bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of dendritic cell differentiation pathways from cord blood CD34+CD7+CD45RA+hematopoietic progenitor cells
Authors: Canque Bruno , Camus Sandrine , Dalloul Ali , Kahn Edmond , Yagello Micaël , Dezutter-Dambuyant Colette , Schmitt Daniel , Schmitt Christian , Gluckman Jean Claude 
Published: October 2019

AbstractTo better characterize human dendritic cells (DCs) that originate from lymphoid progenitors, the authors examined the DC differentiation pathways from a novel CD7+CD45RA+ progenitor population found among cord blood CD34+ cells. Unlike CD7−CD45RA+ and CD7+CD45RA− progenitors, this population displayed high natural killer (NK) cell differentiation capacity when cultured with stem cell factor (SCF), interleukin (IL)-2, IL-7, and IL-15, attesting to its lymphoid potential. In cultures with SCF, Flt3 ligand (FL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α (standard condition), CD7+CD45RA+ progenitors expanded less (37- vs 155-fold) but yielded 2-fold higher CD1a+ DC percentages than CD7−CD45RA+ or CD7+CD45RA− progenitors. As reported for CD34+CD1a− thymocytes, cloning experiments demonstrated that CD7+CD45RA+ cells comprised bipotent NK/DC progenitors. DCs differentiated from CD7−CD45RA+ and CD7+CD45RA+ progenitors differed as to E-cadherin CD123, CD116, and CD127 expression, but none of these was really discriminant. Only CD7+CD45RA+ or thymic progenitors differentiated into Lag+S100+Langerhans cells in the absence of exogenous transforming growth factor (TGF)-β1. Analysis of the DC differentiation pathways showed that CD7+CD45RA+ progenitors generated CD1a+CD14− precursors that were macrophage-colony stimulating factor (M-CSF) resistant and CD1a−CD14+ precursors that readily differentiated into DCs under the standard condition. Accordingly, CD7+CD45RA+ progenitor-derived mature DCs produced 2- to 4-fold more IL-6, IL-12, and TNF-α on CD40 ligation and elicited 3- to 6-fold higher allogeneic T-lymphocyte reactivity than CD7−CD45RA+ progenitor-derived DCs. Altogether, these findings provide evidence that the DCs that differentiate from cord blood CD34+CD7+CD45RA+ progenitors represent an original population for their developmental pathways and function.
CD2-mediated IL-12–dependent signals render human γδ-T cells resistant to mitogen-induced apoptosis, permitting the large-scale ex vivo expansion of functionally distinct lymphocytes: implications for the development of adoptive immunotherapy strategies
Authors: Lopez Richard D. , Xu Shan , Guo Ben , Negrin Robert S. , Waller Edmund K. 
Published: October 2019

AbstractThe ability of human γδ-T cells to mediate a number of in vitro functions, including innate antitumor and antiviral activity, suggests these cells can be exploited in selected examples of adoptive immunotherapy. To date, however, studies to examine such issues on a clinical scale have not been possible, owing in large measure to the difficulty of obtaining sufficient numbers of viable human γδ-T cells given their relative infrequency in readily available tissues. Standard methods used to expand human T cells often use a combination of mitogens, such as anti–T-cell receptor antibody OKT3 and interleukin (IL)-2. These stimuli, though promoting the expansion of αβ-T cells, usually do not promote the efficient expansion of γδ-T cells. CD2-mediated, IL-12–dependent signals that result in the selective expansion of human γδ-T cells from cultures of mitogen-stimulated human peripheral blood mononuclear cells are identified. It is first established that human γδ-T cells are exquisitely sensitive to apoptosis induced by T-cell mitogens OKT3 and IL-2. Next it is shown that the CD2-mediated IL-12–dependent signals, which lead to the expansion of γδ-T cells, do so by selectively protecting subsets of human γδ-T cells from mitogen-induced apoptosis. Finally, it is demonstrated that apoptosis-resistant γδ-T cells are capable of mediating significant antitumor cytotoxicity against a panel of human-derived tumor cell lines in vitro. Both the biologic and the practical implications of induced resistance to apoptosis in γδ-T cells are considered and discussed because these findings may play a role in the development of new forms of adoptive cellular immunotherapy.
Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study
Authors: Slovak Marilyn L. , Kopecky Kenneth J. , Cassileth Peter A. , Harrington David H. , Theil Karl S. , Mohamed Anwar , Paietta Elizabeth , Willman Cheryl L. , Head David R. , Rowe Jacob M. , Forman Stephen J. , Appelbaum Frederick R. 
Published: October 2019

