bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fetal liver stroma consists of cells in epithelial-to-mesenchymal transition
Authors: Chagraoui Jalila , Lepage-Noll Adeline , Anjo Aurora , Uzan Georges , Charbord Pierre 
Published: April 2003

AbstractLiver becomes the predominant site of hematopoiesis by 11.5 dpc (days after coitus) in the mouse and 15 gestational weeks in humans and stays so until the end of gestation. The reason the liver is the major hematopoietic site during fetal life is not clear. In this work, we tried to define which of the fetal liver microenvironmental cell populations would be associated with the development of hematopoiesis and found that a population of cells with mixed endodermal and mesodermal features corresponded to hematopoietic-supportive fetal liver stroma. Stromal cells generated from primary cultures or stromal lines from mouse or human fetal liver in the hematopoietic florid phase expressed both mesenchymal markers (vimentin, osteopontin, collagen I, α smooth muscle actin, thrombospondin-1, EDa fibronectin, calponin, Stro-1 antigens, myocyte-enhancer factor 2C) and epithelial (α-fetoprotein, cytokeratins 8 and 18, albumin, E-cadherin, hepatocyte nuclear factor 3 α) markers. Such a cell population fits with the description of cells in epithelial-to-mesenchymal transition (EMT), often observed during development, including that of the liver. The hematopoietic supportive capacity of EMT cells was lost after hepatocytic maturation, induced by oncostatin M in the cell line AFT024. EMT cells were observed in the fetal liver microenvironment during the hematopoietic phase but not in nonhematopoietic liver by the end of gestation and in the adult. EMT cells represent a novel stromal cell type that may be generated from hepatic endodermal or mesenchymal stem cells or even from circulating hematopoietic stem cells (HSCs) seeding the liver rudiment.
Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia
Authors: Hong Aaron P. , Cook Deborah J. , Sigouin Christopher S. , Warkentin Theodore E. 
Published: April 2003

Abstract
Heparin-induced thrombocytopenia (HIT) is a transient antibody-mediated hypercoagulability state strongly associated with lower-limb deep-vein thrombosis (DVT). Whether HIT is additionally associated with upper-limb DVT—either with or without central venous catheter (CVC) use—is unknown. We therefore studied 260 patients with antibody-positive HIT to determine the influence of CVC use on frequency and localization of upper-extremity DVT in comparison with 2 non-HIT control populations (postoperative orthopedic surgery and intensive-care unit patients). Compared with the control populations, both upper- and lower-extremity DVTs were found to be associated with HIT. Upper-extremity DVTs occurred more frequently in HIT patients with a CVC (14 of 145 [9.7%]) versus none of 115 (0%) patients without a CVC (P = .000 35). All upper-extremity DVTs occurred at the CVC site (right, 12; left, 2; kappa = 1.0; P = .011). We conclude that a localizing vascular injury (CVC use) and a systemic hypercoagulability disorder (HIT) interact to explain upper-extremity DVT complicating HIT.
Sustained complete hematologic remission after administration of the tyrosine kinase inhibitor imatinib mesylate in a patient with refractory, secondary AML
Authors: Kindler Thomas , Breitenbuecher Frank , Marx Andreas , Hess Georg , Gschaidmeier Harald , Gamm Heinold , Kirkpatrick Charles J. , Huber Christoph , Fischer Thomas 
Published: April 2003

Abstract
Imatinib mesylate, a tyrosine kinase inhibitor targeting bcr-abl, platelet-derived growth factor receptor (PDGF-R), and c-Kit, effectively induces hematologic and cytogenetic remissions in bcr-abl+ chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) with only mild to moderate side effects. Here, we describe the successful treatment of a 64-year-old man with c-Kit+ secondary acute myeloid leukemia (AML) refractory to standard chemotherapy. Upon 2 weeks of imatinib mesylate administration, the patient achieved a complete hematologic remission in peripheral blood. In addition, complete clearance of leukemic blasts in bone marrow and a significant cytogenetic response lasting for more than 5 months was observed. Sequence analysis of exons 2, 8, 10, 11, and 17 of the c-Kit receptor did not reveal structural alterations as previously described in a subset of AML cases. This is the first report of complete remission achieved upon administration of imatinib mesylate in a patient with highly refractory, secondary AML.
Mitochondrial DNA mutations in patients with myelodysplastic syndromes
Authors: Shin Myung Geun , Kajigaya Sachiko , Levin Barbara C. , Young Neal S. 
Published: April 2003

