Shear coaxial injector instability mechanisms

There is no definitive knowledge of which of several concurrent processes ultimately results in unstable combustion within liquid rocket chambers employing shear coaxial injectors. Possible explanations are a detrimental change in the atomization characteristics due to a decrease in the gas-to-liquid velocity ratio, a change in the gas side injector pressure drop allowing acoustic coupling to the propellant feed system or the disappearance of a stabilizing recirculation region at the base of the LOX post. The aim of this research effort is to investigate these proposed mechanisms under conditions comparable to actual engine operation. Spray characterization was accomplished with flash photography and planar laser imaging to examine the overall spray morphology and liquid jet breakup processes and with a PDPA to quantify the spatial distribution of droplet size and mean axial velocity. A simplified stability model based on the Rayleigh criterion was constructed for the flow dynamics occurring within the chamber and injector to evaluate the potential coupling between the chamber and injector acoustic modes and was supported by high frequency measurements of chamber and injector pressure oscillations. To examine recirculation within the LOX post recess, velocity measurements were performed in the recess region by means of LDV. Present experiments were performed under noncombusting conditions using LOX/GH2 stimulants at pressures up to 4 MPa

Reproductibilité de l’évaluation de la fonction endothéliale cutanée par méthode laser mono-point et laser speckle chez l’homme

Objectifs.– La dysfonction endothéliale est la première étape conduisant à l’athérosclérose. La vasodilatation induite par l’acétylcholine (ACh) est un test spécifique de la fonction endothéliale. Plusieurs techniques comme la mesure du flux sanguin par Laser doppler Fluxmètre (LDF) et le Laser Speckle Contrast Imaging (LSCI) ont été développées afin de quantifier cette vasodilatation. Actuellement, la fiabilité de ces techniques et l’expression de leurs résultats sont à l’étude, ces derniers manquants de standardisation. Les objectifs de cette étude étaient d’évaluer à sept jours d’intervalle : – la reproductibilité de la mesure inter-sujets ; – la reproductibilité de la mesure intra-sujets ; – l’effet du mode d’expression des résultats sur la variabilité. Méthode.– Nous avons évalué deux protocoles d’iontophorèse d’ACh (stimulation unique, multiples stimulations) dont les réponses étaient mesurées simultanément par le LDF et le LSCI. Le maximum de la vasodilatation provoqué par l’ACh (pic d’ACh) a été exprimé sous forme de valeurs de conductance absolue ou en flux normalisé. La reproductibilité inter-sujets a été exprimée en coefficient de variation (inter-CV, %). La reproductibilité intra-sujet a été exprimée en coefficient de variation (intra-CV, %) et en coefficient de corrélation intra-classe (ICC). Quinze sujets sains âgés de 18 ans ou plus ont été inclus dans cette étude. Résultats.– La reproductibilité inter-sujets du pic d’ACh change en fonction de la manière d’exprimer les résultats et s’échelonne de 55 % à 162 % pour le LDF et de 17 % à 83 % pour le LSCI. La reproductibilité intra-sujet (Intra-CV/ICC) du pic d’ACh a été meilleure mesurée par le LSCI que par le LDF quels que soient le mode d’expression et le protocole utilisé. Les meilleures reproductibilités intra-sujets ont été obtenues avec le LSCI. Elles étaient de 18,7 %/0,87 (résultat exprimé en valeur absolue de conductance vasculaire cutanée) lors d’une stimulation unique et de 11,4 %/0,61 (résultat exprimé en valeur absolue) lors d’une multiple stimulation. Conclusion.– La iontophorèse d’ACh couplée au LSCI est un outil d’avenir afin d’accéder à la fonction endothéliale car elle est reproductible, non dangereuse et non invasive

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

Reproducibility of Non-Invasive Assessment of Skin Endothelial Function Using Laser Doppler Flowmetry and Laser Speckle Contrast Imaging

