bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defects of the Mismatch Repair Gene MSH2 Are Implicated in the Development of Murine and Human Lymphoblastic Lymphomas and Are Associated With the Aberrant Expression of Rhombotin-2 (Lmo-2) and Tal-1 (SCL)
Authors: Lowsky Robert , DeCoteau John F. , Reitmair Armin H. , Ichinohasama Ryo , Dong Wei-Feng , Xu Yi , Mak Tak W. , Kadin Marshall E. , Minden Mark D. 
Published: October 2019

AbstractMutations in the DNA mismatch repair (MMR) gene hMSH2 underlie a novel pathway of tumorigenesis for some cancers of epithelial origin. Mice deficient in MSH2 are susceptible to lymphomas but defects in this gene have not been identified in human lymphoid tumors. To determine if the lymphomas these mice develop are related to a particular subtype of human lymphoma we evaluated 20 clinically ill homozygous MSH2−/− mice ranging in age from 2 to 13 months. The murine tumors comprised a single histopathologic entity representing the malignant counterpart of precursor thymic T cells and closely resembled human precursor T-cell lymphoblastic lymphoma (LBL). Evaluation of the expression of three T-cell malignancy associated genes showed that Rhombotin-2 (RBTN-2 also known as Lmo-2), TAL-1 (also known as SCL), and HOX-11 were expressed in 100%, 40%, and 0% of the murine tumors, respectively. The MSH2−/− murine model of precursor T-cell LBL was substantiated by the finding of a nearly identical expression profile of RBTN-2, TAL-1, and HOX-11 in 10 well-characterized cases of human LBL. Direct evidence for MSH2 abnormalities in human LBL was established by sequence analysis of exon 13 of hMSH2, which revealed coding region mutations in 2 of 10 cases. Our findings implicate defects in the MMR system with the aberrant expression of T-cell specific proto-oncogenes and define a new pathway of human lymphomagenesis.
Lineage- and Stage-Specific Expression of Runt Box Polypeptides in Primitive and Definitive Hematopoiesis
Authors: Corsetti Maria Teresa , Calabi Franco 
Published: October 2019

AbstractTranslocations involving the human CBFA2 locus have been associated with leukemia. This gene, originally named AML1, is a human homologue of the Drosophila gene runt that controls early events in fly embryogenesis. To clarify the role of mammalian runt products in normal and leukemic hematopoiesis, we have studied their pattern of expression in mouse hematopoietic tissues in the adult and during ontogeny using an anti-runt box antiserum. In the adult bone marrow, we found expression of runt polypeptides in differentiating myeloid cells and in B lymphocytes. Within the erythroid lineage, runt expression is biphasic, clearly present in the erythroblasts of early blood islands and of the fetal liver, but absent in the adult. Biochemical analysis by Western blotting of fetal and adult hematopoietic populations shows several runt isoforms. At least one of them appears to be myeloid specific.
Regulation of Plasminogen Gene Expression by Interleukin-6
Authors: Jenkins G. Ronald , Seiffert Dietmar , Parmer Robert J. , Miles Lindsey A. 
Published: October 2019