Abstract
The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P &lt; .0001) among the 4 groups: favorable, 84% (95% confidence interval [CI], 77%-90%); intermediate, 76% (CI, 71%-81%); unfavorable, 55% (CI, 48%-63%); and unknown, 54% (CI, 33%-74%). There was similar significant heterogeneity of OS (P &lt; .0001), with the estimated relative risk of death from any cause being 1.50 (CI, 1.10-2.05), 3.33 (CI, 2.43-4.55), and 2.66 (CI, 1.59-4.45) for the intermediate, unfavorable, and unknown risk groups, respectively, compared with the favorable group. In multivariate analyses, the effects of cytogenetic risk status on CR rate and OS could not be explained by other patient or disease characteristics. Among postremission patients, survival from CR varied significantly among favorable, intermediate, and unfavorable groups (P = .0003), with significant evidence of interaction (P = .017) between the effects of treatment and cytogenetic risk status on survival. Patients with favorable cytogenetics did significantly better following ABMT and alloBMT than with chemotherapy alone, whereas patients with unfavorable cytogenetics did better with alloBMT. Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.
Interferon α prevents spontaneous apoptosis of clonal Th2 cells associated with chronic hypereosinophilia
Authors: Schandené Liliane , Roufosse Florence , de Lavareille Aurore , Stordeur Patrick , Efira André , Kennès Bernard , Cogan Elie , Goldman Michel 
Published: October 2019

AbstractA recent study identified a clonal expansion of CD3−CD4+cells secreting Th2-type cytokines in 4 patients with chronic hypereosinophilia. Because interferon α (IFN-α) is used in the therapy of the idiopathic hypereosinophilic syndrome, the effects of this cytokine on the survival of clonal Th2 cells isolated from the blood of 2 patients were determined. First, these cells displayed a high rate of spontaneous apoptosis on culture in cytokine-free medium and were also sensitive to Fas-mediated apoptosis induced by soluble Fas ligand. Addition of IFN-α or interleukin-2 (IL-2) to culture medium resulted in significant protection against spontaneous but not Fas-induced apoptosis. Although spontaneous apoptosis of the clonal Th2 cells was clearly associated with down-regulation of both bcl-2 and bcl-xL levels, IFN-α had no significant effect on the expression of these antiapoptotic proteins, whereas addition of IL-2 resulted in higher levels of bcl-2. On the other hand, IFN-α decreased the numbers of cells with disrupted mitochondrial transmembrane potential both during spontaneous apoptosis and after exposure to protoporphyrin IX. Thus, IFN-α might promote the survival of clonal Th2 cells, an effect that could be relevant to the therapeutic approach for patients with chronic hypereosinophilia caused by clonal expansion of Th2-type cells.
Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy
Authors: Yokozaki Shouichi , Takamatsu Junki , Nakano Isao , Katano Yoshiaki , Toyoda Hidenori , Hayashi Kazuhiko , Hayakawa Tetsuo , Fukuda Yoshihide 
Published: October 2019

AbstractInfection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV) or both is common in hemophiliac patients due to putative transmission through clotting factor concentrates. Recently, highly active antiretroviral therapy (HAART) has been found to markedly improve viremia and immunologic parameters in patients infected with HIV. This report considers interactions between these viral infections, the immune system, and antiretroviral therapy. A total of 130 male hemophiliac patients were grouped according to type of viremia (HCV, HIV, both, or neither). Along with 30 healthy men age-matched to viremic patients, these groups were compared with respect to viral load and immunologic parameters. Thirty-five patients treated as above for HIV were serially followed up. HCV infection was associated with reduced peripheral B-cell and CD4+-cell counts and with increased serum IgG and IgM levels, whereas HIV infection was associated with reduced peripheral CD4+-cell counts and increased serum IgG and IgA levels. In patients with both viruses, HCV and HIV RNA load correlated inversely with peripheral B-cell and CD4+-cell counts, respectively. HAART reduced levels of both viruses in the blood. Of the 25 patients with both viruses, HAART eliminated HCV in 2. In conclusion, immunologic dynamics differed between hemophiliac patients infected with HCV, HIV, or both. The relative dynamics of HCV viral load, peripheral B-cell count, and serum IgM level were similar to those of HIV viral load, CD4+-cell count, and serum IgA.
BAL is a novel risk-related gene in diffuse large B-cell lymphomas that enhances cellular migration
Authors: Aguiar Ricardo C. T. , Yakushijin Yoshihiro , Kharbanda Samir , Salgia Ravi , Fletcher Jonathan A. , Shipp Margaret A. 
Published: October 2019

Abstract
Clinical risk factor models such as the International Prognostic Index are used to identify diffuse large B-cell lymphoma (DLB-CL) patients with different risks of death from their diseases. To elucidate the molecular bases for these observed clinical differences in outcome, differential display was used to identify a novel gene, termed BAL (B-aggressivelymphoma), which is expressed at significantly higher levels in fatal high-risk DLB-CLs than in cured low-risk tumors. The major BAL complementary DNA encodes a previously uncharacterized 88-kd nuclear protein with a duplicated N-terminal domain homologous to the nonhistone portion of histone-macroH2A and a C-terminal alpha-helical region with 2 short coiled-coil domains. Of note, the BAL N-terminus and secondary structure resemble those of a recently identified human protein, KIAA1268. In addition, bothBAL and KIAA1268 map to chromosome 3q21, further suggesting that these genes belong to a newly identified family. BAL is expressed at increased levels in DLB-CL cell lines with an activated peripheral B cell, rather than a germinal center B cell, phenotype. This observation and the characteristic dissemination of high risk DLB-CLs prompted studies regarding the role of BAL in B-cell migration. In classical transwell assays, stable BAL-overexpressing B-cell lymphoma transfectants had significantly higher rates of migration than vector-only transfectants, indicating that the risk-related BAL gene promotes malignant B-cell migration.
Similar pattern of thymic-dependent T-cell reconstitution in infants with severe combined immunodeficiency after human leukocyte antigen (HLA)–identical and HLA-nonidentical stem cell transplantation
Authors: Müller Susanna M. , Kohn Thomas , Schulz Ansgar S. , Debatin Klaus-Michael , Friedrich Wilhelm 
Published: October 2019

AbstractDonor T cells after stem cell transplantation reconstitute by 2 different pathways: by expansion from grafted, mature T cells and by intrathymic maturation from progenitor cells. This study characterized thymic-dependent reconstitution of CD4+ T cells following different transplant modalities in patients with severe combined immunodeficiency (SCID). Three groups of patients were studied: one group after transplantation from human leukocyte antigen (HLA)–identical siblings with unmanipulated grafts without conditioning, a second group after transplantation from HLA-nonidentical parents with T-cell–depleted grafts without preconditioning, and a third group with prior conditioning. Reconstitution of the T-cell compartment was monitored by determining the expression of CD45 isoforms by developing CD4+ cells in the peripheral blood and in discriminating expanded (CD45RO+) and newly generated (CD45RA+) T cells. Concomitantly, changes in the size of the thymus were evaluated sequentially by ultrasonography. Reconstitution of CD4+CD45RA+ cells was delayed in all patients for several months, including patients after HLA-identical transplantation, and was always paralleled by normalization of the size of the thymus. No engraftment of donor progenitor cells was observed, as studied in one patient transplanted without conditioning. CD4+CD45RO+ cells were detected early after transplantation only in patients given unmanipulated grafts. The study showed that thymic-dependent T-cell maturation in these patients with SCID runs an autonomous course, independent of graft manipulation, of major HLA disparities, and of whether conditioning is used or not. In addition, thymic maturation may not require engraftment of donor-derived CD34+ cells in the marrow.
Abnormalities of primitive myeloid progenitor cells expressing granulocyte colony-stimulating factor receptor in patients with severe congenital neutropenia
Authors: Nakamura Kazuhiro , Kobayashi Masao , Konishi Nakao , Kawaguchi Hiroshi , Miyagawa Shin-ichiro , Sato Takashi , Toyoda Hidemi , Komada Yoshihiro , Kojima Seiji , Katoh Osamu , Ueda Kazuhiro 
Published: October 2019