Abstract
We undertook to systematically analyze the entire mitochondrial genome by gene amplification and direct sequencing in 10 patients with myelodysplasia; results were compared with concomitantly studied 8 healthy volunteers as well as mtDNA sequences in a standard database. Nucleotide changes that were present in our healthy controls as well as those in published databases were counted as polymorphisms. Overall, there was no increase in the number of mtDNA genes harboring polymorphisms or “new” mutations between our patients and healthy controls, although there were a few more mtDNA changes resulting in amino acid changes in myelodysplasia (9 in 8 controls versus 16 in 10 patients). Thirty new mutations, all nucleotide substitutions, were found among the 10 patients, distributed throughout the mitochondrial genome; 5 mutations resulted in amino acid changes. None of the mutations in controls produced amino acid changes. We were not able to confirm previously described mutations in sideroblastic anemia or “hot spots” in the cytochrome c oxidase I and II genes. Our data do not support a major role for mitochondrial genomic instability in myelodysplasia, and they fail to reproduce previous reports of significant or widespread mitochondrial mutations in this disease. Modest changes in mutation numbers and mitochondrial microsatellites may be evidence of increased mutagenesis in mtDNA, or, more likely, a reflection of limited clonality among hematopoietic stem cells in this bone marrow failure syndrome.
Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells
Authors: Serafeim Adamantios , Holder Michelle J. , Grafton Gillian , Chamba Anita , Drayson Mark T. , Luong Quang T. , Bunce Christopher M. , Gregory Christopher D. , Barnes Nicholas M. , Gordon John 
Published: April 2003

Abstract
Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for clinical depression and a range of anxiety-related disorders. They are well tolerated over extended periods with more than 50 million people worldwide benefiting from their use. Here we show that 3 structurally distinct SSRIs—fluoxetine, paroxetine, and citalopram—act directly on Burkitt lymphoma (BL) cells to trigger rapid and extensive programmed cell death. SSRIs unexpectedly stimulated calcium flux, tyrosine phosphorylation, and down-regulation of the c-myc and nm23 genes in Burkitt lymphoma cells remaining faithful to the biopsy phenotype. Resultant SSRI-induced apoptosis was preceded by caspase activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, a loss of mitochondrial membrane potential, and the externalization of phosphatidylserine, and reversed by the overexpression of bcl-2. Normal peripheral blood mononuclear cells and tonsil B cells, whether resting or stimulated into cycle, were largely resistant to SSRI-induced death as were 5 non-BL lymphoid cell lines tested. We discuss these findings within the context of whether the SSRI class of antidepressants could find future application as potential therapeutics for the highly aggressive and—because of its association with AIDS—increasingly more common Burkitt lymphoma.
Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig
Authors: Guillot Cécile , Ménoret Séverine , Guillonneau Carole , Braudeau Cécile , Castro Maria G. , Lowenstein Pedro , Anegon Ignacio 
Published: April 2003

AbstractCostimulatory blockade using cytotoxic T lymphocyte–associated antigen 4 immunoglobulin (CTLA4Ig) efficiently down-regulates immune responses in animal models and is currently used in autoimmune and transplantation clinical trials, but the precise cellular and molecular mechanisms involved remain unclear. Rats that received allogeneic heart transplants and were treated with adenoviruses coding for CTLA4Ig show long-term allograft survival. The immune mechanisms regulating induction of long-term allograft acceptance were analyzed in splenocytes using mixed leukocyte reactions (MLRs). MLRs of splenocytes but not purified T cells from CTLA4Ig-treated rats showed higher than 75% inhibition compared with controls. Splenocytes from CTLA4Ig-treated rats inhibited proliferation of naive and allogeneically primed splenocytes or T cells. MLR suppression was dependent on soluble secreted product(s). Production of soluble inhibitory product(s) was triggered by a donor antigen-specific stimulation and inhibited proliferation in an antigen-nonspecific manner. CTLA4Ig levels in the culture supernatant were undetectable and neither interleukin-10 (IL-10), transforming growth factor β1 (TGFβ1), IL-4, nor IL-13 were responsible for suppression of MLRs. Inhibition of nitrous oxide (NO) production or addition of IL-2 could not restore proliferation independently, but the combined treatment synergistically induced proliferation comparable with controls. Stimulation of APCs using tumor necrosis factor (TNF)–related activation-induced cytokine (TRANCE) or CD40L and addition of IL-2 normalized MLRs of CTLA4Ig-treated splenocytes. Finally, dendritic cells (DCs), but not T cells, from CTLA4Ig-treated rats inhibited naive MLRs. Altogether, these results provide evidence that after in vivo CTLA4Ig treatment, splenocytes, and in particular DCs, can inhibit alloantigen-induced proliferative responses through secretion of inhibitory products, thus promoting alloantigen-specific tolerance in vivo.
UbcH5A, a member of human E2 ubiquitin-conjugating enzymes, is closely related to SFT, a stimulator of iron transport, and is up-regulated in hereditary hemochromatosis
Authors: Gehrke Sven G. , Riedel Hans-Dieter , Herrmann Thomas , Hadaschik Boris , Bents Karin , Veltkamp Claudia , Stremmel Wolfgang 
Published: April 2003

Abstract
SFT, a stimulator of iron (Fe) transport, has been described as a transmembrane protein that facilitates the uptake of ferrous and ferric iron in mammalian cells. This study was initiated to investigate the 5′ regulatory region of SFT and its role in the etiology of hereditary hemochromatosis. Sequence analyses of the putative 5′ regulatory region revealed that the SFT cDNA sequence corresponds to intron 6/exon 7 of UbcH5A, a member of E2 ubiquitin-conjugating enzymes, which is involved in the iron-dependent ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Further mRNA expression studies using a sequence-specific reverse transcriptase–polymerase chain reaction (RT-PCR) assay showed that UbcH5A is significantly up-regulated in the liver of iron-overloaded patients with hereditary hemochromatosis, as previously published for SFT. However, in vitro studies on HepG2 cells failed to demonstrate any significant UbcH5A regulation in response to iron loading or iron chelation. In conclusion, in vivo mRNA expression data previously obtained for SFT might be attributed to UbcH5A. The role of UbcH5A and the ubiquitination pathway in the etiology of hereditary hemochromatosis remains to be elucidated further.
Regulation of the cell-surface expression of an HTLV-I binding protein in human T cells during immune activation
Authors: Nath Manisha D. , Ruscetti Francis W. , Petrow-Sadowski Cari , Jones Kathryn S. 
Published: April 2003

AbstractLittle is known about the requirements for human T-cell leukemia virus type I (HTLV-I) entry, including the identity of the cellular receptor(s). Recently, we have generated an HTLV-I surface glycoprotein (SU) immunoadhesin, HTSU-IgG, which binds specifically to cell-surface protein(s) critical for HTLV-I–mediated entry in cell lines. Here, expression of the HTLV-I SU binding protein on primary cells of the immune system was examined. The immunoadhesin specifically bound to adult T cells, B cells, NK cells, and macrophages. Cell stimulation dramatically increased the amount of binding, with the highest levels of binding on CD4+ and CD8+ T cells. Naive (CD45RAhigh, CD62Lhigh) CD4+ T cells derived from cord blood cells, in contrast to other primary cells and all cell lines examined, bound no detectable HTLV-I SU. However, following stimulation, the level of HTSU-IgG binding was rapidly induced (fewer than 6 hours), reaching the level of binding seen on adult CD4+ T cells by 72 hours. In contrast to HTLV-I virions, the soluble HTSU-IgG did not effect T-cell activation or proliferation. When incubated with human peripheral blood mononuclear cells in a mixed leukocyte reaction, HTSU-IgG inhibited proliferation at less than 1 ng/mL. These results indicate that cell-surface expression of the HTLV SU binding protein is up-regulated during in vitro activation and suggest a role for the HTLV-I SU binding proteins in the immunobiology of CD4+ T cells.
Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1 (PAI-1) promoter regulates TNFα-induced PAI-1 expression
Authors: Gruber Florian , Hufnagl Peter , Hofer-Warbinek Renate , Schmid Johannes A. , Breuss Johannes M. , Huber-Beckmann Renate , Lucerna Markus , Papac Nikolina , Harant Hanna , Lindley Ivan , de Martin Rainer , Binder Bernd R. 
Published: April 2003

