenhos de produção de borracha. Os clones IAC 15 e IAC 44 apresentaram os melhores resultados de vigor. As correlações genéticas e fenotípicas foram significativas e positivas entre todos os anos de produção. Para o vigor, a significância dos coeficientes de correlação genotípica e fenotípica diferiram na pré-sangria e na pós-sangria. Pelos valores de produção de borracha observados, os clones IRCA 111 e PB 235 são considerados favoráveis à recomendação em pequena escala para a região de Votuporanga. Com base nos resultados obtidos, é possível realizar uma seleção precoce para o caráter de produtividade, usando-se os dados obtidos no primeiro ano de avaliação. Por causa das diferenças observadas entre os períodos de pré-sangria e pós-sangria, não é aconselhável realizar uma seleção precoce no período de pré-sangria, visando ao caráter de vigor.
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Bai, J., S. X. Zhang, L. Zheng, et al. "SAT0357 LEVELS OF PERIPHERAL LYMPHOCYTE SUBPOPULATIONS IN PATIENTS WITH ANKYLOSING SPONDYLITIS AND THEIR CHANGES AFTER RECEIVING IMMUNOREGULATORY COMBINATION THERAPIES." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1125–26. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1853.
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Background:Ankylosing spondylitis is an immune-mediated inflammatory disease involving of the axial skeleton, joints, and entheses1. Although the homeostatic balance of effector T cells (Teffs) and regulatory T cells (Tregs) is considered to play an important role in the pathogenesis of ankylosing spondylitis(AS)2, it is unclear whether the levels of peripheral blood lymphocyte subpopulations in patients with ankylosing spondylitis are abnormal or not.Objectives:To explore the differences of lymphocyte subpopulations of peripheral blood (PB) between AS patients and healthy controls (HCs), and further evaluate the therapeutic effect of immunoregulatory drugs on the lymphocyte subpopulations.Methods:Total 1141 patients with AS and 206 healthy individuals were enrolled in the study and donated their blood to measure the levels of T, B, NK, CD4+T, CD8+T, Th1, Th2, Th17 and Tregs by flow cytometry combined with standard absolute counting beads. And 456 patients received immunoregulatory combination treatments which includes low-dose interleukin-2, rapamycin, metformin, retinoic acid etc. and donated their PB after the therapies. Data were expressed as mean ± standard deviation to the distribution. Independent-samples T test and paired-samples T test were applied.Pvalue <0.05 were considered statistically significant.Results:Compared with HCs, AS patients had a lower absolute number of Tregs but higher numbers of peripheral T, B, CD4+T, CD8+T and Th17 cells (P<0.05). Further, there was a significant increase in the percentage of B, CD4+T and the ratios of Teffs/Tregs such as Th1/Tregs, Th2/Tregs and Th17/Tregs compared with HCs (P<0.05)(Figure 1). Although, after receiving the immunoregulatory combination treatments, the absolute numbers of various peripheral lymphocyte subpopulations such as T, B, NK, CD4+T, CD8+T, Th1, Th17 and Tregs and the percentage of Tregs, Th1 and CD8+T significantly increased (P<0.05), the ratios of Th2/Tregs significantly decreased (P<0.05)(Figure 2), suggesting a rebalance of immune systems.Conclusion:The insufficiency of Tregs may involve in pathogenesis of AS. Immunoregulatory combination therapies could promote the proliferation of Tregs as well as other lymphocytes to some degree, which may be a new target for AS treatment.References:[1]van der Heijde D, Song IH, Pangan AL, et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet 2019;394(10214):2108-17. doi: 10.1016/S0140-6736(19)32534-6 [published Online First: 2019/11/17][2]Xu D, Fan J, Chen Q, et al. OP0028 Low dose IL-2 therapy can recovery TH17/TREG cell balance in patients with ankylosing spondylitis. Oral Presentations, 2017:63.1-63.Disclosure of Interests:None declared
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Chu, Yaya, Julie-An Talano, Lee Ann Baxter-Lowe, et al. "Sustained Donor Chimerism and Rapid Immune Cell Reconstitution Following Familial Haploidentical (FHI) CD34 Enriched Stem Cell Transplantation with Pbmnc Addback in Patients with High Risk Sickle Cell Disease (SCD) (IND 14359)." Blood 134, Supplement_1 (2019): 1990. http://dx.doi.org/10.1182/blood-2019-126757.