AbstractPlasmin, the primary fibrinolytic enzyme, has a broad substrate spectrum and participates in other biological processes dependent upon proteolytic activity. Consequently, plasmin activity is tightly regulated by plasminogen activators and protease inhibitors. In this study, we examined whether regulation of plasminogen gene expression also might provide a new mechanism for controlling this system. We examined the effects of recombinant human interleukin-6 (rhIL-6), a pleiotropic cytokine, on plasminogen mRNA expression in primary murine hepatocytes and Hep3B human hepatoma cells. In primary hepatocytes, rhIL-6 and hydrocortisone separately increased plasminogen mRNA expression, but hydrocortisone did not markedly enhance the response to rhIL-6. Hep3B hepatoma cells exhibited more modest responses to rhIL-6. We used the polymerase chain reaction to amplify a 1,067-bp fragment of the human plasminogen promoter/5′ flanking region. This fragment was cloned upstream of a luciferase reporter gene. Hep3B cells transiently transfected with this construct provided ∼100-fold higher luciferase activity compared to cells transfected with control plasmids, and luciferase activity was increased ∼4.5-fold when these cells were treated with rhIL-6. Furthermore, mice injected with rhIL-6 exhibited increases in hepatic plasminogen mRNA. Circulating plasminogen levels were significantly higher in the mice injected with rhIL-6 compared to mice injected with saline. Mice injected with lipopolysaccharide (an inducer of IL-6 in vivo) also showed increased hepatic plasminogen mRNA. Thus, plasminogen gene expression can be modulated by rhIL-6, suggesting a new mechanism for regulating biological systems that use plasmin.
A Molecular Model for the Triplicated A Domains of Human Factor VIII Based on the Crystal Structure of Human Ceruloplasmin
Authors: Pemberton S. , Lindley P. , Zaitsev V. , Card G. , Tuddenham E.G.D. , Kemball-Cook G. 
Published: October 2019

AbstractThe hemophilia A mutation database lists more than 160 missense mutations: each represents a molecular defect in the FVIII molecule, resulting in the X-linked bleeding disorder hemophilia A with a clinical presentation varying from mild to severe. Without a three-dimensional FVIII structure it is in most cases impossible to explain biological dysfunction in terms of the underlying molecular pathology. However, recently the crystal structure of the homologous human plasma copper-binding protein ceruloplasmin (hCp) has been solved, and the A domains of FVIII share approximately 34% sequence identity with hCp. This advance has enabled the building of a molecular model of the A domains of FVIII based on the sequence identity between the two proteins. The model allows exploration of predictions regarding the general features of the FVIII molecule, such as the binding-sites for factor IXa and activated protein C; it has also allowed the mapping of more than 30 selected mutations with known phenotype from the database, and the prediction of hypothetical links to dysfunction in all but a few cases. A computer-generated molecular model such as that reported here cannot substitute for a crystal structure. However, until such a structure for FVIII becomes available, the model represents a significant advance in modeling FVIII; it should prove a useful tool for exploiting the increasing amount of information in the hemophilia A mutation database, and for selecting appropriate targets for investigation of the structure-function relationships via mutagenesis and expression in vitro.
Apoptotic Vascular Endothelial Cells Become Procoagulant
Authors: Bombeli Thomas , Karsan Aly , Tait Jonathan F. , Harlan John M. 
Published: October 2019

AbstractWhereas unperturbed endothelial cells provide potent anticoagulant properties, exposure to inflammatory and atherogenic stimuli can rapidly lead to a procoagulant behavior. Because recent studies provide evidence that apoptosis of vascular cells may occur under conditions such as atherosclerosis and inflammation, we investigated whether apoptotic endothelial cells may contribute to the development of a prothrombotic state. In this report, it is shown that both adherent and detached apoptotic human umbilical vein endothelial cells (HUVECs) become procoagulant. Apoptosis was induced by staurosporine, a nonspecific protein kinase inhibitor, or by culture in suspension with serum deprivation. Both methods resulted in similar findings. As assessed by flow cytometric determination of annexin V binding, HUVECs undergoing cell death exhibited typically a more rapid exposure of membrane phosphatidylserine (PS) than DNA fragmentation. Depending on the stage of apoptosis, this redistribution of phospholipids was found to induce an increase of the activity of the intrinsic tenase complex by 25% to 60%. Although apoptotic cells did not show antigenic or functional tissue factor (TF ) activity, when preactivated with lipopolysaccharide, TF procoagulant activity increased by 50% to 70%. At 8 hours after apoptosis induction, antigenic thrombomodulin, heparan sulfates, and TF pathway inhibitor decreased by about 83%, 80%, and 59%, respectively. The functional activity of these components was reduced by about 36%, 52%, and 39%, respectively. Moreover, the presence of apoptotic HUVECs led to a significant increase of thrombin formation in recalcified citrated plasma. In conclusion, apoptotic HUVECs, either adherent or in suspension, become procoagulant by increased expression of PS and the loss of anticoagulant membrane components.
Adoptive Transfer of Anti-CD3–Activated CD4+ T Cells Plus Cyclophosphamide and Liposome-Encapsulated Interleukin-2 Cure Murine MC-38 and 3LL Tumors and Establish Tumor-Specific Immunity
Authors: Saxton Mark L. , Longo Dan L. , Wetzel Holly E. , Tribble Henry , Alvord W. Gregory , Kwak Larry W. , Leonard Arnold S. , Ullmann Claudio Dansky , Curti Brendan D. , Ochoa Augusto C. 
Published: October 2019

AbstractThe infusion of anti-CD3–activated murine T cells plus interleukin-2 (IL-2) exerts antitumor effects against several tumors in murine immunotherapy models. This study compares the therapeutic efficacy of anti-CD3–activated CD4+ or CD8+ T-cell subsets, when given with cyclophosphamide (Cy) and liposome-encapsulated IL-2 (L-IL2) in a murine model. C57BL/6 mice bearing subcutaneous (SC) MC-38 colon adenocarcinoma, 3LL Lewis lung carcinoma, or 38C13 lymphoma for 7 to 14 days were pretreated with low-dose intraperitoneal (IP) Cy before intravenous (IV) injection of anti-CD3–activated T cells or T-cell subsets. Cell administration was followed by IP administration of L-IL2 for 5 days. Mice receiving activated CD4+ T cells showed significantly reduced tumor growth or complete remissions with prolonged disease-free survival in MC-38, 3LL, and 38C13. The timing of Cy doses in relation to adoptive transfer was critical in obtaining the optimal antitumor effect by CD4+ cells. Injecting Cy 4 days before the infusion of CD4+ cells greatly enhanced the antitumor effect of the CD4+ cells and improved survival of the mice compared with other Cy regimens. C57BL/6 mice cured of MC-38 after treatment with CD4+ T cells developed tumor-type immunologic memory as demonstrated by their ability to reject rechallenges with MC-38, but not 3LL. Similarly, mice cured of 3LL tumors rejected rechallenges of 3LL, but not MC-38. The immunologic memory could be transferred with an IV injection of splenocytes from mice cured of MC-38 or 3LL. No cytotoxic T-lymphocyte activity was detected in T cells or T-cell subsets from mice cured of MC-38 or 3LL. Increased IL-2 and interferon-γ (IFN-γ) production was observed from CD4+ subsets in cured animals when stimulated in vitro with the original tumor, but not with an unrelated syngeneic tumor. These results suggest that tumor-specific immunity can be achieved in vivo with anti-CD3–stimulated CD4+ T cells in this cellular therapy model.
Decrease of Very Late Activation Antigen-4 and CD36 on Reticulocytes in Sickle Cell Patients Treated With Hydroxyurea
Authors: Styles Lori A. , Lubin Bertram , Vichinsky Elliott , Lawrence Sandy , Hua Mandy , Test Samuel , Kuypers Frans 
Published: October 2019

