Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.

Inducing cell death by the sphingolipid ceramide is a potential anti-cancer strategy, but the underlying mechanisms remain poorly defined. Here, we show that triggering accumulation of ceramide in acute myeloid leukaemia (AML) cells by inhibition of sphingosine kinase induces an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This leads to transcription of the BH3-only protein, Noxa, and degradation of the pro-survival Mcl-1 protein on which AML cells are highly dependent on for survival. Targeting this novel ISR pathway in combination with the Bcl-2 inhibitor venetoclax synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anti-cancer effects of ceramide and pre-clinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.Alexander C. Lewis, Victoria S. Pope, Melinda N. Tea, Manjun Li, Gus O. Nwosu, Thao M. Nguyen, Craig T. Wallington-Beddoe, Paul A. B. Moretti, Dovile Anderson, Darren J. Creek, Maurizio Costabile, Saira R. Ali, Chloe A. L. Thompson-Peach, B. Kate Dredge, Andrew G. Bert, Gregory J. Goodall, Paul G. Ekert, Anna L. Brown, Richard D'Andrea, Nirmal Robinson, Melissa R. Pitman, Daniel Thomas, David M. Ross, Briony L. Gliddon, Jason A. Powell, and Stuart M. Pitso

DES13S2cmm: the first superluminous supernova from the Dark Energy Survey

We present DES13S2cmm, the first spectroscopically-confirmed superluminous supernova (SLSN) from the Dark Energy Survey (DES). We briefly discuss the data and search algorithm used to find this event in the first year of DES operations, and outline the spectroscopic data obtained from the European Southern Observatory (ESO) Very Large Telescope to confirm its redshift (z = 0.663 +/- 0.001 based on the host-galaxy emission lines) and likely spectral type (type I). Using this redshift, we find M_U_peak = -21.05 +0.10 -0.09 for the peak, rest-frame U-band absolute magnitude, and find DES13S2cmm to be located in a faint, low metallicity (sub-solar), low stellar-mass host galaxy (log(M/M_sun) = 9.3 +/- 0.3); consistent with what is seen for other SLSNe-I. We compare the bolometric light curve of DES13S2cmm to fourteen similarly well-observed SLSNe-I in the literature and find it possesses one of the slowest declining tails (beyond +30 days rest frame past peak), and is the faintest at peak. Moreover, we find the bolometric light curves of all SLSNe-I studied herein possess a dispersion of only 0.2-0.3 magnitudes between +25 and +30 days after peak (rest frame) depending on redshift range studied; this could be important for 'standardising' such supernovae, as is done with the more common type Ia. We fit the bolometric light curve of DES13S2cmm with two competing models for SLSNe-I - the radioactive decay of 56Ni, and a magnetar - and find that while the magnetar is formally a better fit, neither model provides a compelling match to the data. Although we are unable to conclusively differentiate between these two physical models for this particular SLSN-I, further DES observations of more SLSNe-I should break this degeneracy, especially if the light curves of SLSNe-I can be observed beyond 100 days in the rest frame of the supernova.Comment: Accepted by MNRAS (2015 January 23), 13 pages, 6 figures, 2 table

DES15E2mlf: a spectroscopically confirmed superluminous supernova that exploded 3.5 Gyr after the big bang

We present the Dark Energy Survey (DES) discovery of DES15E2mlf, the most distant superluminous supernova (SLSN) spectroscopically confirmed to date. The light curves and Gemini spectroscopy of DES15E2mlf indicate that it is a Type I superluminous supernova (SLSN-I) at z = 1.861 (a lookback time of ∼10 Gyr) and peaking at MAB = −22.3 ± 0.1 mag. Given the high redshift, our data probe the rest-frame ultraviolet (1400–3500 Å) properties of the SN, finding velocity of the C III feature changes by ∼5600 km s−1 over 14 d around maximum light. We find the host galaxy of DES15E2mlf has a stellar mass of 3.5+3.6 −2.4 × 109 M, which is more massive than the typical SLSN-I host galaxy

First cosmology results using SNe Ia from the dark energy survey: analysis, systematic uncertainties, and validation

International audienceWe present the analysis underpinning the measurement of cosmological parameters from 207 spectroscopically classified type Ia supernovae (SNe Ia) from the first three years of the Dark Energy Survey Supernova Program (DES-SN), spanning a redshift range of 0.01

First cosmology results using type Ia supernovae from the Dark Energy Survey: constraints on cosmological parameters

We present the first cosmological parameter constraints using measurements of type Ia supernovae (SNe Ia) from the Dark Energy Survey Supernova Program (DES-SN). The analysis uses a subsample of 207 spectroscopically confirmed SNe Ia from the first three years of DES-SN, combined with a low-redshift sample of 122 SNe from the literature. Our "DES-SN3YR" result from these 329 SNe Ia is based on a series of companion analyses and improvements covering SN Ia discovery, spectroscopic selection, photometry, calibration, distance bias corrections, and evaluation of systematic uncertainties. For a flat LCDM model we find a matter density Omega_m = 0.331 +_ 0.038. For a flat wCDM model, and combining our SN Ia constraints with those from the cosmic microwave background (CMB), we find a dark energy equation of state w = -0.978 +_ 0.059, and Omega_m = 0.321 +_ 0.018. For a flat w0waCDM model, and combining probes from SN Ia, CMB and baryon acoustic oscillations, we find w0 = -0.885 +_ 0.114 and wa = -0.387 +_ 0.430. These results are in agreement with a cosmological constant and with previous constraints using SNe Ia (Pantheon, JLA)

