bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity
Authors: Sakamaki Sumio , Hirayama Yasuo , Matsunaga Takuya , Kuroda Hiroyuki , Kusakabe Toshiro , Akiyama Takehide , Konuma Yuichi , Sasaki Katsunori , Tsuji Naoki , Okamoto Tetsuro , Kobune Masayoshi , Kogawa Katsuhisa , Kato Junji , Takimoto Rishu , Koyama Ryuzo , Niitsu Yoshiro 
Published: October 2019

AbstractThe present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-β1 (TGF-β1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-β receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-β1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit–granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-β1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-β1 is one of the pathophysiological feedback regulators of megakaryopoiesis.
Osteoclast-Derived Zinc Finger (OCZF) Protein With POZ Domain, a Possible Transcriptional Repressor, Is Involved in Osteoclastogenesis
Authors: Kukita Akiko , Kukita Toshio , Ouchida Mamoru , Maeda Hidefumi , Yatsuki Hitomi , Kohashi Osamu 
Published: October 2019

AbstractThe differentiation of osteoclasts is regulated by transcription factors expressed in cells of osteoclast lineage. We isolated here a potential transcription factor from a cDNA library of an enriched population of preosteoclasts and osteoclasts. The cDNA encodes a protein with N-terminal POZ domain and C-terminalKrüppel-like zinc fingers. We designate this protein as osteoclast-derived zinc finger (OCZF). OCZF was found to be rat homologue of mouse leukemia/lymphoma-related factor (LRF). Northern blot and in situ hybridization analysis showed OCZF mRNA at a high level in osteoclasts and kidney cells. OCZF had a nuclear targeting sequence and was localized in the nucleus of transfected cells. In addition, OCZF specifically bound to the guanine-rich consensus sequences of Egr-1 and c-Krox. Transient transfection assays indicate that OCZF can repress transcription activity like other POZ domain proteins. Furthermore, antisense but not sense phosphorothioate oligodeoxynucleotides (ODNs) for OCZF cDNA suppressed the formation of osteoclast-like multinucleated cells (MNCs) in bone marrow culture, whereas the same ODNs did not significantly affect the formation of macrophage polykaryons and mononuclear preosteoclast-like cells (POCs). These results suggest that OCZF is a unique transcription factor that plays an important role in the late stage of osteoclastogenesis.
Cultured Endothelial Cells From Human Arteriovenous Malformations Have Defective Growth Regulation
Authors: Wautier Marie-Paule , Boval Bernadette , Chappey Olivier , Enjolras Odile , Wernert Nicolas , Merland Jean-Jacques , Wautier Jean-Luc 
Published: October 2019

AbstractVascular malformations are frequent in newborns, and they persist throughout life, which differentiates them from vascular tumors (eg, hemangiomas). Arteriovenous malformations are high-flow vascular malformations. They are considered nonmalignant but can expand and become a significant clinical risk when extensive. To characterize endothelial cells from arteriovenous malformations (AMEC), we cultured cells obtained from surgical specimens and studied their properties. After selection, the cells that grew out from explants had phenotypic and antigenic features (platelet endothelial cell adhesion molecule, von Willebrand factor) of human endothelial cells. Their spontaneous proliferation rate was higher (1.8 to 6.4 times) than that of human umbilical vein, arterial, or microvascular endothelial cells. The proliferation rate of AMEC was not sensitive to the inhibitory activity of various cytokines (interleukin-1β, tumor necrosis factor-, transforming growth factor-β, Interferon-γ). In basal conditions, intercellular adhesion molecule (ICAM-1) was detected at a higher level of expression (6- to 10-fold) on AMEC, but these cells failed to express E-selectin or the vascular cell adhesion molecule (VCAM-1) after cytokine stimulation. Expression of c-ets-1 proto-oncogene was shown by in situ hybridization. The low response to cytokines, the higher propensity to proliferate, and the ets-1 expression suggest that AMEC have a defective regulation of proliferation that may be due to a reduced apoptotic process.
Fibrin Fragment Induction of Plasminogen Activator Inhibitor Transcription Is Mediated by Activator Protein-1 Through a Highly Conserved Element
Authors: Olman Mitchell A. , Hagood James S. , Simmons Warren L. , Fuller Gerald M. , Vinson Charles , White Kimberly E. 
Published: October 2019