BACKGROUND: Endothelial dysfunction precedes atherosclerosis. Vasodilation induced by acetylcholine (ACh) is a specific test of endothelial function. Reproducibility of laser techniques such as laser-Doppler-flowmetry (LDF) and Laser-speckle-contrast-imaging (LSCI) to detect ACh vasodilation is debated and results expressions lack standardization. We aimed to study at a 7-day interval (i) the inter-subject reproducibility, (ii) the intra-subjects reproducibility, and (iii) the effect of the results expressions over variability. METHODS AND RESULTS: Using LDF and LSCI simultaneously, we performed two different ACh-iontophoresis protocols. The maximal ACh vasodilation (peak-ACh) was expressed as absolute or normalized flow or conductance values. Inter-subject reproducibility was expressed as coefficient of variation (inter-CV,%). Intra-subject reproducibility was expressed as within subject coefficients of variation (intra-CV,%), and intra-class correlation coefficients (ICC). Fifteen healthy subjects were included. The inter-subject reproducibility of peak-ACh depended upon the expression of the results and ranged from 55% to 162% for LDF and from 17% to 83% for LSCI. The intra-subject reproducibility (intra-CV/ICC) of peak-ACh was reduced when assessed with LSCI compared to LDF no matter how the results were expressed and whatever the protocol used. The highest intra-subject reproducibility was found using LSCI. It was 18.7%/0.87 for a single current stimulation (expressed as cutaneous vascular conductance) and 11.4%/0.61 for multiple current stimulations (expressed as absolute value). CONCLUSION: ACh-iontophoresis coupled with LSCI is a promising test to assess endothelial function because it is reproducible, safe, and non-invasive. N°: NCT01664572

Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy

Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers

Acadesine Kills Chronic Myelogenous Leukemia (CML) Cells through PKC-Dependent Induction of Autophagic Cell Death

CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients

A Review on Automatic Analysis of Human Embryo Microscope Images

Over the last 30 years the process of in vitro fertilisation (IVF) has evolved considerably, yet the efficiency of this treatment remains relatively poor. The principal challenge faced by doctors and embryologists is the identification of the embryo with the greatest potential for producing a child. Current methods of embryo viability assessment provide only a rough guide to potential. In order to improve the odds of a successful pregnancy it is typical to transfer more than one embryo to the uterus. However, this often results in multiple pregnancies (twins, triplets, etc), which are associated with significantly elevated risks of serious complications. If embryo viability could be assessed more accurately, it would be possible to transfer fewer embryos without negatively impacting IVF pregnancy rates. In order to assist with the identification of viable embryos, several scoring systems based on morphological criteria have been developed. However, these mostly rely on a subjective visual analysis. Automated assessment of morphological features offers the possibility of more accurate quantification of key embryo characteristics and elimination of inter- and intra-observer variation. In this paper, we describe the main embryo scoring systems currently in use and review related works on embryo image analysis that could lead to an automatic and precise grading of embryo quality. We summarise achievements, discuss challenges ahead, and point to some possible future directions in this research field

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens. Keywords: AML; RUNX1; CKMT1; cyclocreatine; arginine metabolismNational Cancer Institute (U.S.) (NIH 1R35 CA210030-01)Stand Up To CancerBridge ProjectNational Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. Grant P30-CA14051

Differentiation of Chronic Lymphocytic Leukemia B Cells into Immunoglobulin Secreting Cells Decreases LEF-1 Expression

Lymphocyte enhancer binding factor 1 (LEF-1) plays a crucial role in B lineage development and is only expressed in B cell precursors as B cell differentiation into mature B and plasma cells silences its expression. Chronic lymphocytic leukemia (CLL) cells aberrantly express LEF-1 and its expression is required for cellular survival. We hypothesized that modification of the differentiation status of CLL cells would result in loss of LEF-1 expression and eliminate the survival advantage provided by its aberrant expression. In this study, we first established a methodology that induces CLL cells to differentiate into immunoglobulin (Ig) secreting cells (ISC) using the TLR9 agonist, CpG, together with cytokines (CpG/c). CpG/c stimulation resulted in dramatic CLL cell phenotypic and morphologic changes, expression of cytoplasmic Ig, and secretion of light chain restricted Ig. CpG/c stimulation also resulted in decreased CLL cell LEF-1 expression and increased Blimp-1 expression, which is crucial for plasma cell differentiation. Further, Wnt pathway activation and cellular survival were impaired in differentiated CLL cells compared to undifferentiated CLL cells. These data support the notion that CLL can differentiate into ISC and that this triggers decreased leukemic cell survival secondary to the down regulation of LEF-1 and decreased Wnt pathway activation