bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma: Up-front or Rescue Treatment? Results of a Multicenter Sequential Randomized Clinical Trial
Authors: Fermand Jean-Paul , Ravaud Philippe , Chevret Sylvie , Divine Marine , Leblond Véronique , Belanger Coralie , Macro Margaret , Pertuiset Edouard , Dreyfus François , Mariette Xavier , Boccacio Catherine , Brouet Jean-Claude 
Published: October 2019

Abstract
Results to date indicate that high-dose therapy (HDT) with autologous stem cell support improves survival of patients with symptomatic multiple myeloma (MM). We performed a multicenter, sequential, randomized trial designed to assess the optimal timing of HDT and autotransplantation. Among 202 enrolled patients who were up to 56 years old, 185 were randomly assigned to receive HDT and peripheral blood stem cell (PBSC) autotransplantation (early HDT group, n = 91) or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n = 94). In the late HDT group, HDT and transplantation were performed as rescue treament, in case of primary resistance to CCT or at relapse in responders. PBSC were collected before randomization, after mobilization by chemotherapy, and, in the two groups, HDT was preceded by three or four treatments with vincristine, doxorubicin, and methylprednisolone. Data were analyzed on an intent-to-treat basis using a sequential design. Within a median follow-up of 58 months, estimated median overall survival (OS) was 64.6 months in the early HDT group and 64 months in the late group. Survival curves were not different (P = .92, log-rank test). Median event-free survival (EFS) was 39 months in the early HDT group whereas median time between randomization and CCT failure was 13 months in the late group. Average time without symptoms, treatment, and treatment toxicity (TWiSTT) were 27.8 months (95% confidence interval [CI]; range, 23.8 to 31.8) and 22.3 months (range, 16.0 to 28.6) in the two groups, respectively. HDT with PBSC transplantation obtained a median OS exceeding 5 years in young patients with symptomatic MM, whether performed early, as first-line therapy, or late, as rescue treatment. Early HDT may be preferred because it is associated with a shorter period of chemotherapy.
© 1998 by The American Society of Hematology.
Anti–B-Cell Monoclonal Antibody Treatment of Severe Posttransplant B-Lymphoproliferative Disorder: Prognostic Factors and Long-Term Outcome
Authors: Benkerrou Malika , Jais Jean-Philippe , Leblond Véronique , Durandy Anne , Sutton Laurent , Bordigoni Pierre , Garnier Jane Luce , Le Bidois Jérôme , Le Deist Françoise , Blanche Stéphane , Fischer Alain 
Published: October 2019

AbstractB-lymphoproliferative disorder (BLPD) is a rare but severe complication of organ and bone marrow transplantation (BMT). Profound cytotoxic T-cell deficiency is thought to allow the outgrowth of Epstein-Barr virus–transformed B cells. When possible, reduction of immunosuppressive treatment or surgery for localized disease may cure BLPD. Therapeutic approaches using chemotherapy or antiviral drugs have limited effects on survival. Adoptive immunotherapy with donor T-cell infusions has given promising results in BMT recipients. We previously reported that administration of two monoclonal anti–B-cell antibodies (anti-CD21 and anti-CD24) could contribute to the control of oligoclonal BLPD. Here we report the long-term results of treatment with these monoclonal anti–B-cell antibodies for cases of severe BLPD. In an open multicenter trial, 58 patients in whom aggressive B-cell lymphoproliferative disorder developed after BMT (n = 27) or organ (n = 31) transplantation received 0.2 mg/kg/d of specific anti-CD21 and anti-CD24 murine monoclonal antibodies (MoAbs) for 10 days. The treatment was well tolerated. Thirty-six of the 59 episodes of BLPD in the 58 patients presented complete remission (61%). The relapse rate was low (3 of 36, 8%). Multivariate analysis identified the following risk factors for partial or no response to anti–B-cell MoAb therapy: multivisceral disease (P ≤ .005), central nervous system involvement (P ≤ .05), and late onset of BLPD (P ≤ .005). The overall long-term survival was 46% (median follow-up, 61 months); it was lower among BMT patients (35%) than organ transplant patients (55%). None of the patients who had received BMT for hematological malignancy survived for 1 year. Eight of these 11 patients presented monoclonal BLPD. Tumor burden was the only other variable that contributed significantly to poor survival. Thus, as assessed from this long-term study, the use of anti–B-cell MoAbs therefore appears to be a safe and relatively effective therapy for severe posttransplant BLPD.© 1998 by The American Society of Hematology.
Four-Color Flow Cytometric Investigation of Terminal Deoxynucleotidyl Transferase–Positive Lymphoid Precursors in Pediatric Bone Marrow: CD79a Expression Precedes CD19 in Early B-Cell Ontogeny
Authors: Dworzak Michael N. , Fritsch Gerhard , Fröschl Gertraud , Printz Dieter , Gadner Helmut 
Published: October 2019

