Runx1 orchestrates sphingolipid metabolism and glucocorticoid resistance in lymphomagenesis

The three-membered RUNX gene family includes RUNX1, a major mutational target in human leukemias, and displays hallmarks of both tumour suppressors and oncogenes. In mouse models the Runx genes appear to act as conditional oncogenes, as ectopic expression is growth suppressive in normal cells but drives lymphoma development potently when combined with over-expressed Myc or loss of p53. Clues to underlying mechanisms emerged previously from murine fibroblasts where ectopic expression of any of the Runx genes promotes survival through direct and indirect regulation of key enzymes in sphingolipid metabolism associated with a shift in the ‘sphingolipid rheostat’ from ceramide to sphingosine-1-phosphate (S1P). Testing of this relationship in lymphoma cells was therefore a high priority. We find that ectopic expression of Runx1 in lymphoma cells consistently perturbs the sphingolipid rheostat, while an essential physiological role for Runx1 is revealed by reduced S1P levels in normal spleen after partial Cre-mediated excision. Furthermore we show that ectopic Runx1 expression confers increased resistance of lymphoma cells to glucocorticoid-mediated apoptosis, and elucidate the mechanism of cross-talk between glucocorticoid and sphingolipid metabolism through Sgpp1. Dexamethasone potently induces expression of Sgpp1 in T-lymphoma cells and drives cell death which is reduced by partial knockdown of Sgpp1 with shRNA or direct transcriptional repression of Sgpp1 by ectopic Runx1. Together these data show that Runx1 plays a role in regulating the sphingolipid rheostat in normal development and that perturbation of this cell fate regulator contributes to Runx-driven lymphomagenesis

Dynamical model and nonextensive statistical mechanics of a market index on large time windows

The shape and tails of partial distribution functions (PDF) for a financial signal, i.e. the S&P500 and the turbulent nature of the markets are linked through a model encompassing Tsallis nonextensive statistics and leading to evolution equations of the Langevin and Fokker-Planck type. A model originally proposed to describe the intermittent behavior of turbulent flows describes the behavior of normalized log-returns for such a financial market index, for small and large time windows, both for small and large log-returns. These turbulent market volatility (of normalized log-returns) distributions can be sufficiently well fitted with a $\chi^2$-distribution. The transition between the small time scale model of nonextensive, intermittent process and the large scale Gaussian extensive homogeneous fluctuation picture is found to be at $ca.$ a 200 day time lag. The intermittency exponent ($\kappa$) in the framework of the Kolmogorov log-normal model is found to be related to the scaling exponent of the PDF moments, -thereby giving weight to the model. The large value of $\kappa$ points to a large number of cascades in the turbulent process. The first Kramers-Moyal coefficient in the Fokker-Planck equation is almost equal to zero, indicating ''no restoring force''. A comparison is made between normalized log-returns and mere price increments.Comment: 40 pages, 14 figures; accepted for publication in Phys Rev

Modeling Hot Tearing during Solidification of Steels: Assessment and Improvement of Macroscopic Criteria through the Analysis of Two Experimental Tests

International audienceHot tearing is an unacceptable defect found in products and parts obtained by solidification processes such as ingot and continuous casting. It consists of the development of cracks during solidification, in regions that are not completely solidified, more precisely, in areas of mushy zones with a high fraction of solid (typically 0.9 and beyond), when the material undergoes deformations associated with tensile stress. In this study, two hot tearing tests have been studied in order to evaluate the predictive capability of several macroscopic criteria published in the literature. The first test is a new test specifically designed for constrained shrinkage by the present authors, while the second test is an ingot bending test developed in the 1980s. For both tests, a thermal-mechanical analysis is performed, in order to provide the key variables for the different selected criteria. A comparison with experimental results allows us to make a critical assessment of those criteria regarding their ability to predict crack occurrence. The criterion initially proposed by Won et al.[7] has been found to be the best suited for the prediction of solidification cracking. Because this criterion is essentially based on the "brittle temperature range," (BTR) critical considerations regarding nonequilibrium solidification have led to suggest an extension of this criterion. This new macroscopic criterion improves the prediction capacity

Pharmacological Emergency management of Agitation in Children and Young people: protocol for a randomised controlled trial of intraMuscular medication (PEAChY-M)

