Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis

AbstractThe promyelocytic leukemia (PML) protein is a potent growth suppressor and proapototic factor, whereas aberrant fusions of PML and retinoic acid receptor (RAR)-α are causal agents in human acute promyelocytic leukemia. Arsenic trioxide (As2O3) treatment induces apoptosis in acute promyelocytic leukemia cells through an incompletely understood mechanism. We report here that As2O3 treatment induces phosphorylation of the PML protein through a mitogen-activated protein (MAP) kinase pathway. Increased PML phosphorylation is associated with increased sumoylation of PML and increased PML-mediated apoptosis. Conversely, MAP kinase cascade inhibitors, or the introduction of phosphorylation or sumoylation-defective mutations of PML, impair As2O3-mediated apoptosis by PML. We conclude that phosphorylation by MAP kinase cascades potentiates the antiproliferative functions of PML and helps mediate the proapoptotic effects of As2O3

GATA2 zinc finger 2 mutation found in acute myeloid leukemia impairs myeloid differentiation

AbstractWe identified two novel GATA2 mutations in acute myeloid leukemia (AML). One mutation (p.R308P-GATA2) was a R308P substitution within the zinc finger (ZF)-1 domain, and the other (p.A350_N351ins8-GATA2) was an eight-amino-acid insertion between A350 and N351 residues within the ZF-2 domain. p.R308P-GATA2 did not affect DNA-binding and transcriptional activities, while p.A350_N351ins8-GATA2 reduced them, and impaired G-CSF-induced granulocytic differentiation of 32D cells. Although p.A350_N351ins8-GATA2 did not show a dominant-negative effect over wild-type (Wt)–GATA2 by the reporter assay, it might be involved in the pathophysiology of AML by impairing myeloid differentiation because of little Wt-GATA2 expression in primary AML cells harboring the p.A350_N351ins8 mutation

U-duality from Matrix Membrane Partition Function

We analyse supermembrane instantons (fully wrapped supermembranes) by computing the partition function of the three-dimensional supersymmetrical U(N) matrix model under periodic boundary conditions. By mapping the model to a cohomological field theory and considering a mass-deformation of the model, we show that the partition function exactly leads to the U-duality invariant measure factor entering supermembrane instanton sums. On the other hand, a computation based on the quasi-classical assumption gives the non U-duality invariant result of the zero-mode analysis by Pioline et al. This is suggestive of the importance of supermembrane self-interactions and shows a crucial difference from the matrix string case.Comment: harvmac, 16 pages. v2: minor textual changes. version to appear in Physics Letter

Oligodendrocyte Precursor Cells Support Blood-Brain Barrier Integrity via TGF-β Signaling

Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity

BCL6 inhibition ameliorates resistance to ruxolitinib in <i>CRLF2</i>-rearranged acute lymphoblastic leukemia

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is an intractable disease and most cases harbor genetic alterations that activate JAK or ABL signaling. The commonest subtype of Ph-like ALL exhibits a CRLF2 gene rearrangement that brings about JAK1/2-STAT5 pathway activation. However, JAK1/2 inhibition alone is insufficient as a treatment, so combinatorial therapies targeting multiple signals are needed. To better understand the mechanisms underlying the insufficient efficacy of JAK inhibition, we explored gene expression changes upon treatment with a JAK1/2 inhibitor (ruxolitinib) and found that elevated BCL6 expression was one such mechanism. Upregulated BCL6 suppressed the expression of TP53 along with its downstream cell cycle inhibitor p21 (CDKN2A) and pro-apoptotic molecules, such as FAS, TNFRSF10B, BID, BAX, BAK, PUMA, and NOXA, conferring cells some degree of resistance to therapy. BCL6 inhibition (with FX1) alone was able to upregulate TP53 and restore the TP53 expression that ruxolitinib had diminished. In addition, ruxolitinib and FX1 concertedly downregulated MYC. As a result, FX1 treatment alone had growth-inhibitory and apoptosis- sensitizing effects, but the combination of ruxolitinib and FX1 more potently inhibited leukemia cell growth, enhanced apoptosis sensitivity, and prolonged the survival of xenografted mice. These findings provide one mechanism for the insufficiency of JAK inhibition for the treatment of CRLF2-rearranged ALL and indicate BCL6 inhibition as a potentially helpful adjunctive therapy combined with JAK inhibition

Results of the search for inspiraling compact star binaries from TAMA300's observation in 2000-2004

We analyze the data of TAMA300 detector to search for gravitational waves from inspiraling compact star binaries with masses of the component stars in the range 1-3Msolar. In this analysis, 2705 hours of data, taken during the years 2000-2004, are used for the event search. We combine the results of different observation runs, and obtained a single upper limit on the rate of the coalescence of compact binaries in our Galaxy of 20 per year at a 90% confidence level. In this upper limit, the effect of various systematic errors such like the uncertainty of the background estimation and the calibration of the detector's sensitivity are included.Comment: 8 pages, 4 Postscript figures, uses revtex4.sty The author list was correcte

Observation results by the TAMA300 detector on gravitational wave bursts from stellar-core collapses

We present data-analysis schemes and results of observations with the TAMA300 gravitational-wave detector, targeting burst signals from stellar-core collapse events. In analyses for burst gravitational waves, the detection and fake-reduction schemes are different from well-investigated ones for a chirp-wave analysis, because precise waveform templates are not available. We used an excess-power filter for the extraction of gravitational-wave candidates, and developed two methods for the reduction of fake events caused by non-stationary noises of the detector. These analysis schemes were applied to real data from the TAMA300 interferometric gravitational wave detector. As a result, fake events were reduced by a factor of about 1000 in the best cases. The resultant event candidates were interpreted from an astronomical viewpoint. We set an upper limit of 2.2x10^3 events/sec on the burst gravitational-wave event rate in our Galaxy with a confidence level of 90%. This work sets a milestone and prospects on the search for burst gravitational waves, by establishing an analysis scheme for the observation data from an interferometric gravitational wave detector

Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group

The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR\u27ABL-negative ALL. Patients aged 15\u2724 years (n = 139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58\u2775%) and 73% (95% CI 64\u2780%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, Po0.001).These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR\u27ABL-negative ALL

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements