bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of cytokines in leukemic type growth of myelodysplastic CD34+ cells
Authors: Sawada K , Ieko M , Notoya A , Tarumi T , Koizumi K , Kitayama S , Nishio H , Fukada Y , Yasukouchi T , Yamaguchi M , Katoh S , Koike T 
Published: October 2019

Abstract
The clonal growth of progenitor cells from myelodysplastic syndromes (MDS) can be subdivided into four growth patterns: (1) normal, (2) no growth or low plating efficiency, (3) low colony and high cluster number, and (4) normal or high colony number with a large number of clusters. The former two (1 and 2) can be referred to as nonleukemic patterns and latter two (3 and 4) as leukemic. In a search for a role for cytokines in leukemic-type growth of MDS progenitor cells, marrow CD34+ cells were purified up to 94% for 8 normal individuals and 88% for 12 MDS patients, using monoclonal antibodies and immunomagnetic microspheres (MDS CD34+ cells). The purified CD34+ cells were cultured for 14 days with various combinations of cytokines, including recombinant human macrophage colony-stimulating factor (rM-CSF), granulocyte-CSF (rG-CSF), granulocyte-macrophage-CSF (rGM-CSF), interleukin-3 (rIL-3), and stem cell factor (SCF; a ligand for c-kit) in serum-free medium. The clonal growth of MDS CD34+ cells supported by a combination of all of the above cytokines was subdivided into the two patterns of leukemic or nonleukemic, and then the role of individual or combined cytokines in proliferation and differentiation of MDS CD34+ cells was analyzed in each group. Evidence we obtained showed that SCF plays a central role in the leukemic-type growth of MDS CD34+ cells and that G-CSF, GM-CSF; and/or IL-3 synergize with SCF to increase undifferentiated blast cell colonies and clusters over that seen in normal CD34+ cells. SCF is present in either normal or MDS plasma at a level of nanograms per milliliter, and this physiologic concentration of SCF can stimulate progenitor cells. This means that progenitor cells are continuously exposed to stimulation by SCF in vivo and that MDS leukemic cells have a growth advantage over normal blast cells. This depends, at least in part, on cytokines such as G-CSF, GM-CSF, IL-3, and SCF.
Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen
Authors: Cardoso AA , Schultze JL , Boussiotis VA , Freeman GJ , Seamon MJ , Laszlo S , Billet A , Sallan SE , Gribben JG , Nadler LM 
Published: October 2019

Abstract
Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7–1 (CD80) and only a subset express B7–2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7–1 and B7–2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.
Bone marrow collected 14 days after in vivo administration of granulocyte colony-stimulating factor and stem cell factor to mice has 10-fold more repopulating ability than untreated bone marrow
Authors: Bodine DM , Seidel NE , Orlic D 
Published: October 2019

Abstract
We have examined the repopulating ability of bone marrow and peripheral blood cells collected immediately and at intervals after treatment of donor mice with the combination of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF). Using a competitive repopulation assay we showed that the repopulating ability of peripheral blood cells was highest immediately after cytokine treatment and declined to normal levels within 6 weeks of the termination of treatment with G-CSF and SCF. In contrast the repopulating ability of bone marrow cells was low immediately after cytokine treatment and increased to levels that were 10-fold or more greater than marrow from untreated mice by 14 days after termination of treatment with G-CSF and SCF. This high level of repopulating activity declined to normal levels by 6 weeks after termination of treatment with G-CSF and SCF. The high level of repopulating ability was confirmed by injecting cells from G- CSF- and SCF-treated donors into unconditioned recipients. Peripheral blood cells collected immediately after treatment with G-CSF and SCF engrafted into unconditioned mice sevenfold better than an equivalent number of bone marrow cells from untreated mice. Likewise, bone marrow cells collected 14 days after treatment of the donor animal with G-CSF and SCF engrafted at 10-fold higher levels than an equivalent number of bone marrow cells from untreated mice. We conclude that the treatment of donor mice with G-CSF and SCF causes a transient increase in the repopulating ability of peripheral blood and later of bone marrow. These observations may have applications to clinical hematopoietic stem cell transplantation.
Mechanism and effects of the binding of lupus anticoagulant IgG and prothrombin to surface phospholipid
Authors: Rao LV , Hoang AD , Rapaport SI 
Published: October 2019

