Lack of effect of the human GM-CSF analog E21R on the survival of primary human acute myeloid leukemia cells

The granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R binds to the GM-CSF receptor complex with low affinity and acts as a competitive antagonist. In addition, it has been reported to be a potent direct activator of apoptosis in primary human acute myeloid leukemia (AML) cells. We have confirmed the ability of E21R to neutralize the biologic effects of GM-CSF and investigated its activity on primary AML blasts. We find that it failed to induce cell death in blast cells from 23 separate AML cases treated in vitro at concentrations of E21R up to 30 µg/mL. Significant cell death resulted in all cases after incubation with cytosine arabinoside. The lack of effect of E21R on AML blasts was unlikely to be due to an absence of functional GM-CSF receptors because 13 cases demonstrated an increase in cell number with the addition of exogenous GM-CSF. These results do not support the use of E21R for the treatment of AML

Supergravity loop contributions to brane world supersymmetry breaking

We compute the supergravity loop contributions to the visible sector scalar masses in the simplest 5D `brane-world' model. Supersymmetry is assumed to be broken away from the visible brane and the contributions are UV finite due to 5D locality. We perform the calculation with N = 1 supergraphs, using a formulation of 5D supergravity in terms of N = 1 superfields. We compute contributions to the 4D effective action that determine the visible scalar masses, and we find that the mass-squared terms are negative.Comment: 12 pages, LaTeX 2

Impaired bone marrow homing of cytokine-activated CD34⁺ cells in the NOD/SCID model

The reduced engraftment potential of hematopoietic stem/progenitor cells (HSPCs) after exposure to cytokines may be related to the impaired homing ability of actively cycling cells. We tested this hypothesis by quantifying the short-term horning of human adult CD34+ cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) animals. We show that the loss of engraftment ability of cytokine-activated CD34+ cells is associated with a reduction in homing of colony-forming cells (CFCs) to bone marrow (BM) at 24 hours after transplantation (from median 2.8% [range, 1.9%-6.1%] to 0.3% [0.0%-0.7%]; n = 3; P < .01), coincident with an increase in CFC accumulation in the lungs (P < .01). Impaired BM homing of cytokine-activated cells was not restored by using sorted cells in G 0G1 or by inducing cell cycle arrest at the G 1/S border. Blocking Fas ligation in vivo did not increase the BM homing of cultured cells. Finally, we tested cytokine combinations or culture conditions previously reported to restore the engraftment of cultured cells but did not find that any of these was able to reverse the changes in homing behavior of cytokine-exposed cells. We suggest that these changes in homing and, as a consequence, engraftment result from the increased migratory capacity of infused activated cells, leading to the loss of selectivity of the homing process. © 2004 by The American Society of Hematology

Chiral Supergravitons Interacting with a 0-Brane N-Extended NSR Super-Virasoro Group

We continue the development of the actions, S_{AFF}, by examining the cases where there are N fermionic degrees of freedom associated with a 0-brane. These actions correspond to the interaction of the N-extended super Virasoro algebra with the supergraviton and the associated SO(N) gauge field that accompanies the supermultiplet. The superfield formalism is used throughout so that supersymmetry is explicit.Comment: PACS: 04.65.+e, 11.15.-q, 11.25.-w, 12.60.

Additional impact of mutational genotype on prognostic determination in resistant and relapsed acute myeloid leukaemia

Outcome after failure of initial therapy in younger adult patients with acute myeloid leukaemia (AML) is highly variable. Cytogenetics, length of first remission (CR1) before relapse, and allogeneic transplantation are known prognostic factors, but the contribution of leukaemic genotype is less clear, particularly in resistant disease. Of 5,651 younger adult patients entered into UK MRC/NCRI AML trials between 1988 and 2014 with available FLT3ITD and NPM1 genotype, 326 (6%) had resistant disease and 2338 (41 %) relapsed after achieving CR1. Overall survival (OS) was significantly higher in relapsed compared to resistant disease (p = 0·03). Independent favourable prognostic factors for OS in resistant disease included lower blast cell percentage after two courses of induction therapy (p = 0.0006) and NPM1 mutant (NPM1MUT) (p = 0.04). In relapsed disease, longer CR1 was a favourable independent factor for attainment of CR2 (p < 0.0001) and OS from time of relapse (p < 0.0001), but CR2 rate and OS from relapse were significantly worse in those who had received an allograft in CR1 (respectively p < 0.05, p < 0·002). NPM1MUT was marginally beneficial for OS (p = 0.04). FLT3ITD and DNMT3AMUT were adverse factors for OS (respectively p < 0.0001, p = 0.02). Mutational analysis adds additional independent prognostic information to demographic features and previous therapy in patients with resistant and relapsed disease

Covariant N=2 heterotic string in four dimensions

We construct a covariant formulation of the heterotic superstring on K3 times T^2 with manifest N=2 supersymmetry. We show how projective superspace appears naturally in the hybrid formulation giving a (partially) geometric interpretation of the harmonic parameter. The low-energy effective action for this theory is given by a non-standard form of N=2 supergravity which is intimately related to the N=1 old-minimal formulation. This formalism can be used to derive new descriptions of interacting projective superspace field theories using Berkovits' open string field theory and the the heterotic Berkovits-Okawa-Zwiebach construction.Comment: 11+3 page

Impact of PTEN abnormalities on outcome in pediatric patients with T-cell acute lymphoblastic leukemia treated on the MRC UKALL2003 trial.