AbstractTerminal deoxynucleotidyl transferase (TdT)-positive cells in human bone marrow (BM) are a phenotypically inhomogeneous population of precursor cells. In their majority, these TdT+ cells are unambiguously committed to the B lineage, as evidenced by CD19 expression. However, TdT+ precursors that lack CD19 also exist and these may encompass a differentiation potential for the B as well as for other lineages. Because recent data suggested that CD19 expression is not the earliest differentiation event in B-cell ontogeny, we sought to reevaluate TdT+ lymphoid precursors in pediatric BM to define the phenotypic denominator of B-lineage affiliation upstream of CD19. Using four-color flow cytometry, we focused on the assessment of the CD79a antigen, which is highly B-cell specific and which may also be expressed very early in B-cell ontogeny. We found that a majority of TdT+ cells coexpressed CD19 and CD79a in addition to CD10 and CD34, whereas, in all investigated samples, some TdT+ precursors lacked CD19 but expressed CD79a, which suggestively indicates also their B-lineage affiliation. In contrast to the CD19+precursors, which were usually CD10hi and CD79b+, these CD19−CD79a+putative B-cell precursors preferentially expressed CD10 at low levels and were CD79b+ in only 41%. About 17% of these TdT+CD19−CD79a+ precursors also coexpressed CD33 and CD7, but not myeloperoxidase, CD14, or cytoplasmic CD3, which is discussed in the light of cellular activation rather than lineage promiscuity. Our data confirm that the earliest differentiation stages of B cells can be dissected upon expression of the lineage antigens CD79a and CD19 and imply that CD79a is earlier expressed than CD19. This raises the chance to follow the sequential events heralding B-cell commitment in the most immature precursors by correlating phenotypic and genetic differentiation markers.© 1998 by The American Society of Hematology.
Long-Term Contribution to the Myeloid Compartment by Lineage-Committed Stem Cells
Authors: Chen Chiann-Chyi , Rivera Amariliz , Ron Naomi , Sutkowski Natalie , Dougherty Joseph P. , Ron Yacov 
Published: October 2019

AbstractThe current paradigm concerning the kinetics of hematopoiesis is that only the most primitive pluripotential bone marrow stem cells can support prolonged hematopoiesis whereas more differentiated, lineage-committed stem cells can only contribute to a particular lineage for a limited period of time. In this study, we present evidence that in mice, the spleen contains a long-lived myeloid-committed stem cell population(s) that continuously replenishes the mature myeloid lineage for at least 9 months. After myeloid-specific retroviral-mediated gene transfer, the exogenous gene could be detected in thioglycollate-induced macrophages and granulocytes by Southern blot analysis and by in situ polymerase chain reaction on an individual cell basis. The targeted stem cell population does not repopulate the bone marrow in secondary recipients and did not give rise to cells other than cells of the myeloid lineage. It therefore represents the first nonpluripotential stem cell population capable of replenishing a hemopoietic lineage for a long period of time. The ability to target a myeloid-specific stem cell could facilitate gene therapy of congenital disorders of the myeloid system such as lysosomal storage diseases. It also offers a unique opportunity to assess the immunologic consequences of expressing an exogenous gene of choice exclusively in the myeloid lineage.© 1998 by The American Society of Hematology.
Adhesive and Signaling Properties of a Naturally Occurring Allele of Glycoprotein IIIa With an Amino Acid Substitution Within the Ligand Binding Domain—The Pena/PenbPlatelet Alloantigenic Epitopes
Authors: Wang Ronggang , Newman Peter J. 
Published: October 2019

AbstractPlatelet membrane glycoprotein IIIa (GPIIIa) is the most polymorphic integrin subunit in man, with at least seven recognized allelic isoforms present in the human gene pool. Whether these allelic variants of the GPIIb-IIIa complex differ in the ability to interact with the adhesive ligand fibrinogen (Fg) is still unknown. Since the Pena and Penb allelic forms of GPIIIa are distinguished by a single Arg143Gln amino acid substitution within the RGD binding domain of GPIIIa and anti-Pena human alloantibodies have been shown to bind GPIIb-IIIa on the platelet surface and inhibit ADP-induced platelet aggregation, we expressed both forms of this integrin in Chinese hamster ovary (CHO) cells and examined the relative adhesive properties. Both allelic forms of GPIIb-IIIa were expressed on the cell surface and were recognized by a well-characterized panel of murine and human monoclonal and polyclonal antibodies. Like Pena, the Penb form of GPIIb-IIIa could undergo conformational changes in response to RGD peptide binding, and could be induced by activating antibodies to bind Fg and the Fg mimetic antibody P1-55. The binding affinity for Fg of the Pena form of the GPIIb-IIIa complex was not significantly different from that of the Penb form, nor was its ability to signal to focal adhesion kinase, suggesting that Arg143Gln polymorphism has little or no effect on integrin function. Examination of the functional consequences of other integrin polymorphisms may be necessary to determine whether they constitute a risk factor for thrombosis or hemorrhage.© 1998 by The American Society of Hematology.
Activation of Clotting Factor XI Without Detectable Contact Activation in Experimental Human Endotoxemia
Authors: Minnema M.C. , Pajkrt D. , Wuillemin W.A. , Roem D. , Bleeker W.K. , Levi M. , van Deventer S.J.H. , Hack C.E. , ten Cate H. 
Published: October 2019

AbstractEvidence of factor XI (FXI) activation in vivo is scarce. In addition, it remains uncertain whether thrombin, factor XIIa (FXIIa), or perhaps another protease is responsible for FXI conversion. We investigated the activation of FXI in eight healthy volunteers after infusion of a low dose of endotoxin (4 ng/kg of body weight). Activation of prekallikrein FXII, FXI, and prothrombin was measured with sensitive enzyme-linked immunosorbent assays (ELISAs), and FXI activation was measured with a novel enzyme capture assay that detects noncomplexed FXIa. Activation of FXI was apparent with a significant plasma peak level of noncomplexed FXIa of 10 to 11 pmol/L at 1 and 2 hours after endotoxin infusion, followed by a gradual increase in FXIa-FXIa inhibitor complexes, measured in the ELISAs, with a summit of 11 to 15 pmol/L at 6 and 24 hours, respectively. In accordance with previous studies, thrombin generation was detected 1 hour after endotoxin infusion to become maximal after 3 to 4 hours. In contrast, we did not find any evidence of contact activation, because markers of activation of prekallikrein and FXII remained undetectable. From the FXIa data a theoretical model was constructed which suggested that inhibition of FXIa does not take place in the plasma compartment, but is localized on a surface. These data provide the first evidence for FXI activation in low-grade endotoxemia and suggest that FXI is activated independently of FXII.© 1998 by The American Society of Hematology.
Identification of Four Genes in Endothelial Cells Whose Expression Is Affected by Tumor Cells and Host Immune Status—A Study in Ex Vivo–Isolated Endothelial Cells
Authors: Liliensiek Birgit , Rocha Marian , Umansky Victor , Benner Axel , Lin Jie , Ziegler Reinhard , Nawroth Peter P. , Schirrmacher Volker 
Published: October 2019

AbstractA spontaneously metastasizing, well-defined mouse lymphoma was chosen as an in vivo model to study the effect of tumor-host interaction on gene expression in liver sinusoidal endothelial cells. Forty-nine bovine aortic endothelial cell (BAEC) genes, recently isolated by a differential screening approach of a cDNA library enriched for tumor necrosis factor- (TNF-) suppressed genes, were investigated. Four of these genes were finally selected because they were affected differentially by host immuno-competence, TNF-, and tumor cells. Sequence analysis showed them to encode the bovine polyubiquitin (A4), elongation factor 1 (B2), the acidic ribosomal phosphoprotein PO (C3), and the ribosomal protein S2 (E10). Gene expression was analyzed by dot-blot or Northern blot analysis. TNF- and tumor cell conditioned supernatant suppressed the genes additive in BAEC but not in other endothelial cells except for bovine capillary endothelial cells. Ex vivo–isolated liver endothelial cells of tumor-bearing syngeneic DBA/2 mice showed strong downregulation of these four genes in comparison to normal control values. In contrast, endothelial cells of tumor-bearing immuno-incompetent Balb/c (nu/nu) mice showed no downregulation but upregulation of these genes. Consistently, all four genes were also downregulated when BAEC were incubated with supernatants derived from ex vivo–isolated liver metastases from immuno-competent but not from -incompetent mice. Thus, the expression of a group of genes involved in protein translation and processing was more profoundly altered in endothelial cells in vivo than in vitro, suggesting that microenviromental factors and cell-cell and cell-matrix interactions play an important role.© 1998 by The American Society of Hematology.
Enhanced Adherence of Sickle Erythrocytes to Thrombin-Treated Endothelial Cells Involves Interendothelial Cell Gap Formation
Authors: Manodori Annamaria B. , Matsui Neil M. , Chen James Y. , Embury Stephen H. 
Published: October 2019