Abstract
Sickle cell disease (SCD) is characterized by repeated vaso-occlusive events, which result in substantial morbidity. Abnormal adhesion of sickle red blood cells (RBC) to the vascular endothelium is postulated to play a role in the pathogenesis of vaso-occlusion. Two adhesion receptors, very late activation antigen-4 (VLA-4) and CD36, are found in unusually high numbers on sickle cell reticulocytes and do mediate adhesion of sickle RBC to endothelium. Hydroxyurea (HU) therapy results in fewer vaso-occlusive episodes, and we postulated that HU-related modulation of VLA-4 and CD36 receptors may contribute to its clinical benefit. Using flow cytometry, eight patients were followed from the onset of HU treatment through a mean treatment length of 200 ± 49 days. Mean corpuscular volume and percent fetal hemoglobin (Hb F ) increased from 87% ± 6% to 98% ± 9% and 6.6% ± 3.9% to 12.7% ± 5.6%, respectively. The percentage of reticulocytes expressing VLA-4 decreased from 29.0% ± 5.9% to 14.9% ± 2.3% (P = .0003). Two thirds of the total decrease in VLA-4 expression occurred after 10 weeks of HU and plateaued by 20 weeks. Changes in VLA-4 expression occurred before substantial increases in Hb F. The percentage of reticulocytes expressing CD36 decreased from 55.3% ± 6.4% to 42.6% (P = .0046). Changes in adhesion receptor expression were not caused by a decrease in reticulocytosis with HU therapy. This report is the first to associate a decrease in adhesion receptor expression with a therapy known to reduce the clinical severity of SCD.
The Characterization, Molecular Cloning, and Expression of a Novel Hematopoietic Cell Antigen From CD34+ Human Bone Marrow Cells
Authors: Uchida Nobuko , Yang Zhi , Combs Jesse , Pourquié Olivier , Nguyen Megan , Ramanathan Rajeev , Fu Joan , Welply Annemarie , Chen Shirley , Weddell Greg , Sharma Arun K. , Leiby Kevin R. , Karagogeos Domna , Hill Beth , Humeau Laurent , Stallcup William B. , Hoffman Ron , Tsukamoto Ann S. , Gearing David P. , Péault Bruno 
Published: October 2019

AbstractThe adhesion molecule BEN/SC1/DM-GRASP (BEN) is a marker in the developing chicken nervous system that is also expressed on the surface of embryonic and adult hematopoietic cells such as immature thymocytes, myeloid progenitors, and erythroid progenitors. F84.1 and KG-CAM, two monoclonal antibodies to rat neuronal glycoproteins with similarity to BEN, cross-react with an antigen on rat hematopoietic progenitors, but F84.1 only also recognizes human blood cell progenitors. We have defined the antigen recognized by F84.1 as the hematopoietic cell antigen (HCA). HCA expression was detected on 40% to 70% of CD34+ fetal and adult bone marrow cells and mobilized peripheral blood cells. Precursor cell activity for long-term in vitro bone marrow cell culture was confined to the subset of CD34+ cells that coexpress HCA. HCA is expressed by the most primitive subsets of CD34+ cells, including all rhodamine 123lo, Thy-1+, and CD38−/lo CD34+ adult bone marrow cells. HCA was also detected on myeloid progenitors but not on early B-cell progenitors. We also describe here the cloning and characterization of cDNAs encoding two variants of the human HCA antigen (huHCA-1 and huHCA-2) and of a cDNA clone encoding rat HCA (raHCA). The deduced amino acid sequences of huHCA and raHCA are homologous to that of chicken BEN. Recombinant proteins produced from either human or rat HCA cDNAs were recognized by F84.1, whereas rat HCA but not human HCA was recognized by antirat KG-CAM. Expression of either form of huHCA in CHO cells conferred homophilic adhesion that could be competed with soluble recombinant huHCA-Fc. The molecular cloning of HCA and the availability of recombinant HCA should permit further evaluation of its role in human and rodent hematopoiesis.
Selective Expression of the Receptor Tyrosine Kinase, HTK, on Human Erythroid Progenitor Cells
Authors: Inada Tomohisa , Iwama Atsushi , Sakano Seiji , Ohno Mitsuharu , Sawada Ken-ichi , Suda Toshio 
Published: October 2019