PTEN gene inactivation by mutation or deletion is common in pediatric T-cell acute lymphoblastic leukemia (T-ALL), but the impact on outcome is unclear, particularly in patients with NOTCH1/FBXW7 mutations. We screened samples from 145 patients treated on the MRC UKALL2003 trial for PTEN mutations using heteroduplex analysis and gene deletions using single nucleotide polymorphism arrays, and related genotype to response to therapy and long-term outcome. PTEN loss-of-function mutations/gene deletions were detected in 22% (PTEN(ABN)). Quantification of mutant level indicated that 67% of mutated cases harbored more than one mutant, with up to four mutants detected, consistent with the presence of multiple leukemic sub-clones. Overall, 41% of PTEN(ABN) cases were considered to have biallelic abnormalities (mutation and/or deletion) with complete loss of PTEN in a proportion of cells. In addition, 9% of cases had N- or K-RAS mutations. Neither PTEN nor RAS genotype significantly impacted on response to therapy or long-term outcome, irrespective of mutant level, and there was no evidence that they changed the highly favorable outcome of patients with double NOTCH1/FBXW7 mutations. These results indicate that, for pediatric patients treated according to current protocols, routine screening for PTEN or RAS abnormalities at diagnosis is not warranted to further refine risk stratification.Leukemia advance online publication, 21 August 2015; doi:10.1038/leu.2015.206

In situ labeling of DNA reveals interindividual variation in nuclear DNA breakdown in hair and may be useful to predict success of forensic genotyping of hair

Hair fibers are formed by keratinocytes of the hair follicle in a process that involves the breakdown of the nucleus including DNA. Accordingly, DNA can be isolated with high yield from the hair bulb which contains living keratinocytes, whereas it is difficult to prepare from the distal portions of hair fibers and from shed hair. Nevertheless, forensic investigations are successful in a fraction of shed hair samples found at crime scenes. Here, we report that interindividual differences in the completeness of DNA removal from hair corneocytes are major determinants of DNA content and success rates of forensic investigations of hair. Distal hair samples were permeabilized with ammonia and incubated with the DNA-specific dye Hoechst 33258 to label DNA in situ. Residual nuclear DNA was visualized under the fluorescence microscope. Hair from some donors did not contain any stainable nuclei, whereas hair of other donors contained a variable number of DNA-positive nuclear remnants. The number of DNA-containing nuclear remnants per millimeter of hair correlated with the amount of DNA that could be extracted and amplified by quantitative PCR. When individual hairs were investigated, only hairs in which DNA could be labeled in situ gave positive results in short tandem repeat typing. This study reveals that the completeness of DNA degradation during cornification of the hair is a polymorphic trait. Furthermore, our results suggest that in situ labeling of DNA in hair may be useful for predicting the probability of success of forensic analysis of nuclear DNA in shed hair

Mediation of supersymmetry breaking in extra dimensions

We review the mechanisms of supersymmetry breaking mediation that occur in sequestered models, where the visible and the hidden sectors are separated by an extra dimension and communicate only via gravitational interactions. By locality, soft breaking terms are forbidden at the classical level and reliably computable within an effective field theory approach at the quantum level. We present a self-contained discussion of these radiative gravitational effects and the resulting pattern of soft masses, and give an overview of realistic model building based on this set-up. We consider both flat and warped extra dimensions, as well as the possibility that there be localized kinetic terms for the gravitational fields.Comment: LaTex, 15 pages; brief review prepared for MPLA. v2: minor correction

Massive Supergravity and Deconstruction

We present a simple superfield Lagrangian for massive supergravity. It comprises the minimal supergravity Lagrangian with interactions as well as mass terms for the metric superfield and the chiral compensator. This is the natural generalization of the Fierz-Pauli Lagrangian for massive gravity which comprises mass terms for the metric and its trace. We show that the on-shell bosonic and fermionic fields are degenerate and have the appropriate spins: 2, 3/2, 3/2 and 1. We then study this interacting Lagrangian using goldstone superfields. We find that a chiral multiplet of goldstones gets a kinetic term through mixing, just as the scalar goldstone does in the non-supersymmetric case. This produces Planck scale (Mpl) interactions with matter and all the discontinuities and unitarity bounds associated with massive gravity. In particular, the scale of strong coupling is (Mpl m^4)^1/5, where m is the multiplet's mass. Next, we consider applications of massive supergravity to deconstruction. We estimate various quantum effects which generate non-local operators in theory space. As an example, we show that the single massive supergravity multiplet in a 2-site model can serve the function of an extra dimension in anomaly mediation.Comment: 24 pages, 2 figures, some color. Typos fixed and refs added in v