AbstractPlasminogen activator inhibitor type-1 (PAI-1), a serine protease inhibitor, affects the processes of fibrinolysis, wound healing, and vascular remodeling. We have demonstrated that PAI-1 transcription is induced by D dimer, a plasmin proteolytic fragment of fibrin, supporting its role in negative feedback on peri-cellular proteolysis. The focus of this study was to define the mechanism of D dimer’s effects on PAI-1 transcription. D dimer increased the binding activity of the transcription factor activator protein-1 components c-fos/junD and c-fos mRNA levels in a time- and concentration-dependent manner to a greater extent than fibrinogen. Both basal and D dimer-induced PAI-1 transcriptional activity were entirely dependent on elements within the −161 to −48 bp region of the PAI-1 gene in fibroblasts. Mutations within the AP-1–like element (−59 to −52 bp) in the PAI-1 gene affected D dimer-induced transcriptional activity, c-fos/junD DNA binding, and basal and c-fos inducible PAI-1 transcriptional activity. Furthermore, expression of either wild-type or mutant c-fos proteins augmented or diminished the response of the PAI-1 promoter (−161 to +26 bp) to D dimer, respectively. D dimer-induced binding of c-fos/junD to the highly conserved and unique AP-1 like element in the PAI-1 gene provides a mechanism whereby specific fibrin fragments control fibrin persistence at sites of inflammation, fibrosis, and neoplasia.
Hodgkin/Reed-Sternberg Cells Induce Fibroblasts to Secrete Eotaxin, a Potent Chemoattractant for T Cells and Eosinophils
Authors: Jundt Franziska , Anagnostopoulos Ioannis , Bommert Kurt , Emmerich Florian , Müller Gerd , Foss Hans-Dieter , Royer Hans-Dieter , Stein Harald , Dörken Bernd 
Published: October 2019

Abstract
Hodgkin’s disease is histopathologically characterized by the relative scarcity of neoplastic Hodgkin and Reed-Sternberg cells and for yet unknown reasons by an abundant reactive background of T lymphocytes and often eosinophils. Eotaxin is a CC-chemokine attracting eosinophils and T helper 2 (Th2) cells in allergic inflammation. We now report that eotaxin is strongly expressed in fibroblasts of Hodgkin’s disease tissues, whereas Hodgkin/Reed-Sternberg cells do not express this chemokine. In tissue culture, Hodgkin’s disease tumor cells induce eotaxin expression in cocultured dermal fibroblasts in a concentration leading to a specific chemotactic response of a Th2 cell clone. Production of tumor necrosis factor- (TNF-) by Hodgkin/Reed-Sternberg cells appears to be responsible for this induction, because blocking of TNF- by neutralizing antibodies prevented fibroblast eotaxin expression. Our data suggest that eotaxin is involved in the pathobiology of Hodgkin’s disease by contributing to eosinophil and T-lymphocyte recruitment.
Interleukin-6 Regulation of Matrix Metalloproteinase (MMP-2 and MMP-9) and Tissue Inhibitor of Metalloproteinase (TIMP-1) Expression in Malignant Non-Hodgkin’s Lymphomas
Authors: Kossakowska Anna E. , Edwards Dylan R. , Prusinkiewicz Christopher , Zhang Melissa C. , Guo Dianlin , Urbanski Stefan J. , Grogan Thomas , Marquez Leah A. , Janowska-Wieczorek Anna 
Published: October 2019

AbstractWe showed previously that human malignant non-Hodgkin’s lymphomas (NHL) degrade extracellular matrix (ECM) components through the action of metalloproteinases and that elevated expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) correlated with a poor clinical outcome in patients with NHL. In the present study we sought to investigate whether there is any correlation between the expression of gelatinases (MMP-2 and MMP-9), TIMP-1, and the expression of cytokines and growth factors such as interleukin-1β (IL-1β), IL-6, IL-10, tumor necrosis factor  (TNF-), transforming growth factor β (TGFβ), and basic fibroblast growth factor (bFGF) in human NHL. In lymphoma tissues obtained from 32 patients, elevated expression of IL-6 correlated significantly with elevated messenger RNA (mRNA) levels of MMP-9, MMP-2, and TIMP-1. Moreover, in human lymphoid cell lines of B- and T-cell origin (Raji, Jurkat, and NC-37), IL-6 stimulated production of MMP-9 and MMP-2 but not TIMP-1. In the Matrigel invasion assay IL-6 significantly upregulated transmigration of Raji and Jurkat cells, which in turn was inhibited by recombinant human TIMP-1 and anti-MMP-9 and MMP-2 antibodies. We postulate that IL-6 may play a role in the clinical aggressiveness of human NHL by stimulating MMP production.
Different Roles of Glycosylphosphatidylinositol in Various Hematopoietic Cells as Revealed by a Mouse Model of Paroxysmal Nocturnal Hemoglobinuria
Authors: Murakami Y. , Kinoshita T. , Maeda Y. , Nakano T. , Kosaka H. , Takeda J. 
Published: October 2019