AbstractHTK is a receptor tyrosine kinase of the Eph family. To characterize the involvement of HTK in hematopoiesis, we generated monoclonal antibodies against HTK and investigated its expression on human bone marrow cells. About 5% of the bone marrow cells were HTK+, which were also c-Kit+, CD34low, and glycophorin A−/low. Assays of progenitors showed that HTK+c-Kit+ cells consisted exclusively of erythroid progenitors, whereas HTK−c-Kit+ cells contained progenitors of granulocytes and macrophages as well as those of erythroid cells. Most of the HTK+ erythroid progenitors were stem cell factor-dependent for proliferation, indicating that they represent mainly erythroid burst-forming units (BFU-E). During the erythroid differentiation of cultured peripheral CD34+ cells, HTK expression was upregulated on immature erythroid cells that corresponded to BFU-E and erythroid colony-forming units and downregulated on erythroblasts with high levels of glycophorin expression. These findings suggest that HTK is selectively expressed on the restricted stage of erythroid progenitors, particularly BFU-E, and that HTK is the first marker antigen that allows the purification of erythroid progenitors. Furthermore, HTKL, the ligand for HTK, was expressed in the bone marrow stromal cells. Our findings provide a novel regulatory system of erythropoiesis mediated by the HTKL-HTK signaling pathway.
Oligoclonal CD4+CD57+ T-Cell Expansions Contribute to the Imbalanced T-Cell Receptor Repertoire of Rheumatoid Arthritis Patients
Authors: Imberti Luisa , Sottini Alessandra , Signorini Simona , Gorla Roberto , Primi Daniele 
Published: October 2019

AbstractA peculiar feature of rheumatoid arthritis patients is that they carry clonally expanded CD4+ and CD8+ cells in the peripheral blood. While the distortion of the repertoire of CD8+ cells has been ascribed to the increase of CD8+CD57+ large granular lymphocytes, often detected in these patients, the mechanism responsible for the clonal expansion of CD4+ cells remains unexplained. Here, we report that CD4+CD57+ cells, that in healthy individuals represent a small subset of peripheral CD4+ lymphocytes, are significantly expanded in the peripheral blood of a considerable percentage of rheumatoid arthritis patients. Furthermore, the expansion of these lymphocytes appears to correlate with the presence of rheumatoid factor. The molecular analysis of the T-cell receptor variable beta segments expressed by the CD4+CD57+ cells enriched in rheumatoid arthritis patients showed that they use restricted repertoires, that partially overlap with those of their CD4−CD57+ counterpart. The structural feature of the receptor ligand expressed by these cells revealed that their expansion is most likely mediated by strong antigenic pressures. However, since we also found that CD4+CD57+ and CD4−CD57+ cells can share the same clonal specificity, it is likely that their selection is not mediated by conventional major histocompatibility complex restricted mechanisms. Thus, while our data demonstrate that CD4+CD57+ cells play an important role in establishing the imbalance of the CD4+ cell repertoire observed in rheumatoid arthritis patients, they also suggest that these cells have common features with mouse CD4+CD8−NK1.1+/T cells.
Immunostimulatory Oligodeoxynucleotides Containing CpG Motifs Enhance the Efficacy of Monoclonal Antibody Therapy of Lymphoma
Authors: Wooldridge James E. , Ballas Zuhair , Krieg Arthur M. , Weiner George J. 
Published: October 2019

AbstractBacterial DNA and synthetic oligodeoxynucleotides containing the CpG motif (CpG ODN) can activate various immune cell subsets, including natural killer cells and macrophages. We evaluated whether the combination of CpG ODN and antitumor monoclonal antibody is effective at preventing tumor growth in an immunocompetent murine lymphoma model. CpG ODN–activated murine splenocytes induced lysis of tumor targets more effectively than unactivated splenocytes. These effector cells were also superior to unactivated splenocytes or cells activated with a control methylated ODN at inducing antibody-mediated lysis of 38C13 murine lymphoma cells. In vivo, CpG ODN alone had no effect on survival of mice inoculated with 38C13 cells. However, a single injection of CpG ODN enhanced the antitumor response to antitumor monoclonal antibody therapy. Ninety percent of mice treated with monoclonal antibody alone developed tumor compared with 20% of mice treated with antibody and CpG ODN. These antitumor effects were less pronounced when treatment consisted of an identical ODN containing methylated CpG dinucleotides. A single dose of CpG ODN appeared to be as effective as multiple doses of interleukin-2 at inhibiting tumor growth when combined with antitumor monoclonal antibody. We conclude that immunostimulatory CpG ODN can enhance antibody dependent cellular cytotoxicity and warrant further evaluation as potential immunotherapeutic reagents in cancer.
Donor Leukocyte Infusion for Leukemic Relapse After Allogeneic Marrow Transplantation: Lack of Residual Donor Hematopoiesis Predicts Aplasia
Authors: Keil Felix , Haas Oskar A. , Fritsch Gerhard , Kalhs Peter , Lechner Klaus , Mannhalter Christine , Reiter Elisabeth , Niederwieser Dietger , Hoecker Paul , Greinix Hildegard T. 
Published: October 2019