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Background: Allogeneic stem cell transplantation (AlloSCT) from an HLA-matched sibling donor is the only known curative therapy in patients with high-risk SCD (Talano/Cairo, EJH, 2015). Unfortunately only about 15% of high risk patients with SCD have an HLA-matched unaffected sibling donor. T cell depletion has been employed to reduce AGVHD e.g., CD3/CD19 cell depletion (Barfiled RC, et al, Cytotherapy, 2004), αβ T-cell/CD19 cell depletion (Locatelli F, et al, Blood, 2017), CD34+ positive selection (Aversa F, et al, NEJM, 1998). MUD transplantation in high-risk SCD recipients has shown unexpectedly high rates of CGVHD (Shenoy et al, Blood, 2016). We reported a very low incidence of acute and chronic GVHD in pediatric recipients receiving CD34 enriched HPC products with PB MNC addback with 2 x 105 CD3/kg from MUD donors (Geyer/Cairo et al, BJH, 2012). Furthermore, rapid NK cell reconstitution after AlloSCT is associated with a significant improvement in 1yr OS (Pical-Izard, BBMT, 2015; Dunbar et al, Hematologica, 2008). Recently, we reported promising results for high-risk SCD patients at 1 year follow-up after FHI CD34 enriched/PBMNC with addback AlloSCT with the probability of 1-year overall survival (OS) n=17; 88.2% (CI95: 60.6-96.9) (Talano/Cairo, ASH, 2017), expanding the donor pool and hopefully improving outcomes for high-risk patients with SCD. Objective: To investigate donor chimerism, immune cell reconstitution and NK cell function in high-risk patients with SCD following AlloSCT using FHI CD34 enrichment/PBMNC (2 x 105 CD3/kg) addback. Methods: Twenty-one eligible SCD patients (2-<21 yrs) were enrolled. Nineteen patients received hydroxyurea, azathioprine, fludarabine, busulfan, thiotepa, cyclophosphamide, R-ATG, and TLI followed by FHI AlloSCT to date (Talano/Cairo, ASH, 2017). CD34 cells were enriched using the CliniMACS® system, kindly provided by Miltenyi Biotec, with a target dose of 10 x 106 CD34+ cells/kg with a PBMNC addback dose of 2x10*5 CD3/kg in the final product. Whole blood and RBC chimerism (estimated using CD71 to isolate an eythroid lineage-enriched fraction) were determined by STR. Immune cell and subset reconstitution was assessed by flow cytometry as previously described (Geyer/Cairo et al. BJH, 2012). NK function was determined by cytotoxic activity against K562 tumor targets at 10:1 E:T ratio by europium release assay and intracellular LAMP-1 (CD107a) and granzyme B expression by flow cytometry as previously described (Chu/Cairo et al, Can Imm Res, 2015). Results: There was 100% engraftment of neutrophils and platelets. The median day post-HISCT to neutrophil and platelet engraftment was +9 and +19, respectively. Whole blood donor chimerism (mean±SEM) at 1-year, 2-year, and 3-year post-HISCT was 97±1%, 97±1%, 97±1%, respectively (Fig.1). Donor chimerism for CD71+ RBCs (mean±SEM) at 1-year, 2-year, 3-year post-HISCT was 97±2%, 98±1%, 98±1%, respectively (Fig.1). Immune reconstitution of CD3, CD4, CD8, and CD19 was evaluated. The time to recovery of minimally normal levels post-HISCT of CD3 (800 cells/ul), CD4 (400 cells/ul), CD8 (200 cells/ul), and CD19 (200 cells/ul), was approximately 365, 365, 270, and 60 days post-HISCT (Fig.2), respectively. Probability of Grade II-IV AGVHD, CGVHD and 1 year EFS/OS was 6.2%, 6.7% and 90%, respectively. NK reconstitution was rapid and peaked at d+30 (36±9%, 2710cells/ml). NK cytotoxicity against K562 at a E:T=10:1 peaked at d+30 (26±3%) and d+180 (28±3%) vs at pre-t (16±2%) (p<0.01) (Fig. 3A). Consistent with increased NK cytotoxicity, CD56dimCD3- subset was increased at d+30 vs pre- HISCT (p<0.05). The NK activation marker, CD107a peaked at d+30 (38±9%) and d+180 (41±6%) (Fig.3B). More over, reconstituted NK cells expressed higher level of activating receptors NKp46 (24±9%), NKG2D (32±9%) and KIR2DS (8±3%) and inhibitory receptors NKG2A (33±9%), CD94 (28±9%) and KIR2DL2/3 (11±2%) at d+30 compared to other time points. Conclusion: Despite a 5 log depletion of T cells, the PBMNC addback (fixed at 2 x 105 CD3/kg) facilitated rapid donor chimerism and immune reconstitution with a low probability of Grade II-IV AGVHD. The rapid NK reconstitution may have in part contributed to the excellent 1yr OS in the FHI study. (Supported by FDA R01FD004090 (MSC)). Disclosures Cairo: Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau; Osuka: Research Funding; Miltenyi: Other: MTA.
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Zhang, J., and Z. J. Wu. "First Report of Kudzu mosaic virus on Pueraria montana (Kudzu) in China." Plant Disease 97, no. 1 (2013): 148. http://dx.doi.org/10.1094/pdis-07-12-0671-pdn.
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Kudzu (Pueraria montana), a weed widely distributed in southern China, is common in the Fuzhou region of Fujian Province, where many plants show yellow vein mosaic disease. In September 2008, four leaf samples from different plants exhibiting yellow vein mosaic symptom were collected in suburban district of Fuzhou (25°15′ N, 118°08′ E). Whitefly (Bemisia tabaci) infestation was also observed in this region. Total DNA was extracted from all samples using a CTAB method (4). Universal primers (PA/PB) were used to amplify part of the intergenic region and coat protein gene of DNA-A of begomoviruses (1). An amplicon of approximately 500 bp was obtained from all four samples and then sequenced. Comparison of 500-bp fragments (GenBank Accession Nos. FJ539016-18 and FJ539014) revealed the presence of the same virus (98.8 to 99.4%). A pair of back-to-back primers (Yg3FL-F: 5′-GGATCCTTTGTTGAACGCCTTTCC-3′/Yg3FL-R: 5′-GGATCCCACATGTTTAAAGTAAAGC-3′) were designed to amplify the full-length DNA-A from the Chinese isolate identified as Yg3. Sequence analysis showed that full-length DNA-A of Yg3 isolate comprised 2,729 nucleotides (GenBank Accession No. FJ539014) and shared the highest nucleotide sequence identity (91.9%) with Kudzu mosaic virus (KuMV, GenBank Accession No. DQ641690) from Vietnam. To further test the association of DNA-B fragments with the four samples from southern China, rolling circle amplification (RCA) was performed (3). When RCA products were digested with Sph I, approximately 2.7 kb was obtained from all samples. Yg3 isolate was chosen to be sequenced. Sequence analysis showed that full-length DNA-B of Yg3 isolate comprised 2,677 nucleotides (GenBank Accession No. FJ539015) and shared the highest nucleotide sequence identity (76.8%) with KuMV DNA-B (GenBank Accession No. DQ641691) from Vietnam. Based on the current convention of begomovirus species demarcation of <89% sequence identity cut-off criterion (2), Yg3 was identified as an isolate of KuMV. To our knowledge, this is the first report of association of KuMV with yellow vein mosaic symptom of kudzu in China. References: (1). D. Deng et al. Annals Appl. Biol. 125:327, 1994. (2). C. M. Fauquet et al. Arch. Virol. 148:405, 2003. (3). D. Haible et al. J. Virol. Methods 135:9, 2006. (4). Y. Xie et al. Chinese Sci. Bull. 47:197, 2002.