AbstractPatients with paroxysmal nocturnal hemoglobinuria (PNH) have one or a few clones of mutant hematopoietic stem cells defective in glycosylphosphatidylinositol (GPI) synthesis as a result of somatic mutation in the X-linked gene PIG-A. The mutant stem cell clone dominates hematopoiesis by a mechanism that is unclear. To test whether a lack of multiple GPI-anchored proteins results in dysregulation and expansion of stem cells, we generated mice in which GPI-anchor negative cells are present only in the hematopoietic system. We transplanted lethally irradiated mice with female fetal liver cells bearing one allele of the Piga gene disrupted by conditional gene targeting. Because of the X-chromosome inactivation, a significant fraction of the hematopoietic stem cells in fetal livers was GPI-anchor negative. In the transplanted mice, cells of all hematopoietic lineages contained GPI-anchor negative cells. The percentage of GPI-anchor negative cells was much higher in T lymphocytes including immature thymocytes than in other cell types, suggesting a regulatory role for GPI-anchored proteins at an early stage of T-lymphocyte development. However, the proportions of GPI-anchor negative cells in various blood cell lineages were stable over a period of 42 weeks, indicating thatPiga mutation alone does not account for the dominance of the mutant stem cells and that other phenotypic changes are involved in pathogenesis of PNH.
SDF-1 Responsiveness Does Not Correlate With CXCR4 Expression Levels of Developing Human Bone Marrow B Cells
Authors: Honczarenko Marek , Douglas Raymond S. , Mathias Clarissa , Lee Benhur , Ratajczak Mariusz Z. , Silberstein Leslie E. 
Published: October 2019

AbstractChemokines and their receptors are broadly expressed in different tissues and are involved in diverse biologic processes. Gene inactivation studies have shown that both stromal cell derived factor-1 (SDF-1) and chemokine receptor 4 (CXCR4) are essential for B lymphopoiesis. However, it is not yet clear by which mechanisms B lymphopoiesis is affected. In the present study, we have examined CXCR4 expression and function on primary B cells representing sequential stages of development (eg, pro-B, pre-B, immature, and mature B cells) in fetal and adult bone marrow. The expression of CXCR4 was observed to be sinusoidal. Expression was highest on pre-B cells, decreased as cells developed into immature B cells, and then increased again upon transition to the mature B-cell stage. The corresponding ligand SDF-1 was shown to trigger vigorous cell signaling and migration responses, which are restricted to early lineage B cells. The responsiveness to SDF-1 was markedly decreased for immature and mature B cells despite relatively high levels of CXCR4 expression. Thus, the diminished responsiveness to SDF-1 by more mature B cells was determined to be disproportionate to the level of CXCR4 expression. These findings raise the possibility that CXCR4 function is differentially controlled during B lymphopoiesis and may be relevant to the compartmentalization of B-cell precursors in the bone marrow.
Restoration of Lymphoid Populations in a Murine Model of X-Linked Severe Combined Immunodeficiency by a Gene-Therapy Approach
Authors: Lo Mindy , Bloom Michael L. , Imada Kazunori , Berg Maria , Bollenbacher Julie M. , Bloom Eda T. , Kelsall Brian L. , Leonard Warren J. 
Published: October 2019

AbstractX-linked severe combined immunodeficiency (XSCID) is a life-threatening syndrome in which both cellular and humoral immunity are profoundly compromised. This disease results from mutations in theIL2RG gene, which encodes the common cytokine receptor γ chain, γc. Previously, we generated γc-deficient mice as a murine model of XSCID. We have now used lethally irradiated γc-deficient mice to evaluate a gene therapeutic approach for treatment of this disease. Transfer of the human γc gene to repopulating hematopoietic stem cells using an ecotropic retrovirus resulted in an increase in T cells, B cells, natural killer (NK) cells, and intestinal intraepithelial lymphocytes, as well as normalization of the CD4:CD8 T-cell ratio and of serum Ig levels. In addition, the restored cells could proliferate in response to interleukin-2 (IL-2). Thus, our results provide added support that gene therapy is a feasible therapeutic strategy for XSCID. Moreover, because we used a vector directing expression of human γc to correct a defect in γc-deficient mice, these data also indicate that human γc can cooperate with the distinctive cytokine receptor chains such as IL-2Rβ and IL-7R to mediate responses to murine cytokines in vivo.
Rapid Determination of Epstein-Barr Virus–Specific CD8+T-Cell Frequencies by Flow Cytometry
Authors: Kuzushima Kiyotaka , Hoshino Yo , Fujii Ken , Yokoyama Naoaki , Fujita Masatoshi , Kiyono Tohru , Kimura Hiroshi , Morishima Tsuneo , Morishima Yasuo , Tsurumi Tatsuya 
Published: October 2019