Abstract
We assessed the chimerism of CD34+ bone marrow cells before donor leukocyte infusion (DLI) on nine occasions in seven patients with leukemic relapse after allogeneic marrow transplantation. The patients suffered from acute lymphoblastic leukemia (n = 1), acute myeloid leukemia (n = 3), and chronic myeloid leukemia (CML; n = 3). Two patients received a second DLI because of disease progression after the first one. The origin of the CD34+ cells was determined by analyzing variable number of tandem repeats with polymerase chain reaction and, in sex-mismatched cases, by fluorescence in situ hybridization. Before DLI CD34+ cells were exclusively of donor origin in four patients. In another patient 41% of CD34+ cells were derived from the donor. No aplasia occurred in these patients after DLI, whereas in the two patients with exclusively recipient hematopoiesis severe aplasia lasting for 5 and 13 weeks necessitated hematopoietic stem cell support. One patient who had only 5% CD34+ donor cells before DLI recovered without stem cell support after 10 days. Two patients in relapse of CML showed a high percentage of BCR-ABL− CD34+ cells of recipient origin before DLI. These BCR-ABL− cells of recipient type did not prevent severe aplasia which indicates that the assessment of BCR-ABL+ hematopoiesis alone is insufficient for predicting aplasia. Our data indicate that in case of sufficient donor hematopoiesis before DLI no persistent aplasia will occur. Thus, evaluation of donor hematopoiesis allows prediction of aplasia after DLI and makes early therapeutic interventions possible.
Synergistic Effect of FLT-3 Ligand on the Granulocyte Colony-Stimulating Factor–Induced Mobilization of Hematopoietic Stem Cells and Progenitor Cells Into Blood in Mice
Authors: Sudo Yoshikazu , Shimazaki Chihiro , Ashihara Eishi , Kikuta Takehisa , Hirai Hideyo , Sumikuma Toshiya , Yamagata Noboru , Goto Hideo , Inaba Tohru , Fujita Naohisa , Nakagawa Masao 
Published: October 2019

Abstract
We have previously shown that FLT-3 ligand (FL) mobilizes murine hematopoietic primitive and committed progenitor cells into blood dose-dependently. Whether FL also acts synergistically with granulocyte colony-stimulating factor (G-CSF ) to induce such mobilization has now been investigated. Five- to 6-week-old C57BL/6J mice were injected subcutaneously with recombinant human G-CSF (250 μg/kg), Chinese hamster ovarian cell-derived FL (20 μg/kg), or both cytokines daily for 5 days. The number of colony-forming cells (CFCs) in peripheral blood increased approximately 2-, 21-, or 480-fold after administration of FL, G-CSF, or the two cytokines together, respectively, for 5 days. The number of CFCs in bone marrow decreased after 3 days but was increased approximately twofold after 5 days of treatment with G-CSF. The number of CFCs in the bone marrow of mice treated with both FL and G-CSF showed a 3.4-fold increase after 3 days and subsequently decreased to below control values. The number of CFCs in spleen was increased 24.2- and 93.7-fold after 5 days of treatment with G-CSF alone or in combination with FL, respectively. The number of colony-forming unit-spleen (CFU-S) (day 12) in peripheral blood was increased 13.2-fold by G-CSF alone and 182-fold by G-CSF and FL used together after 5 days of treatment. Finally, the number of preCFU-S mobilized into peripheral blood was also increased by the administration of FL and G-CSF. These observations show that FL synergistically enhances the G-CSF–induced mobilization of hematopoietic stem cells and progenitor cells into blood in mice, and that this combination of growth factors may prove useful for obtaining such cells in humans for transplantation.