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Raval, Aparna, Hearn Jay Cho, Cherie Green, et al. "Dynamics of Activated CD8+ T-cells and Decreased Osteoclasts in the Tumor Microenvironment are Associated with Clinical Efficacy of Anti-PD-L1 and Anti-CD38 Combination Treatment in Relapsed or Refractory Multiple Myeloma." Blood 134, Supplement_1 (2019): 1907. http://dx.doi.org/10.1182/blood-2019-123652.
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Introduction: Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway is insufficient to induce clinical response in relapsed or refractory (R/R) multiple myeloma (MM). We postulated that combining atezolizumab (A; anti-PD-L1) with daratumumab (D; anti-CD38), which targets myeloma cells and has immunomodulatory activity, may alter the tumor microenvironment (TME) to favor cytotoxic T-cell activation and clinical activity. To assess the immunologic efficacy of this combination, we studied changes in CD8+ T cells in D-naïve and D-refractory pts from a Phase Ib study (GO29695; NCT02431208). Methods: Flow cytometry was performed using longitudinal peripheral blood (PB) and bone marrow aspirates (BMA) to characterize CD8+ cytotoxic T cells using 8 color flow panels. RNA sequencing (RNAseq) and dual-plex immunohistochemistry (IHC) (CD138/CD8, CD8/Ki-67, CD138/osteoclast) were performed using longitudinal CD138+ fraction and bone biopsies, respectively. For IHC, CD138+ cell masses of >5000μm2 were defined as tumor clusters. Osteoclasts were enumerated based on TRAP positivity and morphology. Table 1 shows on-treatment changes in Cohorts D1-D3. Table 2 shows baseline data in Cohorts A, B, D1-D3, and E. The median (bootstrap 95% CI) is used to describe the data. Results: 9/36 (25%) pts in cohorts D1-3 showed clinical efficacy (partial response or better); all were D-naïve. We studied CD8+ T-cell activation and proliferation (%CD8+HLA-DR+Ki-67+), the pharmacodynamic marker for A (Herbst et al. Nature 2014), in PB. All D-naive pts showed on-treatment increase in %CD8+HLA-DR+Ki-67+ cells in the periphery (C1D15-C2D1) compared to baseline, which was not observed in D-refractory pts (Table 1). In BMA, the increase in %CD8+HLA-DR+Ki-67+ (C2D15-C4D1) was observed in D-naïve pts with clinical response to A-D (sensitive), but not in non-responders (resistant) or D-refractory pts (all resistant), suggesting that sensitive pts have an immune-supportive TME. Preliminary IHC staining also showed an increase in CD8+Ki-67+ T cells in two responders after treatment. Gene enrichment analysis (RNAseq data, n=20) showed upregulation of an innate immune response signature, which appeared to be driven by a 'macrophage activation' gene signature post-treatment, in the CD138+ fraction of responders. To understand the mechanisms regulating sensitivity to treatment, we studied the spatial localization of CD8+ T cells with respect to CD138+ tumor cells by IHC. A higher density of CD8+ T cells within tumor clusters was seen at baseline in sensitive versus resistant pts, but this was not observed outside of tumor clusters (Table 1). In addition, the number of osteoclasts in the tumor region was higher in resistant pts, suggesting that these cells may contribute to the inhibition of T-cell function as reported(An et al. Blood 2016). This hypothesis was further supported by higher osteoclast numbers in D-refractory pts at baseline (Table 2), for whom an on-treatment increase in %CD8+HLA-DR+Ki-67+ cells was not observed in PB or BMA. Interestingly, higher median fluorescence intensity of PD-1 on CD8+ T-effector cells and on CD8+ T-effector memory cells was observed at baseline in D-naïve relative to D-refractory pts, while the level of PD-L1 expression on tumor cells was similar. An increase in activated proliferating T cells (%CD8+HLA-DR+Ki-67+) observed after treatment in D-naïve responders suggests that high PD-1 expression in this subset is not a marker of CD8+ T-cell exhaustion, but of functional capability. Conclusions: Clinical efficacy of A-D therapy in R/R MM pts is associated with higher CD8+ cell density in tumor clusters and lower osteoclast numbers in the tumor region at baseline, and an on-treatment increase in activated CD8+ T-cell populations in the bone marrow. The lack of a D-monotherapy arm in this study makes it difficult to assess the individual contribution of A to T-cell activation. The data presented, albeit a small number of samples from a Phase Ib study, support the hypothesis that the TME, including CD8+ T cells, tumor cells, and cells of myeloid lineage such as osteoclasts, has significant impact on the immunologic and clinical efficacy of combination therapy. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential for long-term disease control. Disclosures Raval: Roche: Employment, Equity Ownership. Cho:Agenus: Research Funding; Genentech: Honoraria, Research Funding; Takeda: Research Funding; BMS: Consultancy; The Multiple Myeloma Research Foundation: Employment; Celgene: Honoraria, Research Funding; GSK: Consultancy. Green:Genentech Inc.: Employment. Wassner Fritsch:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ma:Genentech: Employment. Chang:Roche Canada: Employment. Yan:F. Hoffmann-La Roche Ltd, Mississauga, Canada: Employment. Kockx:HistoGeneX: Equity Ownership. Shen:Genentech, Inc.: Employment. Huw:Roche/ Genentech: Employment, Equity Ownership. Balestiere:Genentech: Employment. Lipkind:Roche/Genentech: Employment. Huang:F. Hoffmann-La Roche Ltd: Employment. Byrtek:Genentech: Employment; Roche: Equity Ownership. Colburn:Genentech: Employment; Roche: Equity Ownership. Wong:Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Venstrom:F. Hoffmann-La Roche Ltd: Employment. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. OffLabel Disclosure: Atezolizumab (atezo) is a programmed death-ligand 1 (PD-L1) blocking antibody. In the United States, atezo is approved for treatment of pts with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy (chemo) and whose tumors express PDââ‚â'¬Ã'ÂL1, or are not eligible for any platinumââ‚â'¬Ã'Âcontaining chemo regardless of PDââ‚â'¬Ã'ÂL1 status, or have disease progression during or following any platinum-containing chemo, or within 12 months of neoadjuvant or adjuvant chemo. Atezo is also approved: in combination with bevacizumab, paclitaxel and carboplatin for first-line treatment of pts with metastatic non-squamous non-small-cell lung carcinoma (NSCLC) with no EGFR or ALK genomic tumor aberrations, and for pts with metastatic NSCLC who have disease progression during or following platinum-containing chemo; in combination with paclitaxel protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1; and in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer. Atezo is not approved for treatment of pts with multiple myeloma.
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Amatangelo, Michael, Oliver Van Oekelen, Adeeb H. Rahman, et al. "Multidimensional Single Cell Analysis Shows Increased T/NK Cell Subsets in Both Blood and Bone Marrow of Iberdomide (CC-220) Treated Relapsed/Refractory Multiple Myeloma Patients." Blood 134, Supplement_1 (2019): 1775. http://dx.doi.org/10.1182/blood-2019-126146.
