Decitabine encapsulation in nanovector to improve acute myeloid leukemia treatment

Acute myeloid leukemia (AML) mainly affects adult patients, and for older ones unfit for intensive chemotherapy only few therapies are available. Hypomethylating agents, as decitabine, is a labeled option but its plasma half-life is short whereas a long cell exposure time improves response rate. Only intravenous administration is available, whereas an oral route is generally preferred by patients. Consequently, to enhance plasma half-life and to develop an oral decitabine formulation, in this work decitabine was encapsulated in nanoparticles. Two different strategies were tested: decitabine loaded into lipid nanocapsules (DAC-LNC), and a decitabine-prodrug synthesis [3’(OH)-5’(OH)-(lauroyl)2-modified DAC] encapsulated into LNC (DAC-(C12)2-LNC). DAC-LNC and DAC-(C12)2-LNC particles were obtained with sizes of 26.5 ± 0.5 nm and 27.45 ± 0.05 nm respectively, and drug payloads of 0.47 ± 0.06 mg/mL and 5.8 ± 0.5 mg/mL (corresponding to 2.3 ± 0.2 mg/mL of decitabine). Both formulations were able to increase in vitro human plasma half-life by protecting decitabine from degradations. Compared to free-decitabine solutions, both nanoparticle formulations were able to preserve decitabine cytotoxicity on an AML cell line (HEL). Moreover, permeability studies across an adenocarcinoma cell model (Caco-2 cells) demonstrated that DAC-LNC improve decitabine’s intestinal permeability whereas DAC-(C12)2-LNC decreased it. However, this drawback could be countered by the enhanced decitabine’s stability in gastrointestinal fluids thanks to DAC-(C12)2-LNC, leading to more available drug for absorption. Globally, both formulation have demonstrated their ability to improve DAC plasma half-life in vitro and their potential for oral administration. In vivo pharmacokinetics evaluations may now confirm interests of such strategies

Outcome of Ph negative myeloproliferative neoplasms transforming to accelerated or leukemic phase

Myeloproliferative neoplasms (MPN) are chronic disorders that can sometimes evolve into accelerated or leukemic phases. We retrospectively identified 122 patients with such blastic phases. The overall median survival was four months: 10.2 months for patients treated with intensive treatments compared to three months for best supportive care (p = .005). Azacytidine, intensive chemotherapies, or allogeneic stem cell transplantation gave the highest median survivals with 9, 10.2, and 19.4 months, respectively. Accelerated phases (AP) had a longer median survival compared to acute leukemia (4.8 months vs. 3.1 months; p = .02). In this retrospective and observational study, we observe that the longest survivals are seen in patients eligible for intensive treatments. Azacytidine shows interesting results in patients non-fit for intensive chemotherapy. Supportive care should probably be restricted to elderly patients and those with unfavorable karyotype. An early diagnosis of AP could also result in a better survival rate

Knocking-Down Cyclin A2 by siRNA Suppresses Apoptosis and Switches Differentiation Pathways in K562 Cells upon Administration with Doxorubicin

Cyclin A2 is critical for the initiation of DNA replication, transcription and cell cycle regulation. Cumulative evidences indicate that the deregulation of cyclin A2 is tightly linked to the chromosomal instability, neoplastic transformation and tumor proliferation. Here we report that treatment of chronic myelogenous leukaemia K562 cells with doxorubicin results in an accumulation of cyclin A2 and follows by induction of apoptotic cell death. To investigate the potential preclinical relevance, K562 cells were transiently transfected with the siRNA targeting cyclin A2 by functionalized single wall carbon nanotubes. Knocking down the expression of cyclin A2 in K562 cells suppressed doxorubicin-induced growth arrest and cell apoptosis. Upon administration with doxorubicin, K562 cells with reduced cyclin A2 showed a significant decrease in erythroid differentiation, and a small fraction of cells were differentiated along megakaryocytic and monocyte-macrophage pathways. The results demonstrate the pro-apoptotic role of cyclin A2 and suggest that cyclin A2 is a key regulator of cell differentiation. To the best of our knowledge, this is the first report that knocking down expression of one gene switches differentiation pathways of human myeloid leukemia K562 cells

Genetic diversity, linkage disequilibrium and power of a large grapevine (Vitis vinifera L) diversity panel newly designed for association studies