Abstract
To define the basis for faulty granulopoiesis in patients with severe congenital neutropenia (SCN), the expression of granulocyte colony-stimulating factor receptor (G-CSFR) in primitive myeloid progenitor cells and their responsiveness to hematopoietic factors were studied. Flow cytometric analysis of bone marrow cells based on the expression of CD34, Kit receptor, and G-CSFR demonstrated a reduced frequency of CD34+/Kit+/ G-CSFR+cells in patients with SCN. The granulocyte-macrophage colony formation of CD34+/Kit+/G-CSFR+ cells in patients was markedly decreased in response to G-CSF alone and to the combination of stem cell factor, the ligand for flk2/flt3, and IL-3 with or without G-CSF in serum-deprived semisolid culture. In contrast, no difference in the responsiveness of CD34+/Kit+/G-CSFR− cells was noted between patients with SCN and subjects without SCN. These results demonstrate that the presence of qualitative and quantitative abnormalities of primitive myeloid progenitor cells expressing G-CSFR may play an important role in the impairment of granulopoiesis in patients with SCN.
The PI3 kinase, p38 SAP kinase, and NF-κB signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte–derived dendritic cells
Authors: Ardeshna Kirit M. , Pizzey Arnold R. , Devereux Stephen , Khwaja Asim 
Published: October 2019

AbstractAs a dendritic cell (DC) matures, it becomes more potent as an antigen-presenting cell. This functional change is accompanied by a change in DC immunophenotype. The signal transduction events underlying this process are poorly characterized. In this study, we have investigated the signal transduction pathways involved in the lipopolysaccharide (LPS)-induced maturation of human monocyte–derived DCs (MoDCs) in vitro. We show that exposure of immature MoDCs to LPS activates the p38 stress-activated protein kinase (p38SAPK), extracellular signal–regulated protein kinase (ERK), phosphoinositide 3-OH kinase (PI3 kinase)/Akt, and nuclear factor (NF)-κB pathways. Studies using inhibitors demonstrate that PI3 kinase/Akt but not the other pathways are important in maintaining survival of LPS-stimulated MoDCs. Inhibiting p38SAPK prevented activation of the transcription factors ATF-2 and CREB and significantly reduced the LPS-induced up-regulation of CD80, CD83, and CD86, but did not have any significant effect on the LPS-induced changes in macropinocytosis or HLA-DR, CD40, and CD1a expression. Inhibiting the NF-κB pathway significantly reduced the LPS-induced up-regulation of HLA-DR as well as CD80, CD83, and CD86. Inhibiting the p38SAPK and NF-κB pathways simultaneously had variable effects depending on the cell surface marker studied. It thus appears that different aspects of LPS-induced MoDC maturation are regulated by different and sometimes overlapping pathways.
Differential use of FasL- and perforin-mediated cytolytic mechanisms by T-cell subsets involved in graft-versus-myeloid leukemia responses
Authors: Hsieh Michael H. , Korngold Robert 
Published: October 2019

