Clinical and biological impact of ATP-binding cassette transporter activity in adult acute myeloid leukemia.

Chemotherapy resistance is the main cause of treatment failure in acute myeloid leukemia (AML) and has been related to ATP-binding cassette (ABC) transporter activity. However, the links between ABC activity, immunophenotype, and molecular AML parameters have been poorly evaluated. Moreover, the prognostic value of ABC activity, when compared to new molecular markers, is unknown.

CD28/4-1BB CD123 CAR T cells in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is associated with a remarkably poor prognosis and with no treatment consensus. The identification of relevant therapeutic targets is challenging. Here, we investigated the immune functions, antileukemia efficacy and safety of CD28/4-1BB CAR T cells targeting CD123 the interleukin (IL)-3 receptor alpha chain which is overexpressed on BPDCN.

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed.

Proportion of Cytotoxic Peripheral Blood Natural Killer Cells and T-Cell Large Granular Lymphocytes in Recurrent Miscarriage and Repeated Implantation Failure: Case-Control Study and Meta-analysis.

We aimed to compare the proportion of peripheral blood natural killer (NK) cells (CD3CD56) and T-cell large granular lymphocytes (CD8CD57) during preconception in a homogenous group of women with unexplained well-defined recurrent miscarriage (RM) and repeated implantation failure (RIF) vs healthy controls in relation to pregnancy outcomes. This case-control study followed by a literature review and meta-analysis was conducted in three university hospitals. Patients and controls were consecutively recruited from December 2015 to October 2017.

T-cell prolymphocytic leukemia and tuberculosis: a puzzling association.

T-cell prolymphocytic leukemia can result in severe immune T-cell deficiency. Clinicians should be aware of this complication in this rare lymphoid malignancy, and opportunistic infections should be ruled out before the use of usual immunosuppressive procedures such as alemtuzumab and hematopoietic stem cell transplantation.

Efficacy of a rituximab regimen based on B cell depletion in thrombotic thrombocytopenic purpura with suboptimal response to standard treatment: Results of a phase II, multicenter noncomparative study.

The standard four-rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti-ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study.

The spectrum of chronic CD8+ T-cell expansions: clinical features in 14 patients.

Chronic CD8(+) T-cell expansions can result in parotid gland swelling and other organ infiltration in HIV-infected patients, or in persistent cytopenias. We report 14 patients with a CD8+ T-cell expansion to better characterize the clinical spectrum of this ill-defined entity. Patients (9 women/5 men) were 65 year-old (range, 25-74).

[Polyclonal CD8+/CD57+ T cell expansions: clinical significance].

Polyclonal CD8(+)/CD57(+)T cell lymphocytosis can be observed in various conditions such as chronic viral infections, autoimmune cytopenias, connective tissue diseases, chronic graft-versus-host disease and primary or secondary immune deficiencies. This population results from the chronic stimulation of CD8(+)/CD28(+)/CD57(-)lymphocytes by exogenous (mostly infection-related), autologous or allogeneic antigens. Paralleling chronic antigen stimulation, these CD8(+) T cells acquire a poor capacity to proliferate in standard conditions in relation with the loss of CD28, whereas CD57 antigen becomes expressed at their surface.

Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor.

Objective: Most patients with systemic mastocytosis bear mutations in the tyrosine kinase receptor gene c-Kit. Limited treatment options exist for mast cell leukemia, a rare form of systemic mastocytosis associated with a dire prognosis. Our aim was to investigate c-Kit mutations associated with mast cell leukemia and find new treatment for this severe form of mastocytosis.

Blood CD34-c-Kit+ cell rate correlates with aggressive forms of systemic mastocytosis and behaves like a mast cell precursor.

Mastocytosis is a heterogeneous disease characterized by the accumulation of mast cells in one or more organs. Our objective was to identify a peripheral mast cell precursor and assess its variation rate in mastocytosis. A peripheral blood phenotypic analysis was performed among 50 patients with mastocytosis who were enrolled in a prospective multicentric French study, and the phenotypic analysis results of the patients were compared with those of healthy donors.