AbstractPlasminogen activator inhibitor 1 (PAI-1) is the main fibrinolysis inhibitor, and high plasma levels are associated with an increased risk for vascular diseases. Inflammatory cytokines regulate PAI-1 through a hitherto unclear mechanism. Using reporter gene analysis, we could identify a region in the PAI-1 promoter that contributes to basal expression as well as to tumor necrosis factor α (TNFα) induction of PAI-1 in endothelial cells. Using this region as bait in a genetic screen, we could identify Nur77 (NAK-1, TR3, NR4A1) as an inducible DNA-binding protein that binds specifically to the PAI-1 promoter. Nur77 drives transcription of PAI-1 through direct binding to an NGFI-B responsive element (NBRE), indicating monomeric binding and a ligand-independent mechanism. Nur77, itself, is transcriptionally up-regulated by TNFα. High expression levels of Nur77 and its colocalization with PAI-1 in atherosclerotic tissues indicate that the described mechanism for PAI-1 regulation may also be operative in vivo.
Degenerate specificity of HTLV-1–specific CD8+ T cells during viral replication in patients with HTLV-1–associated myelopathy (HAM/TSP)
Authors: Kubota Ryuji , Furukawa Yoshitaka , Izumo Shuji , Usuku Koichiro , Osame Mitsuhiro 
Published: April 2003

AbstractHuman T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-1 infection, in which HTLV-1–infected CD4+ T cells and HTLV-1–specific CD8+ T cells may play a role in the disease pathogenesis. Patients with HAM/TSP have high proviral loads despite vigorous virus-specific CD8+ T-cell responses; however, it is unknown whether the T cells are efficient in eliminating the virus in vivo. To define the dynamics of HTLV-1–specific CD8+T-cell responses, we investigated longitudinal alterations in HTLV-1 proviral load, amino acid changes in an immunodominant viral epitope, frequency of HTLV-1–specific T cells, and degeneracy of T-cell recognition in patients with HAM/TSP. We showed that the frequency and the degeneracy of the HTLV-1–specific CD8+ T cells correlated well with proviral load in the longitudinal study. The proviral load was much higher in a patient with low degeneracy of HTLV-1–specific T cells compared to that in a patient with comparable frequency but higher degeneracy of the T cells. Furthermore, in a larger number of patients divided into 2 groups by the proviral load, those with high proviral load had lower degeneracy of T-cell recognition than those with low proviral load. Sequencing analysis revealed that epitope mutations were remarkably increased in a patient when the frequency and the degeneracy were at the lowest. These data suggest that HTLV-1–specific CD8+ T cells with degenerate specificity are increased during viral replication and control the viral infection.
A nonsecreted variant of interleukin-4 is associated with apoptosis: implication for the T helper–2 polarization in HIV infection
Authors: Ledru Eric , Février Michèle , Lecoeur Hervé , Garcia Sylvie , Boullier Séverine , Gougeon Marie-Lise 
Published: April 2003

AbstractWe report the detection of an interleukin-4 (IL-4) variant whose expression is tightly associated with deprivation apoptosis. It is detected with the 8D4 anti–IL-4 monoclonal antibody (mAb) not only in T helper-2 (Th2) but also in Th1 clones, and primary T cells, and it is a nonsecreted molecule. It is not expressed during primary necrosis. Our data suggest that de novo IL-4 transcription of an alternative IL-4 mRNA (IL-4δ13) is induced during deprivation apoptosis. In HIV-infected patients, increased expression of IL-4 in T cells is highly correlated to increased apoptosis, restricted to 8D4 reactivity (r2 = 0.84 between % 8D4-8+ and % 7- amino-actinomycin D–positive [7-AAD+] peripheral T cells, P < .0001), and associated with disease progression. The particular reactivity of apoptotic T cells to 8D4 mAb may explain some discordances among studies analyzing the Th1/Th2 balance in HIV infection and questions the function of this intracellular type 2 signal.
Enhancement of ATRA-induced cell differentiation by inhibition of calcium accumulation into the endoplasmic reticulum: cross-talk between RARα and calcium-dependent signaling
Authors: Launay Sophie , Giannı̀ Maurizio , Diomede Luisa , Machesky Laura M. , Enouf Jocelyne , Papp Béla 
Published: April 2003