AbstractThe adherence of sickle erythrocytes to vascular endothelium has the capacity to initiate vasoocclusion. The known effects of thrombin on endothelial cell function and the increased activity of thrombin in sickle cell disease led us to examine the effect of thrombin on the adhesivity of cultured endothelial cells for sickle erythrocytes. In particular, we studied whether the effect of thrombin on interendothelial cell gap formation (ICGF) was involved in endothelial cell adhesivity for sickle erythrocytes. Those endothelial cell monolayers stimulated by thrombin to maximal levels of static sickle erythrocyte adherence also underwent striking cell contraction and enlargement of interendothelial cell gaps. Adhesivity also increased when gaps were induced with antilaminin antibodies or EDTA. Maximally adhesogenic thrombin conditions failed to increase adhesivity when gap formation was prevented by pretreatment of the monolayers with 8-bromo-cyclic adenosine monophosphate (bromo-cAMP) or glutaraldehyde, agents that respectively inhibit actin-myosin–dependent cell contraction or cross-link adjacent cells in the monolayer. The influence of these two agents on EDTA-enhanced adhesivity was linked to their ability to prevent gap formation. Glutaraldehyde prevented both increased adherence and gap formation; bromo-cAMP prevented neither. Interendothelial cell gap formation may contribute to vasoocclusion by facilitating sickle erythrocyte adherence.© 1998 by The American Society of Hematology.
Mechanism of Interleukin-10 Inhibition of T-Helper Cell Activation by Superantigen at the Level of the Cell Cycle
Authors: Perrin George Q. , Johnson Howard M. , Subramaniam Prem S. 
Published: October 2019

AbstractWe have analyzed the effects of interleukin-10 (IL-10) on the entry of quiescent CD4+ T cells into the cell cycle upon stimulation with the superantigen staphylococcal enterotoxin B (SEB). IL-10 arrested cells at G0/G1. IL-10 treatment prevented the downregulation of p27Kip1, an inhibitory protein that controls progression out of the G0 phase of the cell cycle. IL-10 also prevented the upregulation of the G1 cyclins D2 and D3, proteins necessary for entry and progression through the G1 phase of the cell cycle. Associated with the inhibition of the cell cycle, IL-10 suppressed SEB induction of interleukin-2 (IL-2). Addition of exogenous IL-2 to IL-10–treated cells significantly reversed the antiproliferative effects of IL-10. Moreover, IL-10 effects on the early G1proteins p27Kip1 and cyclin D2 were similarly reversed by exogenous IL-2. Although this reversal by IL-2 was pronounced, it was not complete, suggesting that IL-10 may have some effects not directly related to the suppression of IL-2 production. Cell separation experiments suggest that IL-10 can effect purified CD4+ T cells directly, providing functional evidence for the presence of IL-10 receptors on CD4+ T cells. IL-10 also inhibited expression of IL-2 transcriptional regulators c-fos and c-jun, which also inhibit other cell functions. Our studies show that the mechanism of IL-10 regulation of quiescent CD4+ T-cell activation is mainly by blocking induction of IL-2 that is critical to downregulation of p27Kip1 and upregulation of D cyclins in T-cell activation and entry into the cell cycle.
BCR/ABL− CD34+HLA-DR−Progenitor Cells in Early Chronic Phase, But Not in More Advanced Phases, of Chronic Myelogenous Leukemia Are Polyclonal
Authors: Delforge Michel , Boogaerts Marc A. , McGlave Philip B. , Verfaillie Catherine M. 
Published: October 2019