AbstractIn graft-versus-leukemia (GVL) responses, the cellular subsets and effector mechanisms responsible for cytotoxicity against leukemic cells in vivo remain poorly characterized. A murine model of syngeneic GVL that features CD4+ and CD8+T-cell responses against the MMB3.19 myeloid leukemia cell line has been previously described. MMB3.19 expresses high levels of functional Fas and tumor necrosis factor (TNF) receptors that do not transduce proapoptotic signals. Through the use of perforin- and Fas ligand (FasL)-deficient mice, it was demonstrated that CD4+ T cells mediate anti-MMB3.19 effects in vivo primarily through the use of FasL and secondarily through perforin mechanisms. Conversely, CD8+ T cells induce GVL effects primarily through the use of perforin and minimally through FasL mechanisms. Although the in vivo observations of CD8+ T cells were reflective of their in vitro cytotoxic T lymphocyte (CTL) activity, for CD4+ T cells, in vitro responses were dominated by the perforin pathway. In addition, the diminished capacity of T cells from perforin- and FasL-deficient mice to lyse MMB3.19 target cells appeared directly related to their deficient cytotoxic functions rather than to defects in activation because these cells were fully capable of mounting proliferative responses to the tumor cells. These findings demonstrate that GVL responses of T-cell subsets can involve preferential use of different cytotoxic mechanisms. In particular, these findings identify a role for both FasL-employing CD4+CTLs and the more novel perforin-utilizing CD4+ T-cell subset in responses against a myeloid leukemia.
The molecular defect in hypotransferrinemic mice
Authors: Trenor Cameron C. , Campagna Dean R. , Sellers Vera M. , Andrews Nancy C. , Fleming Mark D. 
Published: October 2019

Abstract
Hypotransferrinemic (Trfhpx/hpx) mice have a severe deficiency in serum transferrin (Trf) as the result of a spontaneous mutation linked to the murine Trf locus. They are born alive, but before weaning, die from severe anemia if they are not treated with exogenous Trf or red blood cell transfusions. We have determined the molecular basis of the hpx mutation. It results from a single point mutation, which alters an invariable nucleotide in the splice donor site after exon 16 of the Trf gene. No normalTrf messenger RNA (mRNA) is made from the hpx allele. A small amount of mRNA results from the usage of cryptic splice sites within exon 16. The predominant cryptic splice site produces aTrf mRNA carrying a 27-base pair (bp), in-frame deletion. Less than 1% of normal levels of a Trf-like protein is found in the serum of Trfhpx/hpx mice, most likely resulting from translation of the internally deleted mRNA. Despite their severe Trf deficiency, however,Trfhpx/hpx mice initially treated with transferrin injections can survive after weaning without any further treatment. They have massive tissue iron overload develop in all nonhematopoietic tissues, while they continue to have severe iron deficiency anemia. Their liver iron burden is 100-fold greater than that of wild-type mice and 15- to 20-fold more than that of mice lacking the hemochromatosis gene, Hfe. Trfhpx/hpx mice thus provide an additional model with a defined molecular defect for the study of genetic iron disorders.
Molecular characterization of a granulocyte macrophage–colony-stimulating factor receptor α subunit-associated protein, GRAP
Authors: Tu Jiangling , Karasavvas Nicos , Heaney Mark L. , Vera Juan Carlos , Golde David W. 
Published: October 2019

AbstractThe granulocyte macrophage–colony-stimulating factor receptor (GM-CSF-R) is a heterodimer composed of 2 subunits,  and β, and ligand binding to the high-affinity receptor leads to signalling for the multiple actions of GM-CSF on target cells. In order to explore the role of the  subunit in signalling, we used a yeast-2-hybrid system to identify proteins interacting with the intracellular domain of the GMR-. A cDNA encoding a predicted protein of 198 amino acids, designated GRAP (GM-CSFreceptor  subunit-associatedprotein), was isolated in experiments using the intracellular portion of GMR- as bait. The interaction between GRAP and GMR- was confirmed by coimmunoprecipitation in mammalian cells. GRAP mRNA is widely expressed in normal human and mouse tissues and in neoplastic human cell lines, but it is not restricted to cells or tissues that express GM-CSF receptors. Three discrete GRAP mRNA species were detected in human tissues and cells, with estimated sizes of 3.3, 3.1, and 1.3 kb. GRAP is highly conserved throughout evolution, and homologues are found in yeast. The GRAP locus in Saccharomyces cerevisiae was disrupted, and mutant yeast cells showed an inappropriate stress response under normal culture conditions, manifested by early accumulation of glycogen during the logarithmic growth phase. GRAP is, therefore, a highly conserved and widely expressed protein that binds to the intracellular domain of GMR-, and it appears to play an important role in cellular metabolism.