Introduction: Acute severe behavioural disturbance (ASBD) is a condition seen with increasing frequency in emergency departments (EDs) in adults and young people. Despite the increasing number of presentations and significant associated risks to patients, families and caregivers, there is limited evidence to guide the most effective pharmacological management in children and adolescents. The aim of this study is to determine whether a single dose of intramuscular olanzapine is more effective than intramuscular droperidol at successfully sedating young people with ASBD requiring intramuscular sedation. Methods and analysis: This study is a multicentre, open-label, superiority randomised controlled trial. Young people aged between 9 and 17 years and 364 days presenting to an ED with ASBD who are deemed to require medication for behavioural containment will be recruited to the study. Participants will be randomised in a 1:1 allocation between a single weight-based dose of intramuscular olanzapine and intramuscular droperidol. The primary outcome is the proportion of participants who achieve successful sedation at 1-hour post randomisation without the need for additional sedation. Secondary outcomes will include assessing for adverse events, additional medications provided in the ED, further episodes of ASBD, length of stay in the ED and hospital and satisfaction with management. Effectiveness will be determined using an intention-to-treat analysis, with medication efficacy determined as part of the secondary outcomes using a per-protocol analysis. The primary outcome of successful sedation at 1 hour will be presented as a percentage within each treatment group, with comparisons presented as a risk difference with its 95% CIs. Ethics and dissemination: Ethics approval was received from the Royal Children’s Hospital Human Research Ethics Committee (HREC/69948/RCHM-2021). This incorporated a waiver of informed consent for the study. The findings will be disseminated in a peer-reviewed journal and at academic conferences. Trial registration number: ACTRN12621001238864.Elyssia M Bourke, Meredith L Borland, Amit Kochar, Shane George, Deborah Shellshear, Shefali Jani, Kent Perkins, Doris Tham, Michael Solomon Gordon, Kate Klein, Chidambaram Prakash, Katherine Lee, Andrew Davidson, Jonathan C Knott, Simon Craig, Franz E Babl, On behalf of the Paediatric research in Emergency Departments International Collaborative (PREDICT

Runx regulation of sphingolipid metabolism and survival signaling

The Runx genes (Runx1, 2, and 3) regulate cell fate in development and can operate as either oncogenes or tumor suppressors in cancer. The oncogenic potential of ectopic Runx expression has been shown in transgenic mice that develop lymphoma in potent synergy with overexpressed Myc, and in established fibroblasts that display altered morphology and increased tumorigenicity. Candidate oncogenic functions of overexpressed Runx genes include resistance to apoptosis in response to intrinsic and extrinsic stresses. In a search for gene targets responsible for this aspect of Runx phenotype, we have identified three key enzymes in sphingolipid metabolism (Sgpp1, Ugcg, and St3gal5/Siat9) as direct targets for Runx transcriptional regulation in a manner consistent with survival and apoptosis resistance. Consistent with these changes in gene expression, mass spectrometric analysis showed that ectopic Runx reduces intracellular long-chain ceramides in NIH3T3 fibroblasts and elevated extracellular sphingosine 1 phosphate. Runx expression also opposed the activation of c-Jun-NH2-kinase and p38(MAPK), key mediators of ceramide-induced death, and suppressed the onset of apoptosis in response to exogenous tumor necrosis factor alpha. The survival advantage conferred by ectopic Runx could be partially recapitulated by exogenous sphingosine 1 phosphate and was accompanied by reduced phosphorylation of p38(MAPK). These results reveal a novel link between transcription factor oncogenes and lipid signaling pathways involved in cancer cell survival and chemoresistance. Cancer Res; 70(14); 5860-9

Vomiting with head trauma and risk of traumatic brain injury

© 2018 by the American Academy of Pediatrics. OBJECTIVES: To determine the prevalence of traumatic brain injuries in children who vomit after head injury and identify variables from published clinical decision rules (CDRs) that predict increased risk. METHODS: Secondary analysis of the Australasian Paediatric Head Injury Rule Study. Vomiting characteristics were assessed and correlated with CDR predictors and the presence of clinically important traumatic brain injury (ciTBI) or traumatic brain injury on computed tomography (TBI-CT). Isolated vomiting was defined as vomiting without other CDR predictors. RESULTS: Of the 19 920 children enrolled, 3389 (17.0%) had any vomiting, with 2446 (72.2%) >2 years of age. In 172 patients with ciTBI, 76 had vomiting (44.2%; 95% confidence interval [CI] 36.9%-51.7%), and in 285 with TBI-CT, 123 had vomiting (43.2%; 95% CI 37.5%-49.0%). With isolated vomiting, only 1 (0.3%; 95% CI 0.0%-0.9%) had ciTBI and 2 (0.6%; 95% CI 0.0%-1.4%) had TBI-CT. Predictors of increased risk of ciTBI with vomiting by using multivariate regression were as follows: Signs of skull fracture (odds ratio [OR] 80.1; 95% CI 43.4-148.0), altered mental status (OR 2.4; 95% CI 1.0-5.5), headache (OR 2.3; 95% CI 1.3-4.1), and acting abnormally (OR 1.86; 95% CI 1.0-3.4). Additional features predicting TBI-CT were as follows: Skull fracture (OR 112.96; 95% CI 66.76-191.14), nonaccidental injury concern (OR 6.75; 95% CI 1.54-29.69), headache (OR 2.55; 95% CI 1.52-4.27), and acting abnormally (OR 1.83; 95% CI 1.10-3.06). CONCLUSIONS: TBI-CT and ciTBI are uncommon in children presenting with head injury with isolated vomiting, and a management strategy of observation without immediate computed tomography appears appropriate