AbstractWe have developed an efficient and rapid method for detection of Epstein-Barr virus (EBV)-specific CD8+ T-cell frequencies both in freshly isolated peripheral blood mononuclear cells (PBMCs) and in vitro established cytotoxic T lymphocyte (CTL) lines. Responder cells are thereby stimulated with an autologous lymphoblastoid cell line for 5 hours and intracellular accumulation of interferon γ (IFNγ) is detected by multiparameter flow cytometric analysis. EBV-specific CD8+ T-cell frequencies ranged between 0.63% and 1.29% in PBMCs of 5 healthy long-term EBV carriers. Using EBV-specific T-cell lines, it was shown that flow cytometric analysis is more sensitive than limiting dilution analysis for CTL precursors and enzyme-linked immunospot assay detecting IFNγ-producing T cells. The class I restriction of IFNγ production was confirmed using an anti-class I monoclonal antibody (MoAb). Information on other cytokine production of EBV-specific CTLs could be obtained using combinations of anti-cytokine MoAbs. The sensitive and rapid nature of the flow cytometric assay for EBV-specific CD8+ T-cell frequency has significant advantages for evaluation of EBV-specific CD8+ T-cell responses in PBMCs of patients with EBV-related diseases.
Reduced NFAT1 Protein Expression in Human Umbilical Cord Blood T Lymphocytes
Authors: Kadereit Suzanne , Mohammad Shaden F. , Miller Robin E. , Woods Kathleen Daum , Listrom Chad D. , McKinnon Karen , Alali Alborz , Bos Linda S. , Iacobucci Michelle L. , Sramkoski Michael R. , Jacobberger James W. , Laughlin Mary J. 
Published: October 2019

AbstractUmbilical cord blood (UCB) stem cells from related and unrelated allogeneic donors have emerged as novel treatment for patients with hematologic malignancies. The incidence and severity of acute graft-versus-host disease (GVHD) after UCB transplantation compares favorably with that observed in recipients of matched unrelated donor allogeneic grafts, but remains a major cause of morbidity and mortality. It has been shown that stimulated lymphocytes from UCB have reduced production of cytokines including interferon-γ (IFN-γ) and tumor necrosis factor- (TNF-), which play a role in GVHD pathophysiology. We investigated the molecular mechanisms underlying this reduced cytokine production by analyzing expression of nuclear factor of activated T cells-1 (NFAT1) in UCB T cells. We detected no constitutive expression of NFAT1 protein in unstimulated UCB T cells compared with adult T cells. Moreover, although NFAT1 expression in UCB T cells was upregulated after prolonged (40 hours) T-cell stimulation, it was only partially upregulated when compared with adult controls. Our observation of minimal NFAT1 expression after stimulation correlated with reduced cytoplasmic IFN-γ and TNF- production in UCB T cells studied simultaneously. Reduced NFAT1 expression may blunt amplification of donor UCB T-cell alloresponsiveness against recipient antigens, thereby potentially limiting GVHD incidence and severity after allogeneic UCB transplantation.
Frequent Expression of the B-Cell–Specific Activator Protein in Reed-Sternberg Cells of Classical Hodgkin’s Disease Provides Further Evidence for Its B-Cell Origin
Authors: Foss Hans-Dieter , Reusch Regina , Demel Gudrun , Lenz Georg , Anagnostopoulos Ioannis , Hummel Michael , Stein Harald 
Published: October 2019