Full textAbstract:
Background: Iberdomide (IBER), a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD), is being evaluated in a phase 1/2 clinical trial for treatment (tx) of RRMM, as a monotherapy, in combination with low-dose dexamethasone (DEX), or in combination with DEX and daratumumab, bortezomib, or carfilzomib (CC-220-MM-001; NCT02773030). IBER modulates the CRBN E3 ligase, inducing ubiquitination and proteasome-dependent degradation of Ikaros, Aiolos, and ZFP91, resulting in inhibition of myeloma-cell growth and immunomodulation. Methods: As of June 28, 2019, 95 patients (pts) had received IBER as monotherapy or in combination with DEX at doses ranging from 0.3 to 1.3 mg taken once daily (QD) on Days 1-21 of 28-day cycles (21/28). Longitudinal immune profiling by peripheral blood (PB) flow cytometry was completed at Cycle (C) 1 Day (D) 1 and C2D15 in 90 pts dosed up to 1.3 mg. T cell and NK cell proliferation was assessed by Ki67 staining and T cell activation was assessed by HLA-DR expression. T cell differentiation was assessed using markers for CD45RA, CD45RO, and CCR7. To assess immune changes in the bone marrow (BM) microenvironment, viably frozen CD138- cells from BM aspirates were obtained from pts at screening and C2D15 (10 and 6 samples available respectively; dosed from 0.3 - 0.9 mg). Samples were analyzed using both single-cell RNA sequencing (scRNA-seq) and mass cytometry by time-of-flight (CyTOF) with a novel panel designed to identify B cells, T and NK cell (sub)populations, monocytes, dendritic cells, MDSCs and Tregs. An R based workflow using the CATALYST (Crowell et al. 2019) and Seurat package (Stuart et al. Cell 2019) was used to analyze CyTOF and scRNA-seq data, respectively. Results: PB immune profiling of pts showed increases in total and proliferating NK cells following IBER tx across all doses (median increase = 35.5% and 74.2%, respectively). A dose-dependent increase in proliferating, activated and effector memory CD4+ (median increase = 92.3%, 45.5%, 51.7%, respectively, across all doses) and CD8+ (median increase = 116.0%, 13.9%, 45.8%, respectively, across all doses) T cells was also observed. To understand if these changes were concurrent with changes in the tumor microenvironment, a novel CyTOF panel was produced to analyze BM samples. Analogous to the PB findings, total BM NK cells increased (6.05% cells at screening vs. 9.91% at C2D15). CD16+ NK cells, known for their cytolytic activity, increased most prominently (35.9% of NK cells to 42.4%) vs. CD16- NK cells (64.1% of NK cells to 57.6%). Higher median CD16, CD56 and HLA-DR surface expression at C2D15 was also observed vs screening, demonstrating increased abundance and differentiation of NK cells. Similar to observations in the T cell compartment of PB, decreases in naïve CD4+ (24.4% to 9.09% of CD4+ cells) and CD8+ (6.42% to 2.14% of CD8+ cells) T cells and increases in effector memory CD4+ (35.8% to 40.1%) and CD8+ (26.7% to 39.5%) T cells were observed in BM. Transcriptomic data in BM showed increased expression of genes associated with cytolytic/cytotoxic activity (NKG7, GZMB, CCL3/4) and the interferon response pathway (IFNG, TNF, IFIT2/3) in CD8+ T cells, further supporting a shift towards activation in BM T cells with IBER tx. Conversely, we observed decreased expression of genes associated with a resting state (KLF2, ITGB7, CD52, S100A4) on CD4+ T cells in BM. Consistent with data from PB and of other immunomodulatory drugs, we also observed an increase in CD4+ regulatory T cells upon tx (0.72% to 5.06% of CD4+ T cells) in BM, however, the consequence of this observation in terms of response remains unclear. Conclusions: Pharmacodynamic profiling of immune subsets in PB and BM of RRMM pts receiving IBER showed consistent changes in NK cells and T cell subsets, suggesting increased proliferation and a more activated phenotype. Ongoing analyses will address whether such patterns of immune cell responses are more pronounced at higher doses of IBER and how they may correlate with clinical outcome. Disclosures Amatangelo: Celgene Corporation: Employment, Equity Ownership. Gooding:Celgene: Research Funding. Oppermann:Bayer Pharmaceuticals: Research Funding; GSK: Research Funding; Celgene: Research Funding. Pierceall:Celgene: Employment. Thakurta:Celgene: Employment, Equity Ownership. Parekh:Karyopharm Inc.: Research Funding; Foundation Medicine Inc.: Consultancy; Celgene Corporation: Research Funding.
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Bashey, Asad, Xu Zhang, Zaamin Hussain, et al. "Overall and Disease-Specific Outcomes Following T-Cell Replete Haploidentical Transplants Using Post-Transplant Cyclophosphamide: An Analysis Of 115 Patients Transplanted At a Single Center." Blood 122, no. 21 (2013): 3337. http://dx.doi.org/10.1182/blood.v122.21.3337.3337.