Abstract
We report here experiments on how lupus anticoagulant antibodies (LA IgG) that react with prothrombin bind to surface phospholipid and affect prothrombin's affinity for surface phospholipid and activation to thrombin. LA IgG was purified by protein A chromatography from the plasma of 16 patients of whom four had associated hypoprothrombinemia and 10 had experienced thrombosis. Many LA IgG bound, in the absence of phospholipid and calcium, not only to immobilized prothrombin but to both prothrombin 1 and fragment 1, which established at least an oligoclonal origin of LA IgG. No LA IgG bound to thrombin. Although prothrombin and Ca2+ were required to support binding of LA IgG to immobilized phosphatidylserine (PS), prothrombin at higher concentrations inhibited binding, presumably by competing with prothrombin/LA IgG complexes for PS binding sites. Prothrombin 1, which cannot bind to PS, also inhibited binding of many LA IgG to PS, presumably by forming competing soluble prothrombin 1/LA IgG complexes. Despite their ability to react with prothrombin independent of phospholipid, LA IgG enhanced binding of prothrombin to immobilized phospholipid and to cultured human umbilical vein endothelial cells. Prothrombin bound with LA IgG to the surface of endothelial cell monolayers could be activated to thrombin after supernatant prothrombin and LA IgG were washed away. The relation is discussed of these observations to a hypothesis that LA IgG mediated concentration of prothrombin on cell surface phospholipid represents a mechanism by which LA IgG could increase thrombotic risk.
Cloning and characterization of Fc alpha Rb, a novel Fc alpha receptor (CD89) isoform expressed in eosinophils and neutrophils
Authors: van Dijk TB , Bracke M , Caldenhoven E , Raaijmakers JA , Lammers JW , Koenderman L , de Groot RP 
Published: October 2019

Abstract
The Fc receptor for IgA (Fc alpha R, CD89) is a transmembrane glycoprotein found on monocytes, macrophages, neutrophils, and eosinophils. Here we describe the characterization of a novel isoform of the Fc alpha R cloned from a human eosinophil cDNA library. This clone, Fc alpha Rb, lacks the exon encoding the transmembrane/intracellular region of wild type Fc alpha R, which is replaced by 23 new amino acids. Expression of Fc alpha Rb mRNA could be detected in eosinophils and neutrophils. IIA1.6 murine pro-B cells transfected with Fc alpha Rb cDNA secrete high levels of the protein, but also a substantial amount of Fc alpha Rb is expressed at the cell membrane. Membrane-bound Fc alpha Rb binds IgA-coated beads equally well as wild type Fc alpha R. Surface expression is not affected by phosphatidyl inositol phospholipase C, indicating that glycosyl phosphatidyl inositol-linkage of Fc alpha Rb is not likely. In IIA1.6 cells expressing Fc alpha Rb and FcR gamma, which is necessary for signal transduction by wild type Fc alpha R, no tyrosine phosphorylation or Ca(2+)-mobilization could be observed after receptor cross-linking. These results indicate that Fc alpha Rb is likely to have a different function than wild-type Fc alpha R receptor.
Schistosoma mansoni excretory circulating cathodic antigen shares Lewis- x epitopes with a human granulocyte surface antigen and evokes host antibodies mediating complement-dependent lysis of granulocytes
Authors: van Dam GJ , Claas FH , Yazdanbakhsh M , Kruize YC , van Keulen AC , Ferreira ST , Rotmans JP , Deelder AM 
Published: October 2019

Abstract
Parasitic worms of the genus Schistosoma excrete relatively large amounts of immunogenic glycoproteins (circulating cathodic antigen [CCA]) that contain polysaccharide side chains with the trisaccharide Lewis-x (L(ex)) as a repeating unit. These carbohydrates evoke high titers of specific IgM antibodies that cross-react with the repeating L(ex) units on the surface of granulocytes. Consequently this might lead, in the presence of complement, to lysis of the granulocytes. In the present study, this hypothesis was investigated using anti-CCA mouse monoclonal antibodies (MoAbs) and polyclonal antibodies purified from sera of infected humans. By flow cytometry, it was demonstrated that the mouse MoAbs directed against CCA strongly recognized the granulocytes. It could also be shown that these MoAbs, as well as anti- CCA IgM antibodies purified from infected human sera, caused lysis of granulocytes in a complement-dependent cytotoxicity assay. Sera from healthy controls or from patients with other helminth infections resulted in negligible granulocytotoxicity. These in vitro observed phenomena may explain the mild to moderate neutropenia that occurs in schistosomiasis patients.
Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia
Authors: Sarfati M , Chevret S , Chastang C , Biron G , Stryckmans P , Delespesse G , Binet JL , Merle-Beral H , Bron D 
Published: October 2019

Abstract
Prognosis of B-cell chronic lymphocytic leukemia (CLL) is based on clinical staging whose limitation is the failure to assess whether the disease will progress or remain stable in early stage (Binet A, or Rai 0, I, II) patients. We previously reported that soluble CD23 (sCD23), a protein derived from the B-cell membrane CD23 Ag, is selectively elevated in the serum of CLL patients. This prospective study assessed the predictive value of serum sCD23 level measured at study entry on the overall survival of all CLL patients and on disease progression of stage Binet A patients. Prognostic value of repeated measurements of sCD23 over time in stage A patients was also analyzed. One hundred fifty-three CLL patients were prospectively followed with a median follow-up of 78 months. Eight clinical or biological parameters were collected from the date of the first sCD23 measurement. At study entry, by Cox model, Binet staging (P = .0001) and serum sCD23 level (P = .03) appeared as prognostic factors for survival. Patients with sCD23 level above median value (> 574 U/mL) had a significantly worse prognosis than those with lower values (median survival of 53 v 100+ months, P = .0001). During follow-up, sCD23 doubling time increased by 3.2 the risk of death (P = .001). Among stage A patients (n = 100), sCD23 determination at study entry was the sole variable predictive of disease progression, patients with sCD23 level above 574 U/mL had a median time progression of 42 months versus 88 months for those with lower levels (P = .0001). Stage A patients who doubled their sCD23 level exhibited a 15-fold increased risk of progression (P = .0001) and, in addition, the sCD23 increase preceded by 48 months disease progression. We conclude that in CLL patients, serum sCD23 level provides significant additional prognostic information in terms of overall survival. Most interestingly, among early stage patients, sCD23 determination at diagnosis and during the course of the disease may help to the early identification of patients who will rapidly progress to upper stages.
Microsatellite instability and p53 mutations in therapy-related leukemia suggest mutator phenotype
Authors: Ben-Yehuda D , Krichevsky S , Caspi O , Rund D , Polliack A , Abeliovich D , Zelig O , Yahalom V , Paltiel O , Or R , Peretz T , Ben-Neriah S , Yehuda O , Rachmilewitz EA 
Published: October 2019

Abstract
During the last decade the frequency of therapy-related acute leukemia (t-leuk) and myelodysplastic syndrome (t-MDS) has been increasingly observed. Over the past 15 years, we treated 56 patients with t-leuk who had received prior chemotherapy (39%), radiotherapy (11%), or both (45%). The drugs received included alkylating agents and topoisomerase II inhibitors. The primary tumors included hematological malignancies (49%) and solid tumors such as breast or ovarian cancer. The median age at diagnosis of the primary tumor was relatively young (43 years +/- 18). Twelve patients had more than one primary tumor and 31 patients had a family history of malignancy. Karyotypic abnormalities were found in 91% of the patients. Prognosis was uniformly poor, with an overall median survival of 10 months. Twelve of the 18 patients examined (67%) had a multidrug resistance phenotype. P53 genes of the leukemic cells, as well as the original tumors, were analyzed in 21 patients using polymerase chain reaction (PCR) with single-stranded conformation polymorphism analysis followed by sequencing. P53 mutations were identified in 38% of these patients, a relatively high prevalence compared with other forms of MDS or de novo acute myeloid leukemia. Mutations were nongermline and restricted to the leukemic cells. We identified different p53 mutations in the various primary tumors of individual patients. The presence of a mutator phenotype was assessed by PCR analysis of microsatellites in eight loci (one trinucleotide repeat sequence, four dinucleotide, and three mononuclear repeat sequences). Microsatellite instability in two to seven loci were found in 15 of 16 (94%) of the patients. This instability is compatible with a mutator phenotype, which predisposes the patients to the development of malignancies including t-leuk.
Patterns of hematopoietic lineage involvement in children with neurofibromatosis type 1 and malignant myeloid disorders
Authors: Miles DK , Freedman MH , Stephens K , Pallavicini M , Sievers EL , Weaver M , Grunberger T , Thompson P , Shannon KM 
Published: October 2019