Acute left ventricular dilatation and shock-induced myocardial dysfunction.

Objective: Whether cardiac ventricles can acutely dilate during septic myocardial dysfunction.

Design: A prospective echocardiographic study was performed to assess changes of left ventricular dimensions over time in patients with septic shock.

Settings: A 20-bed surgical intensive care unit of Pitié-Salpêtrière university hospital in Paris.

Isolated and reversible impairment of ventricular relaxation in patients with septic shock.

Objective: Many patients with septic shock and increased cardiac troponin I (cTnI) do not exhibit significant left ventricular systolic dysfunction. We hypothesized that an isolated and reversible impairment of ventricular relaxation may be associated with the increase in cTnI.

Design: Prospective, observational study.

Phenotypic and genotypic characteristics of mastocytosis according to the age of onset.

Adult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114).

Solid-phase synthesis and evaluation of libraries of substituted 4,5-dihydropyridazinones as vasodilator agents.

The solid-phase parallel preparation of a library of 4,5-dihydropyridazin-3(2H)-one derivatives substituted at position 6 with piperazinylmethyl or tetrahydroquinolinylmethyl groups and analogues (3) is reported. Polymer-supported gamma-keto-delta-aminoesters prepared from Wang resin reacted with hydrazine or methylhydrazine to afford pyridazinones in good yields after a cyclization cleavage approach. We have evaluated these novel analogues and several compounds of other series (1, 2) for their vasorelaxant effect.

Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells.

In the present report we have analyzed whether human normal cord blood-derived mast cells (CBMC) could interact with bacterial products, especially lipopolysaccharide (LPS) from Escherichia coli and peptidoglycan (PGN) from Staphylococcus aureus, known as Toll-like receptor (TLR) 4 and TLR2 agonists, respectively. We found that both LPS and PGN induced significant release of not only tumor necrosis factor-alpha (TNF-alpha), but also IL-5, IL-10 and IL-13 by human mast cells (MC). We also established that the stimulation of CBMC with LPS or with PGN is mediated through interactions with TLR4 or with TLR2, respectively.

Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms.

Systemic mastocytosis (SM) is a rare disease caused by an abnormal mast cell accumulation in various tissues. Two classes of constitutive activating c-kit mutations are found in SM. The most frequent class occurs in the catalytic pocket coding region with substitutions at codon 816 and the other in the intracellular juxtamembrane coding region.

Kit and c-kit mutations in mastocytosis: a short overview with special reference to novel molecular and diagnostic concepts.

Mastocytosis is a heterogeneous group of hematopoietic disorders characterized by abnormal growth and accumulation of mast cells (MC) in one or more organs. Clinical symptoms occur as a result of the release of chemical mediators and/or of pathologic infiltration of MC in various tissues. Although the initial events leading to mastocytosis have not yet been unraveled, acquired alterations in the c-kit gene coding for the receptor of stem cell factor (SCF), a major cytokine involved in MC growth, have been described in a significant number of patients.

The role of mast cells in host defense and their subversion by bacterial pathogens.

Mast cells (MCs) play a prominent role in the early immune response to invading pathogenic bacteria. This newly discovered role for MCs involves the release of chemoattractants that recruit neutrophils and the direct phagocytosis and killing of opsonized bacteria. Whereas these activities are clearly beneficial to the host, certain pathogens have evolved mechanisms to evoke anomalous MC responses to the detriment of the host.

MplK, a natural variant of the thrombopoietin receptor with a truncated cytoplasmic domain, binds thrombopoietin but does not interfere with thrombopoietin-mediated cell growth.

Objective: Interaction of thrombopoietin (TPO) with its receptor c-Mpl is responsible for the formation of megakaryocytes and platelets. In humans, there are two major c-mpl molecules, MplP and MplK, which are generated by alternative splicing. In contrast to MplP, MplK has none of the intracellular sequences required for typical signal transduction but instead has a unique 27 amino acid sequence that is coded by intron 10.