UMR-AGAP Equipe DAVV (Diversité, adaptation et amélioration de la vigne) ; équipe ID (Intégration de Données)International audienceAbstractBackgroundAs for many crops, new high-quality grapevine varieties requiring less pesticide and adapted to climate change are needed. In perennial species, breeding is a long process which can be speeded up by gaining knowledge about quantitative trait loci linked to agronomic traits variation. However, due to the long juvenile period of these species, establishing numerous highly recombinant populations for high resolution mapping is both costly and time-consuming. Genome wide association studies in germplasm panels is an alternative method of choice, since it allows identifying the main quantitative trait loci with high resolution by exploiting past recombination events between cultivars. Such studies require adequate panel design to represent most of the available genetic and phenotypic diversity. Assessing linkage disequilibrium extent and panel power is also needed to determine the marker density required for association studies.ResultsStarting from the largest grapevine collection worldwide maintained in Vassal (France), we designed a diversity panel of 279 cultivars with limited relatedness, reflecting the low structuration in three genetic pools resulting from different uses (table vs wine) and geographical origin (East vs West), and including the major founders of modern cultivars. With 20 simple sequence repeat markers and five quantitative traits, we showed that our panel adequately captured most of the genetic and phenotypic diversity existing within the entire Vassal collection. To assess linkage disequilibrium extent and panel power, we genotyped single nucleotide polymorphisms: 372 over four genomic regions and 129 distributed over the whole genome. Linkage disequilibrium, measured by correlation corrected for kinship, reached 0.2 for a physical distance between 9 and 458 Kb depending on genetic pool and genomic region, with varying size of linkage disequilibrium blocks. This panel achieved reasonable power to detect associations between traits with high broad-sense heritability (> 0.7) and causal loci with intermediate allelic frequency and strong effect (explaining > 10 % of total variance).ConclusionsOur association panel constitutes a new, highly valuable resource for genetic association studies in grapevine, and deserves dissemination to diverse field and greenhouse trials to gain more insight into the genetic control of many agronomic traits and their interaction with the environment

Décision, prospective, auto-organisation : mélanges en l'honneur de Jacques Lesourne

504 p., fig,Riche et dense, ce volume d'hommages à Jacques Lesourne explore les différents aspects d'un parcours intellectuel hors du commun. Les textes présentés font à cette occasion le point sur les dernières avancées des théories de la décision, de la prospective et de l'auto-organisation, autant de domaines dont Jacques Lesourne a été l'un des pionniers

Concept Study for a Mach 6 Transport Aircraft

A conceptual study is here presented and discusscd on the possibility to transport 200 passengers over a distance of about 7000km in a nominal point-to-point mission through the Atlantic (either London-New York or London-Rio) at a cruise Mach number of 6 and an altitude abont 30km. The aim of the study is not to design a specific airplane but to explore today's state of the art technology limits to realize such kind of concept, i.e. to identify if such a mission could succeed today. Because of the challenge the mission poses, its is being optimised with the major disciplines involved by means of Multi-Disciplinary Optimisation (MDO) tools as a way to realize an optimum integrated airframe/propulsion aircraft. The environmental impact is being analysed in terms of the resulting sonic boom. No experimental data but CFD results by means of independent assessments has been generated. The study indicates that today the available technology provides with sufficient maturity to accomplish with the mission in areas like aerodynamic and thermal resistance materials but in others like sonic boom mitigation it is required a deeper insight in the physics. Finally while the present investigation clear identify that complex designs involving large amount of variables from different disciplines could be only possible via MDO/MDA strategies, today such processes still suffer on lack of robustness of the involved tools

High flow nasal cannula improves breathing efficiency and ventilatory ratio in COPD patients recovering from an exacerbation.

High flow nasal cannula (HFNC) may improve CO <sub>2</sub> elimination by washing out CO <sub>2</sub> from the upper airways. This study aimed at assessing the effect of HFNC on minute ventilation and ventilatory ratio (VR), a surrogate of dead space, in patients hospitalized for acute hypercapnic COPD exacerbation. Physiological study comparing HFNC at 40 L/min to low flow oxygen. Variations of tidal volume (VT) and minute ventilation between the two treatments were estimated from chest plethysmography. Respiratory rate (RR) and arterial blood gases were measured. Variations in VR were calculated. Data were compared using Wilcoxon tests. Recordings performed in 10 patients. Minute ventilation was reduced with HFNC by -16.2 [-30.9-0.4] % (p = 0.049). VT was not different but RR was lower during HFNC. PaCO <sub>2</sub> was lower with HFNC compared to standard oxygen: 48.7 [46.4-58.1] vs 50.7 [48.4-57.5] mmHg (p = 0.020). VR decreased by -18.0 [-34.7 - -4.0] % (p = 0.020) with HFNC. In patients recovering from acute COPD exacerbation, the use of HFNC reduced RR, minute ventilation, PaCO <sub>2</sub> and VR compared to standard oxygen. These changes are consistent with a decrease in physiologic dead space with HFNC