AbstractThe neoplastic cells of classical Hodgkin’s disease (cHD), ie, Hodgkin and Reed-Sternberg cells (HRS cells), contain clonally rearranged Ig genes, but are dissimilar to normal B cells in that they mostly do not display B-cell antigens such as CD20 or CD19. The transcription factor B-cell–specific activator protein (BSAP) influences numerous B-cell functions such as B-cell antigen expression, Ig expression, and class switch. We analyzed the expression of BSAP in cHD and control tissues by isotopic in situ hybridization and immunohistochemistry to determine whether BSAP is expressed in HRS cells and, if so, whether it may be involved in the genesis of the abnormal phenotype of these cells. Both in normal lymphoid tissue and non-Hodgkin lymphomas, BSAP transcripts and protein were almost exclusively found in B cells and B-cell lymphomas (40 cases), but were absent from the tumor cells of T-cell neoplasms (41 cases), including 19 cases of anaplastic large cell lymphoma of T- and null-cell type. Among cHD, variable numbers of HRS cells exhibited BSAP transcripts (22 of 25 cases) and protein (28 of 31 cases). Our findings show that BSAP is sufficiently specific to serve as B-cell marker. BSAP expression in HRS cells provides further strong evidence for a frequent B-cell origin of cHD and helps distinguish this disease from anaplastic large cell lymphoma of T- and null-cell type. Because BSAP is much more frequently expressed in HRS cells than the conventional B-cell antigens, the abnormal immunophenotype of HRS cells with frequent absence of B-cell antigens does not appear to be due to absent BSAP expression.
Myeloid Transcription Factor C/EBPɛ Is Involved in the Positive Regulation of Lactoferrin Gene Expression in Neutrophils
Authors: Verbeek Walter , Lekstrom-Himes Julie , Park Dorothy J. , Dang Pham My-Chan , Vuong Peter T. , Kawano Seji , Babior Bernard M. , Xanthopoulos Kleanthis , Koeffler H. Phillip 
Published: October 2019

AbstractTargeted mutation of the myeloid transcription factor C/EBPɛ in mice results in gram-negative septic death at 3 to 5 months of age. This study defines the underlying molecular defects in their terminal granulocytic differentiation. The mRNA for the precursor protein of the cathelin-related antimicrobial peptides was almost completely absent in the bone marrow cells of C/EBPɛ−/− mice. This finding may help explain their susceptibility to gram-negative sepsis, because both are bacteriocidal peptides with potent activity against gram-negative bacteria. Superoxide production was found to be reduced in both granulocytes and monocytes of C/EBPɛ−/− mice. While gp91 phox protein levels were normal, p47phox protein levels were considerably reduced in C/EBPɛ −/− granulocytes/monocytes, possibly limiting the assembly of the NADPH oxidase. In addition, expression of mRNA of the secondary and tertiary granule proteins, lactoferrin and gelatinase, were not detected, and levels of neutrophil collagenase mRNA were reduced in bone marrow cells of the knock-out mice. The murine lactoferrin promoter has a putative C/EBP site close to the transcription start site. C/EBPɛ bound to this site in electromobility shift assay studies and mutation of this site abrogated binding to it. A mutation in the C/EBP site reduced the activity of the promoter by 35%. Furthermore, overexpression of C/EBPɛ in U937 cells increased the activity of the wild-type lactoferrin promoter by 3-fold. In summary, our data implicate C/EBPɛ as a critical factor of host antimicrobial defense and suggests that it has a direct role as a positive regulator of expression of lactoferrin in vivo.
The t(11;20)(p15;q11) Chromosomal Translocation Associated With Therapy-Related Myelodysplastic Syndrome Results in anNUP98-TOP1 Fusion
Authors: Ahuja Harish G. , Felix Carolyn A. , Aplan Peter D. 
Published: October 2019

Abstract
The NUP98 gene is involved in 3 distinct chromosomal rearrangements, t(7;11)(p15;p15), t(2;11)(q31;p15), and inv(11)(p15q22); all of these NUP98 rearrangements have been identified in the malignant cells of patients with therapy-related acute myelogenous leukemia or myelodysplastic syndrome (t-AML/MDS). Here we report the cloning and characterization of a t(11;20)(p15;q11) translocation from patients with t-MDS. The breakpoint on chromosome 11p15 targets the NUP98 gene and results in the separation of the N-terminal FXFG repeats from the RNA-binding domain located in the C-terminus. The breakpoint on chromosome 20q11 occurs within the gene encoding human DNA topoisomerase I (TOP1). As a result, a chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of DNA topoisomerase I is produced. These results indicate that NUP98is a recurrent target in therapy-related malignancies, and thatTOP1 is a previously unrecognized target for chromosomal translocations.