Abstract
Chronic myelogenous leukemia (CML) is characterized by the Philadelphia (Ph) translocation and BCR/ABL gene rearrangement which occur in a pluripotent hematopoietic progenitor cell. Ph-negative (Ph−) hematopoiesis can be restored in vivo after treatment with -interferon or intensive chemotherapy, suggesting that normal stem and progenitor cells coexist with the Ph+ clone. We have previously shown that Ph− progenitors are highly enriched in the CD34+HLA-DR− fraction from early chronic phase (ECP) CML patients. Previous studies have suggested that the Ph-translocation represents a secondary clonal hit occurring in an already clonally mutated Ph− progenitor or stem cells, leaving the unanswered question whether Ph−CD34+HLA-DR- progenitors are normal. To show the clonal nature of Ph−CD34+HLA-DR− CML progenitors, we have compared the expression of BCR/ABL mRNA with X-chromosome inactivation patterns (HUMARA) in mononuclear cells and in CD34+HLA-DR+ and CD34+HLA-DR− progenitors in marrow and blood obtained from 11 female CML patients (8 in chronic phase and 3 in accelerated phase [AP] disease). Steady-state marrow-derived BCR/ABL mRNA−, CD34+HLA-DR−progenitors had polyclonal X-chromosome inactivation patterns in 2 of 2 patients. The same polyclonal pattern was found in the progeny of CD34+HLA-DR− derived long-term culture-initiating cells. Mobilization with intensive chemotherapy induced a Ph−, BCR/ABL mRNA−and polyclonal state in the CD34+HLA-DR−and CD34+HLA-DR+ progenitors from 2 ECP patients. In a third ECP patient, polyclonal CD34+ cells could only be found in the first peripheral blood collection. In contrast to ECP CML, steady-state marrow progenitors in late chronic phase and AP disease were mostly Ph+, BCR/ABL mRNA+, and clonal. Further, in the majority of these patients, a Ph−, polyclonal state could not be restored despite mobilization with intensive chemotherapy. We conclude from these studies that CD34+HLA-DR− cells that are Ph− and BCR/ABL mRNA− are polyclonal and therefore benign. This population is suitable for autografting in CML.
Efflux of Rhodamine From CD56+ Cells as a Surrogate Marker for Reversal of P-Glycoprotein–Mediated Drug Efflux by PSC 833
Authors: Robey Robert , Bakke Susan , Stein Wilfred , Meadows Beverly , Litman Thomas , Patil Sheela , Smith Tom , Fojo Tito , Bates Susan 
Published: October 2019

Abstract
The expression of high levels of P-glycoprotein (Pgp) in circulating mononuclear cells allowed us to use an ex vivo assay as a surrogate measure of Pgp antagonism. Efflux of rhodamine from CD56+cells was measured before the start of PSC 833 and at varying times thereafter. Patients receiving PSC 833 had decreased rhodamine efflux from their circulating CD56+ cells. Time course studies showed that following a single oral dose of PSC 833, decreased rhodamine efflux was found in some patients within 15 minutes of treatment. Maximal inhibition was observed at times ranging from 45 minutes to 60 minutes. A dose-response relationship was shown between the concentration of PSC 833 in the blood and the inhibition of rhodamine efflux, with an apparent plateau of the inhibition of rhodamine efflux at approximately 1,000 ng/mL. The Ki, defined as the concentration required for half-maximal inhibition of Pgp-mediated rhodamine efflux, was determined to be in the range of 29 to 181 ng/mL; although results in two patients were distinctly different, with Ki values of 914 and 916 ng/mL. MRK-16 staining was similar among all patients. We conclude that measurement of rhodamine efflux from CD56+ cells provides a surrogate assay with the potential for monitoring Pgp antagonism in clinical trials.
Murine T Lymphocytes Incapable of Producing Macrophage Inhibitory Protein-1 Are Impaired in Causing Graft-Versus-Host Disease Across a Class I But Not Class II Major Histocompatibility Complex Barrier
Authors: Serody Jonathan S. , Cook Donald N. , Kirby Suzanne L. , Reap Elizabeth , Shea Thomas C. , Frelinger Jeffrey A. 
Published: October 2019

AbstractThe routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T-cell depletion, use immunosuppressive agents, or block costimulatory molecule function. The role of proteins in the recruitment of alloreactive lymphocytes has not been well characterized. Chemokines are a large family of proteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage inhibitory protein-1 (MIP-1) in the occurrence of GVHD, splenocytes either from wild-type or from MIP-1−/− mice were administered to class I (B6.C-H2bm1) and class II disparate mice (B6-C-H2bm12). The incidence and severity of GVHD was markedly reduced in bm1 mice receiving splenocytes from MIP-1−/− mice as compared with mice receiving wild-type splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung and liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had a markedly decreased production of antichromatin autoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1−/− splenocytes easily induced GVHD when administered to bm12 mice. This data show that blockade of chemokine production or function may provide a new approach to the prevention or treatment of GVHD but that chemokines that recruit both CD4+ and CD8+ lymphocytes may need to be targeted.