Acute myeloid leukemia (AML) is a heterogeneous disease. Prognosis is mainly influenced by patient age at diagnosis and cytogenetic alterations, two of the main factors currently used in AML patient ...risk stratification. However, additional criteria are required to improve the current risk classification and better adapt patient care. In neoplastic cells, ribosome biogenesis is increased to sustain the high proliferation rate and ribosome composition is altered to modulate specific gene expression driving tumorigenesis. Here, we investigated the usage of ribosome biogenesis factors as clinical markers in adult patients with AML. We showed that nucleoli, the nucleus compartments where ribosome production takes place, are modified in AML by analyzing a panel of AML and healthy donor cells using immunofluorescence staining. Using four AML series, including the TCGA dataset, altogether representing a total of about 270 samples, we showed that not all factors involved in ribosome biogenesis have clinical values although ribosome biogenesis is increased in AML. Interestingly, we identified the regulator of ribosome production nucleolin (NCL) as over-expressed in AML blasts. Moreover, we found in two series that high NCL mRNA expression level was associated with a poor overall survival, particular in elderly patients. Multivariate analyses taking into account age and cytogenetic risk indicated that NCL expression in blast cells is an independent marker of reduced survival. Our study identifies NCL as a potential novel prognostic factor in AML. Altogether, our results suggest that the ribosome biogenesis pathway may be of interest as clinical markers in AML.
AIM To evaluate the importance of the CD34+CD38-cell population when compared to the CD34+CD38+/low and CD34+CD38+/high leukemic cell sub-populations and to determine its correlations with leukemia ...characteristics and known prognostic factors, as well as with response to therapy and survival.METHODS Two hundred bone marrow samples were obtained at diagnosis from 200 consecutive patients with newly diagnosed acute myeloid leukemia(AML) were studied between September 2008 and December 2010 at our Institution(Hematology Department, Lyon, France). The CD34/CD38 cell profile was analyzed by multiparameter flowcytometry approach using 8 C panels and FACS CANTO and Diva software(BD Bioscience).RESULTS We analyzed CD34 and CD38 expression in bone marrow samples of 200 AML patients at diagnosis, and investigated the prognostic value of the most immature CD34+CD38-population. Using a cut-off value of 1% of CD34+CD38-from total “bulk leukemic cells” we found that a high(> 1%) level of CD34+CD38-blasts at diagnosis was correlated with advanced age, adverse cytogenetics as well as with a lower rate of complete response after induction and shorter disease-free survival. In a multivariate analysis considering age, leukocytosis, the % of CD34+ blasts cells and the standardized cytogenetic and molecular risk subgroups, a percentage of CD34+CD38-leukemic cells > 1% was an independent predictor of DFS HR = 2.8(1.02-7.73), P = 0.04 and OS HR = 2.65(1.09-6.43), P = 0.03.CONCLUSION Taken together, these results show that a CD34/CD38 “backbone” for leukemic cell analysis by multicolour flowcytometry at diagnosis provides useful prognostic information.
AIM: To evaluate quantitatively and qualitatively the different CD34+cell subsets after priming by chemotherapy granulocyte colony-stimulating factor(± G-CSF)in patients with acute myeloid ...leukemia.METHODS: Peripheral blood and bone marrow sampleswere harvested in 8 acute myeloid leukemia patients during and after induction chemotherapy. The CD34/CD38 cell profile was analyzed by multi-parameter flow cytometry. Adhesion profile was made using CXC chemokine receptor 4(CXCR4)(CD184), VLA-4(CD49d/CD29) and CD47.RESULTS: Chemotherapy ± G-CSF mobilized immature cells(CD34+CD38 population), while the more mature cells(CD34+CD38lowand CD34+CD38+populations) decreased progressively after treatment. Circulating CD34+cells tended to be more sensitive to chemotherapy after priming with G-CSF. CD34+cell mobilization was correlated with a gradual increase in CXCR4 and CD47expression, suggesting a role in cell protection and the capacity of homing back to the marrow.CONCLUSION: Chemotherapy ± G-CSF mobilizes into the circulation CD34+bone marrow cells, of which, the immature CD34+CD38-cell population. Further manipulations of these interactions may be a means with which to control the trafficking of leukemia stem cells to improve patients’ outcomes.
Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have ...failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development.
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•Chalcones inhibit normal human basophil degranulation.•Piperidinyl unit contribute to the inhibition of the PI3Kδ isoform.•Reduction of expiratory pressure with piperidinyl-embeded chalcones.•Anti-atopic properties as potent as topical betamethasone.
Abstract
Relapse in acute myeloid leukemia (AML) after chemotherapy reflects the persistence of resistant leukemia stem cells (LSCs). These cells have been described in the CD34 + CD38− cell ...fraction. Leukapheresis products were harvested in 123 patients in morphological complete remission and analyzed by multiparameter flow cytometry. The CD34 + CD38− cell population showed a prognostic impact on survival. Median event-free survival (EFS) was 8.2 months (3-year EFS: 29%) for those with a higher percentage of CD34 + CD38− versus 91.9 months (3-year EFS: 62%) for those with a lower percentage for the entire cohort. These differences were confirmed in patients undergoing autologous stem cell transplant, with median EFS of 7.3 months versus 91.1 months (3-year EFS: 31% vs. 70%). Higher proportions of CD34 + CD38− cells were associated with adverse cytogenetics and with earlier relapses. Higher percentages of CD34 + CD38− cells in apheresis products reflect inadequate in vivo purging and reliably distinguish samples enriched in LSCs from those involving mainly normal cells.
Abstract 1485▪▪This icon denotes a clinically relevant abstract
Myeloablative chemotherapy followed by autologous PBSCT remains one treatment strategy in adult AML patients. Relapse has been shown ...higher for those who received the highest CD34+ PB doses. Although highly active against the leukemic bulk, intensive chemotherapy often spare the hardier leukemia stem cells (LSCs) responsible for relapse. Detection of MRD in harvest products may reflect inadequate in vivo purging at least in part responsible for relapses. Although recent data have challenged the CD34+CD38− phenotype of LSCs, this cell population remains generally considered enriched for LSCs. In this setting, MRD remaining during CR should be relatively enriched in CD34+CD38− leukemic cells and their persistence should correlate with disease recurrence.
CD34+ cells were harvested after CR achievement in 123 AML patients median age: 53 y (25–72) treated by induction chemotherapy in our Institution between 10/1994 and 04/2003. Patients were included in different clinical trials planning autologous SC harvest in CR and autologous SCT in absence of donor or allogeneic SCT indication. Seventy-one of them received effectively autologous PBSCT. Harvests performed in 15 normal donors were used as controls. CD34/CD38 cell profile was analyzed in harvests in one single tube by multicolor flow cytometry using multiple MoAbs. The gating strategy was based on CD45low/SSC and CD34+CD45low cell populations from total FSC/SSC viable cells. Three populations of CD34+ were distinguished: CD34+CD38–; CD34+CD38low; and CD34+CD38+.
Patients from the entire cohort with higher percentage of CD34+ cells (cut-off level: 1%) in PBSC products were associated with shorter EFS median: 5.6 months (3-y EFS: 13%) vs 13.6 (37%); p=0.0005 and OS median: 10 months (3-y OS: 19%) vs 23.4 (47%); p=0.004. This was also the case when analyzing only patients who received autologous SCT: median EFS: 5 months (3-y EFS: 13%) vs 22.2 (48%); p=0.0006, and median OS: 9.1 months (3-y OS: 21%) vs 43.3 (57%); p=0.001. Among CD34+ populations, only CD34+CD38– had a prognostic impact on EFS and OS. At a cut-off level of 0.9%, median EFS was 8.2 months (3-y EFS: 29%) for those with higher percentage vs 91.9 (62%) for those with lower percentage and median OS was 14.2 months (3-y OS: 36%) vs 95.4 (69%) respectively for the entire cohort. These results were confirmed in patients undergoing autologous SCT: median EFS was 7.3 months (3-y EFS: 31%) vs 91.1 (70%) (p= 0.05), and median OS was 14.4 months (3-y OS: 39%) vs 94.6 (80%). CD34+CD38low and CD34+CD38+ populations did not show any prognostic impact. Harvests from AML patients were divided into 3 groups: Group A: 51 patients with CR duration <1 y; Group B: 22 patients with CR duration >1 y; and Group C: 50 patients without relapse. Harvests from 15 normal donors (Group D) were used as controls. Significant differences were only observed when comparing Group A and Group D for total CD34+ cells (mean ± SEM 2.5 ± 0.5 vs 1.2 ± 0.3; p < 0.05) and CD34+CD38– (4.5 ± 0.7 vs 2.3 ± 0.5; p < 0.05). To confirm the prognostic value of CD34+CD38–, 19 patients (Group 1) with evidence of leukemic contamination in harvests (abnormal cytogenetics at presentation found in aphereses) were compared with 22 patients (Group 2) without evidence of contamination (abnormal cytogenetics at presentation not found in aphereses). Median EFS was 10.1 months (3-year EFS: 45%) in Group 2 vs 6.3 (13%) in Group 1 (p=0.01), and median OS was 36.6 months (3-year OS: 55%) vs 10.8 (23%), respectively (p=0.03). Harvests from 15 normal donors (Group 3) served as controls. Significant differences were noted in harvest products regarding CD34+CD38– between Group 1 and Group 3 (mean ± SEM 6.0 ± 1.5 vs 2.3 ± 0.5; p = 0.04) and Group 1 and Group 2 (6.0 ± 1.5 vs 2.4 ± 0.5; p = 0.03), while there were no differences between Group 2 and controls. There were no significant differences between groups regarding CD34+CD38low and CD34+CD38+. We also measured MFI of CD13, CD33, CD123, CD117 in CD34+ subpopulations. Phenotypes were compared among the different groups.