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Global DNA methylation analysis identifies key pathway differences between poor (low OCT-1 activity) and standard risk CP-CML patients at diagnosis

Abstract Abstract 3730 Background: DNA methylation, specifically CpG methylation, is an essential mediator of epigenetic gene expression which is of vital importance to many biological processes and human malignancies. DNA hypermethylation has been previously described in a small number of genes in chronic myeloid leukemia (CML); however, current published studies have only examined the methylation status of selected genes, often based on the results of studies in other malignancies. Therefore, the global DNA methylation profile of chronic phase-CML (CP-CML) remains poorly understood, as does the impact of the epigenome on patient response to tyrosine kinase inhibitors (TKIs) including imatinib. The organic cation transport-1 (OCT-1) protein is the major active protein involved in imatinib transport, and we have previously demonstrated that measuring its function in leukemic mononuclear cells, expressed as OCT-1 activity (OA), in patient cells prior to imatinib therapy, provides a strong prognostic indicator. Notably, very low OA (poor risk cohort) is associated with patients at significant risk for poor molecular response, mutation development and leukemic transformation on imatinib therapy. Therefore, it is of particular interest to ascertain whether epigenetic changes are distinct and potentially biologically relevant in these poor risk patients. Aim: To investigate the global DNA methylation profile in CP-CML patients with a particular focus on poor risk patients (very low OCT-1 activity), and to ascertain whether aberrant epigenetic programming may underlie their poor response. Method: Cells were isolated from the blood of 55 CP-CML patients at diagnosis and 5 normal individuals. CP-CML patients were classified according to their OA values, with 29 classified as poor (very low OA) and 26 standard risk (high OA). Whole genome DNA methylation analysis was performed using the Illumina Infinium® HumanMethylation450 BeadChip. Analysis of array data was performed with R v2.15.0, using the minfiBioconductor package. Results: The methylation profile of CP-CML was significantly different to that of normal individuals, as shown in Table 1. GeneGo enrichment analysis revealed a significant enrichment in CML for genes known to be involved in other leukemias (p=4.92e−26) particularly AML and CLL, suggesting similar pathways may be under epigenetic control in CML. A significant number of polycomb group (BMI1 and EZH2) target genes were also identified, suggesting the likely involvement of this pathway in CML. Table 1: Summary of significant CpGs and corresponding genes when comparisons of CP-CML to normal individuals, and poor to standard risk patients, are made using methylation profiles. A significant difference was also observed when the methylation profiles of poor and standard risk CP-CML patients were analysed (Table 1). GeneGo analysis again identified polycomb group (SUZ12 and EZH2) target enrichment and significant enrichment of NOTCH, Hedgehog and WNT signalling (p=7.93e−9, p=2.42e−5 and p=3.66e−5 respectively) in poor risk patients, indicating these pathways may play a significant role in the unfavourable responses observed in many of these patients. Of particular interest were the ten CpGs where a fold change >4 was observed between the methylation profiles of poor and standard risk patients. Using the Prediction Analysis of Microarrays supervised learning algorithm, a classifier for patient OA prediction based on this 10 CpG signature was evaluated. This classifier had an overall accuracy of 94% (sensitivity: 95%, specificity: 93%). Conclusion: We present a comprehensive global DNA methylation analysis of CP-CML that indicates significant and widespread changes to the CML epigenome, compared with that of normal individuals. Importantly, we have generated a classifier, which identifies the poor risk patient subgroup (very low OA) with 94% accuracy. Validation of this classifier is currently in progress. The epigenetic changes identified here may contribute to CML pathogenesis, and also to the response heterogeneity observed between CP-CML patients treated with TKI therapy. Disclosures: Hughes: Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Novartis Oncology: Honoraria, Research Funding; BMS: Research Funding; CSL: Research Funding. Dale B. Watkins, Chung Hoow Kok, Richard J. D'Andrea, Timothy P. Hughes and Deborah L. Whit

Peptide insertions in domain 4 of hbc, the shared signalling receptor subunit for GM-CSF, IL3 and IL5, induce ligand-independent activation

Copyright © 2001 Academic Press. All rights reserved.A mutant form of the common beta-subunit of the GM-CSF, interleukin-3 (IL3) and IL5 receptors is activated by a 37 residue duplicated segment which includes the WSXWS motif and an adjacent, highly conserved, aliphatic/basic element. Haemopoietic expression of this mutant, hbeta(c)FIDelta, in mice leads to myeloproliferative disease. To examine the mechanism of activation of this mutant we targetted the two conserved motifs in each repeat for mutagenesis. Here we show that this mutant exhibits constitutive activity in BaF-B03 cells in the presence of mouse or human GM-CSF receptor alpha-subunit (GMRalpha) and this activity is disrupted by mutations of the conserved motifs in the first repeat. In the presence of these mutations the receptor reverts to an alternative conformation which retains responsiveness to human IL3 in a CTLL cell line co-expressing the human IL3 receptor alpha-subunit (hIL3Ralpha). Remarkably, the activated conformation is maintained in the presence of substitutions, deletions or replacement of the second repeat. This suggests that activation occurs due to insertion of extra sequence after the WSXWS motif and is not dependent on the length or specific sequence of the insertion. Thus hbeta(c) displays an ability to fold into functional receptor conformations given insertion of up to 37 residues in the membrane-proximal region. Constitutive activation most likely results from a specific conformational change which alters a dormant, inactive receptor complex, permitting functional association with GMRalpha and ligand-independent mitogenic signalling.K. L. Jones, C. J. Bagley, C. Butcher, S. C. Barry, M. A. Vadas and R. J. D'Andre