AbstractSarco–endoplasmic reticulum calcium ATPase (SERCA) enzymes control calcium-induced cellular activation by accumulating calcium from the cytosol into the endoplasmic reticulum (ER). To better understand the role of SERCA proteins and cellular calcium homeostasis in all-trans retinoic acid (ATRA)–induced differentiation, we investigated the effect of pharmacologic inhibition of SERCA-dependent calcium uptake into the ER on ATRA-induced differentiation of the HL-60 myelogenous and the NB4 promyelocytic cell lines. SERCA inhibitors di-tert-butyl-benzohydroquinone (tBHQ), thapsigargin, and cyclopiazonic acid significantly enhanced the induction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and CD11b marker expression induced by suboptimal concentrations of ATRA (50 nM) in both cell lines. Analysis of cellular calcium homeostasis revealed that a 60% mobilization of the total SERCA-dependent intracellular calcium pool was necessary to obtain enhancement of ATRA-dependent differentiation by tBHQ. Moreover, after 3 days of ATRA treatment in combination with tBHQ, NB4 cells showed a significantly decreased calcium mobilization compared with treatments with tBHQ or ATRA alone, suggesting that enhanced differentiation and calcium mobilization are causally related. Interestingly, several ATRA-resistant NB4-derived cell lines were partially responsive to the differentiation-inducing effect of the combination of the 2 drugs. In addition, we found that retinoic acid receptor α (RARα) and PML-RARα proteins are protected from ATRA-induced proteolytic degradation by SERCA inhibition, indicating that cellular calcium homeostasis may interact with signaling systems involved in the control of ATRA-dependent transcriptional activity. By linking calcium to ATRA-dependent signaling, our data open new avenues in the understanding of the mechanisms of differentiation-induction therapy of leukemia.
Non–T-cell–depleted HLA haploidentical stem cell transplantation in advanced hematologic malignancies based on the feto-maternal michrochimerism
Authors: Shimazaki Chihiro , Ochiai Naoya , Uchida Ryo , Okano Akira , Fuchida Shin-ichi , Ashihara Eishi , Inaba Tohru , Fujita Naohisa , Maruya Etsuko , Nakagawa Masao 
Published: April 2003

Abstract
Feto-maternal microchimerism suggests that immunologic tolerance exists between mother and fetus. Based on this hypothesis, we performed haploidentical stem cell transplantation (SCT) without T-cell depletion (TCD) in 5 patients with advanced hematologic malignancies. HLA incompatibilities for graft-versus-host disease (GVHD) direction included 3-loci mismatches in 4 patients, and 2-loci mismatches in one patient. Recipient chimeric cells were detected in all patients. The prophylaxis against GVHD was tacrolimus with minidose methotrexate. Engraftment was obtained in all patients. An acute GVHD of less than or equal to grade 2 developed in all patients except one who developed tacrolimus encephalopathy. Two patients died, 1 from fungal pneumonia and 1 from disease progression. The other 3 patients survived, with one patient in complete remission. These observations suggest that haploidentical SCT based on the feto-maternal microchimerism without TCD is possible.
Regulation of human β2-microglobulin transactivation in hematopoietic cells
Authors: Gobin Sam J. P. , Biesta Paula , Van den Elsen Peter J. 
Published: April 2003

Abstractβ2-Microglobulin (β2m) is a chaperone of major histocompatibility complex (MHC) class I (–like) molecules that play a central role in antigen presentation, immunoglobulin transport, and iron metabolism. It is therefore of importance that β2m is adequately expressed in cells that perform these functions, such as hematopoietic cells. In this study, we investigated the transcriptional regulation of β2m in lymphoid and myeloid cell lines through a promoter containing a putative E box, Ets/interferon-stimulated response element (ISRE), and κB site. Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate β2m transactivation. The nuclear factor κB (NF-κB) subunits p50 and p65 bind to the κB box and p65 transactivates β2m. Interferon regulatory factor 1 (IRF1), IRF2, IRF4, and IRF8, but not PU.1, bind to the Ets/ISRE, and IRF1 and IRF3 are strong transactivators of β2m. Together, all 3 boxes are important for the constitutive and cytokine-induced levels of β2m expression in lymphoid and myeloid cell types. As such, β2m transactivation is under the control of important transcriptional pathways, which are activated during injury, infection, and inflammation.