Higher proportions of CD34+CD38− in apheresis products appear to reflect inadequate in vivo purging and distinguish samples as enriched in ‘leukemic cells' from those with lower CD34+CD38− as largely constituted of ‘normal cells'. This could serve as detection of MRD and help to identify samples associated with high-risk of relapse after autologous SCT.
No relevant conflicts of interest to declare.
Relapse in acute myeloid leukemia (AML) after chemotherapy reflects the persistence of resistant leukemia stem cells (LSCs). These cells have been described in the CD34 + CD38− cell fraction. ...Leukapheresis products were harvested in 123 patients in morphological complete remission and analyzed by multiparameter flow cytometry. The CD34 + CD38− cell population showed a prognostic impact on survival. Median event-free survival (EFS) was 8.2 months (3-year EFS: 29%) for those with a higher percentage of CD34 + CD38− versus 91.9 months (3-year EFS: 62%) for those with a lower percentage for the entire cohort. These differences were confirmed in patients undergoing autologous stem cell transplant, with median EFS of 7.3 months versus 91.1 months (3-year EFS: 31% vs. 70%). Higher proportions of CD34 + CD38− cells were associated with adverse cytogenetics and with earlier relapses. Higher percentages of CD34 + CD38− cells in apheresis products reflect inadequate in vivo purging and reliably distinguish samples enriched in LSCs from those involving mainly normal cells.
The structural modifications and the evolution of mechanical behavior of gallium nitride (GaN) thin films irradiated by 92 MeV 129Xe23+ at different fluences have been investigated. The modifications ...induced by irradiation in GaN have been studied using a combination of high resolution X-ray diffraction and Transmission Electron Microscopy observations coupled to nanoindentation. The crystalline lattice of the GaN is modified by irradiation, with an extension of the lattice along the c-direction parallel to the ion path, leading to the development of residual stresses. Correlated to the crystallographic disorder, modification of the deformation mechanisms of the material is observed: damaged areas (highly disordered zones near the surface and black dots deeper in the bulk) hinder the dislocation motion, such as after irradiation, dislocation slip occurs only along the basal plane, and no more prismatic or pyramidal slip is observed. This results in increasing the dislocation loop density, with a subsequent increase in hardness of the GaN film. At higher fluence, the overlapping of the latent tracks created by swift heavy ions results in a significant decrease in the mechanical characteristics of the thin film, and an amorphous-like material behavior.
•Irradiation of GaN leads to a high crystalline disorder and a lattice extension.•The crystalline lattice deformation causes the development of residual stresses.•These structural modifications due to irradiation hinder the dislocations slip.•The mechanical behavior of the irradiated GaN is evaluated by nanoindentation.•The plasticity of the irradiated GaN is reduced and its hardness increases.
Le rapport sur les politiques publiques de lutte contre la pollution de l'air publié en 2016 souligne que l'impact de la pollution de l'air, notamment en termes de santé publique, justifie ...l'instauration d'une politique publique ambitieuse. Or, la gouvernance de la lutte contre la qualité de l'air demeurait défaillante. Les politiques suivies étaient porteuses d'effets contradictoires et les efforts restaient tres inégaux selon les secteurs d'activité. Les plans nationaux qui s'étaient succédé sans jamais étre totalement mis en œuvre étaient davantage des réponses aux injonctions de la Commission européenne que des cadres d'action pérenne, et le rapport coúts/bénéfices des actions engagées n'avait jamais été évalué a posteriori. Les mesures prises ne permettaient pas d'atteindre le respect des seuils européens pour les concentrations de particules et d'oxydes d'azote dans bon nombre de zones, ce qui a conduit a l'engagement de procédures par la Commission européenne. La Cour relevait l'urgence d'une politique claire et ambitieuse, inscrite dans la durée, d'autant que de nouveaux objectifs de réduction des émissions ont été fixés par la directive NEC révisée pour 2030.
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