Abstract
Children with neurofibromatosis type 1 (NF1) are at increased risk of developing malignant myeloid disorders, particularly juvenile chronic myelogenous leukemia/juvenile myelomonocytic leukemia (JCML/JMML). We investigated bone marrows from 11 such patients (8 boys and 3 girls) and detected allelic losses at the NF1 locus in 4 of them and probable losses in 2 others. To determine which hematopoietic cell lineages were derived from the abnormal clones, Epstein-Barr virus (EBV)-transformed cell lines and CD34+ cells were analyzed from 3 children with JCML with allelic losses in unfractionated marrow. CD34 cells from these 3 patients lacked the normal NF1 allele, whereas EBV cell lines retained it. Erythroblasts plucked from the burst-forming unit-erythroid colonies of one of these children lacked the normal NF1 allele. We also studied a 10-month-old boy with NF1 who developed an unusual myeloproliferative syndrome. His bone marrow and EBV cell line both showed loss of the normal NF1 allele. In our series and in the literature, male sex and maternal transmission of NF1 were associated with the highest risk of myeloid leukemia. These data (1) provide strong genetic evidence that NF1 functions as a tumor-suppressor in early myelopoiesis, (2) confirm the clonal nature of JCML/JMML, (3) suggest that the elevation in fetal hemoglobin seen in JCML/JMML is a result of primary involvement of erythroid progenitors in the malignant clone, (4) show consistent loss of NF1 in the CD34 cells of affected children and show that the malignant clone may also give rise to pre-B cells in some cases, and (5) implicate epigenetic factors in the development of leukemia in children with NF1.
Neutrophils from patients after burn injury express a deficiency of the oxidase components p47-phox and p67-phox
Authors: Rosenthal J , Thurman GW , Cusack N , Peterson VM , Malech HL , Ambruso DR 
Published: October 2019

Abstract
Infection is a major cause of morbidity and mortality in patients after thermal injury. This predisposition to infections is related, in part, to abnormal polymorphonuclear leukocyte (PMN) function and a diminished respiratory burst. To evaluate the biochemical basis for the defective respiratory burst after major burns, the status of the oxidase enzyme system and its components was investigated. PMNs were isolated from 24 patients with 12% to 62% burns. Oxidase activity of intact PMNs, measured as superoxide anion (O2-) generation or oxygen consumption, was decreased in burn compared with healthy controls. Subcellular fractions from patient PMNs generated less O2- in the sodium dodecyl sulfate cell-free system, and this was related to a diminished contribution by cytosol but not by plasma membrane. Subsequently, cytosol was separated with CM-Sepharose, yielding two fractions; one contained the p47-phox and p67-phox (47/67 mix) and the other contained the remaining cytosolic components (run through [RT]). Although the contribution to oxidase activity made by RT from patient cytosol was similar to that of control, the activity of p47/67 mix from PMNs of burn patients was deficient. Quantitative assays using an immunoautoradiographic technique showed a consistent, but significant decrease in both p47-phox and p67-phox. The addition of purified or human recombinant p47-phox but not p67-phox corrected the diminished oxidase activity of cytosol from burn patients. Thus, decreased respiratory burst activity found in PMNs from individuals with thermal injury was associated with a specific, quantitative deficiency of p47- phox.
Induction of humoral immune tolerance to major histocompatibility complex antigens by transfusions of UVB-irradiated leukocytes
Authors: Kao KJ 
Published: October 2019

Abstract
To determine whether immune tolerance to donor major histocompatibility complex (MHC) antigens can be induced by transfusions of UVB-irradiated leukocytes, studies were conducted in inbred strains of mice with well-characterized MHC antigens. CBA mice with H-2k phenotype and BALB/c mice with H-2d phenotype were used as recipients and donors, respectively. Humoral immune tolerance is defined as absence of antibody response after challenge with transfusions of untreated donor leukocytes. It was found that transfusions of purified peripheral blood mononuclear leukocytes irradiated with 1,200 mJ/cm2 UVB not only prevented allo-immunization but also induced humoral immune tolerance to donor class-I and -II MHC antigens in all recipient mice. Donor plasma and platelets interfered with the induction of this tolerance. The tolerance induction by UVB-irradiated leukocytes is dose-dependent. Four weekly transfusions of 2 x 10(5) leukocytes were required to ensure tolerance induction in all mice. The results of a long-term follow-up study showed that the induced tolerance is long-lasting and can withstand repeated challenges by untreated donor leukocytes. Recipient mice tolerant to H-2d antigens also became tolerant to H-2b, H-2r, and H-2n MHC antigens but did not have impaired antibody responses to antigens unrelated to donor leukocytes. Adoptive transfer experiments showed the development of negative regulatory cells in spleens of the tolerized mice. In view of recent feasibility of using UVB-irradiated human platelet concentrates for prevention of HLA alloimmunization, the findings of this study support that UVB- irradiated donor leukocytes could have potential, important clinical application in transplantation medicine.
Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery
Authors: Kook H , Goldman F , Padley D , Giller R , Rumelhart S , Holida M , Lee N , Peters C , Comito M , Huling D , Trigg M 
Published: October 2019

Abstract
We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.