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Abstract Many patients with hematologic malignancies who may benefit from the curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) will lack a conventional matched sibling (MRD) or matched unrelated (MUD) donor. An HLA-haploidentical related donor is available for nearly all such patients. Attempts to use haploidentical donors that employ stringent ex-vivo T-cell depletion to abrogate GVHD are associated with poor immune reconstitution and high rates of graft rejection. In contrast, the recent use of T-cell replete grafts with post-transplant cyclophosphamide (haplo-ptCy) has resulted in effective control of alloreactivity with low rates of post-transplant infection, graft-rejection and non-relapse mortality using both non-ablative and ablative regimens (Luznik at al BBMT 2008, Solomon et al BBMT 2012.). We recently demonstrated similar outcomes for 53 haplo-PtCy to contemporaneous MRD and MUD transplants performed at our enter (Bashey et al JCO 2013). However there are limited data with respect to the outcome of specific hematologic malignancies using haplo-ptCy. For this study all consecutive patients who underwent haplo-ptCy as a first allogeneic transplant at our center between Oct 2005 and May 2013 (n=115) were included [median age 50 (20-74); M 57%, F 43%; diagnosis- AML(38), ALL(20), CLL(13), NHL(13) HL(10), CML+MPS (12), MDS (7) others (2); graft-BM(58%),PBSC(42%); prior autotranplant(18%); CIBMTR disease risk score high(35%), intermediate(32%) low(33%). Sorror Comorbidity Index-median =1(0-5)]. Preparative regimens used included non-myeloablative [fludarabine 30 mg/m2/d d -6 to -2; TBI 200cGy d-1, Cy 14.5 mg/kg/d on d-6,-5 and 50mg/kg/d on d+3,+4, n=73 ] and myeloablative [regimen 1- same as non-ablative except busulfan 110-130 mg/m2 /d i.v. on d-7 to-3 instead of TBI n=21; regimen 2- fludarabine 30 mg/m2/d d -7 to -5, TBI 150cGy bid x 8 doses (total dose =1200cGy) and Cy 50mg/kg/d d+3,+4 n=21]. Patient characteristics and outcome data were collected prospectively and obtained from our comprehensive database. Survival and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cumulative incidence of non-relapse mortality (NRM) was calculated using relapse as a competing risk. GVHD was assessed and documented prospectively by a dedicated GVHD nurse. Median CD34+ and CD3+cell doses infused were 4.21 x 10e6/kg (0.84-8.13) and 5.81 x 10e7/kg (1.4-59.5). median time to ANC > 500/mm3 and platelets > 20,000/mm3 were 16 and 26 d. Median % donor chimerism on d 30 were 100% and 100% for PB CD3+ and CD33+ cells respectively. With a median follow-up for living patients of 20 months, the 12 m and 24 m cumulative incidences (CI) of NRM were 10% and 18% and of relapse/progression were 25% and 25% respectively (Fig.1). CI of acute GVHD gd II-IV and gd III-IV at 6 m were 34% and 13% respectively, and of extensive and severe chronic GVHD at 12 m were 40% and 9% respectively. Estimated 12m and 24m probabilities of survival were 73% and 56% and of DFS were 65% and 57% respectively. On a Cox multivariate analysis assessing patient, disease and transplant related covariates, high risk CIBMTR disease score (HR 1.88, p=0.043) and acute GVHD gd 3-4 HR=2.54, p=0.0145) were the only factors significantly associated with survival. For the most frequently treated diagnoses - AML, ALL and mature lymphoid malignancies (CLL, NHL, HL) - the respective estimated 24 m probabilities of DFS were 61%, 58% and 50% respectively (Fig.2). These data demonstrate that haplo-ptCy transplants represent a safe and effective alternative for most patients who may benefit from allo-HCT but lack a conventional donor. They should be offered as standard of care in such patients. Disclosures: No relevant conflicts of interest to declare.