Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant

Adoptive immunotherapy with ex vivo expanded T cells is a promising approach to prevent or treat leukemia. Myeloid leukemias express tumor-associated antigens (TAA) that induce antigen-specific cytotoxic T lymphocyte (CTL) responses in healthy individuals. We explored the feasibility of generating TAA-specific CTLs from stem cell donors of patients with myeloid leukemia to enhance the graft-versus-leukemia effect after stem cell transplantation. CTL lines were manufactured from peripheral blood of 10 healthy donors by stimulation with 15mer peptide libraries of five TAA (proteinase 3 (Pr3), preferentially expressed antigen in melanoma, Wilms tumor gene 1 (WT1), human neutrophil elastase (NE) and melanoma-associated antigen A3) known to be expressed in myeloid leukemias. All CTL lines responded to the mix of five TAA and were multi-specific as assessed by interferon-γ enzyme-linked immunospot. Although donors showed individual patterns of antigen recognition, all responded comparably to the TAAmix. Immunogenic peptides of WT1, Pr3 or NE could be identified by epitope mapping in all donor CTL lines. In vitro experiments showed recognition of partially human leukocyte antigen (HLA)-matched myeloid leukemia blasts. These findings support the development of a single clinical grade multi-tumor antigen-specific T-cell product from the stem cell source, capable of broad reactivity against myeloid malignancies for use in donor-recipient pairs without limitation to a certain HLA-type

Proving Properties of Constraint Logic Programs by Eliminating Existential Variables

We propose a method for proving first order properties of constraint logic programs which manipulate finite lists of real numbers. Constraints are linear equations and inequations over reals. Our method consists in converting any given first order formula into a stratified constraint logic program and then applying a suitable unfold/fold transformation strategy that preserves the perfect model. Our strategy is based on the elimination of existential variables, that is, variables which occur in the body of a clause and not in its head. Since, in general, the first order properties of the class of programs we consider are undecidable, our strategy is necessarily incomplete. However, experiments show that it is powerful enough to prove several non-trivial program properties

Probabilistic Unfoldings and Partial Order Fairness in Petri Nets

International audienceThe article investigates fairness and conspiracy in a probabilistic framework, based on unfoldings of Petri nets. Here, the unfolding semantics uses a new, cluster-based view of local choice. The algorithmic construction of the unfolding proceeds on two levels, choice of steps inside conflict clusters, where the choice may be fair or unfair, and the policy controlling the order in which clusters may act; this policy may or may not conspire, e.g., against a transition. In the context of an example where conspiracy can hide in the partial order behavior of a life and 1-safe Petri net, we show that, under non-degenerate i.i.d. randomization on both levels, both conspiracy and unfair behavior have probability 0. The probabilistic model, using special Gibbs potentials, is presented here in the context of 1-safe nets, but extends to any Petri net

Frequency and prognostic implications of JAK 1-3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia.

No abstract availabl

Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% ± 2% vs 15% ± 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% ± 1% vs 2.0% ± <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% ± 2% vs 81% ± 2%, P < .0001) and overall survival (74% ± 2% vs 89% ± 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 × 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.Trudy D. Buitenkamp, Shai Izraeli, Martin Zimmermann, Erik Forestier, Nyla A. Heerema ... Charles G. Mullighan ... et al

Neuropsychological Assessment Using Virtual Environments: Enhanced Assessment Technology for Improved Ecological Validity

Abstract. Although today’s neuropsychological assessment procedures are widely used, neuropsychologists have been slow to embrace technological advancements. Two essential limitations have resulted from this refusal of techno-logical adaptation: First, current neuropsychological assessment procedures repre-sent a technology that has barely changed since the first scales were developed in the early 1900s. Second, while the historical purpose of clinical neuropsychology was differential diagnosis of brain pathology, technological advances in other clinical neurosciences have changed the neuropsychologist’s role to that of mak-ing ecologically valid predictions about the impact of a given patient’s neurocog-nitive abilities and disabilities on everyday functioning. After a brief discussion of current applications of computer-based neuropsychological assessment, there is a discussion of an increasingly important topic in recent decades—the design of ecologically valid neuropsychological instruments to address real world out-comes. Finally, there is an exploration of virtual reality environments for ecologi-cally valid neuropsychological assessments that make use of current technological advances. It is concluded that a future possible virtual reality-based neuropsy-chological assessment battery will combine the control and rigor of technologi-cally advanced computerized laboratory measures, the psychometric rigor (i.e., veridicality) of traditional paper-and-pencil assessments, and verisimilitude ap-proximating real life situations.

Germline <i>AGO2</i> mutations impair RNA interference and human neurological development

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development. AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference