bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet factor 4 (PF-4)–induced neutrophil adhesion is controlled by src-kinases, whereas PF-4–mediated exocytosis requires the additional activation of p38 MAP kinase and phosphatidylinositol 3-kinase
Authors: Kasper Brigitte , Brandt Ernst , Bulfone-Paus Silvia , Petersen Frank 
Published: November 2003

AbstractAmong the various chemokines that are functionally active on neutrophils, platelet factor 4 (PF-4; CXCL4) appears to have a specialized role. Lacking typical chemokine activities, PF-4 stimulates neutrophils to undergo firm adhesion to endothelial cells and, in the presence of an appropriate costimulus like tumor necrosis factor (TNF), PF-4 induces exocytosis of secondary granule contents. Analyzing the individual contribution of PF-4 and its costimuli in the control of these functions at the signaling level, we demonstrate that TNF-induced activation of p38 mitogen-activated protein (MAP) kinase (but not extracellular regulated kinase [Erk] kinases) acts as general and essential costimulatory signal in PF-4–dependent neutrophil exocytosis. This was shown by the use of a specific inhibitor (SB203580), by biologic (lipopolysaccharide, N-formyl-methionyl-leucyl-phenylalanine) and pharmacologic (anisomycin) activators of p38 MAP kinase, and by phosphorylation studies. Furthermore, TNF-mediated activation of phosphatidylinositol 3-kinase (PI 3-kinase) represents an additional essential signaling component in this process as demonstrated by studies with its inhibitor wortmannin as well as by analysis of the phosphorylation of AKT kinase. PF-4, however, directly activates src-kinases and PF-4–induced adherence as well as PF-4/TNF-mediated exocytosis was inhibited by an src-kinase inhibitor PP1. Taken together, neutrophil exocytosis and adherence are regulated on p38 MAP kinase, PI 3-kinase, and src-kinase activation.
Vav1: an oncogene that regulates specific transcriptional activation of T cells
Authors: Katzav Shulamit 
Published: November 2003

AbstractThe nuclear factor of activated T cells (NFAT) proteins are a family of transcription factors whose activation is controlled by calcineurin, a Ca2+-dependent phosphatase. Once dephosphorylated, these proteins move to the nucleus where they interact with cofactors to form transcription factor complexes. Inhibition of NFAT proteins by immunosuppressants, such as cyclosporin A (CsA) and FK506, is used clinically to prevent transplant rejection. Although these drugs have revolutionized organ transplantation, their use is associated with severe side effects in other organs in which NFAT proteins are important. One of the signal transducers that controls NFAT activity is Vav1, which is exclusively expressed in the hematopoietic system. Vav1 contains numerous modular domains that enable its function as a guanine exchange factor (GEF) toward RhoGTPases as well as participate in protein-protein interactions. This review focuses on the mechanisms by which Vav1 regulates NFAT through GEF-dependent and -independent cascades, emphasizing the newly assigned role of Vav1 in the regulation of Ca2+ release. Because of its restriction to hematopoietic cell lineages and its importance in the regulation of NFAT, targeting Vav1 and, in particular, its association with other proteins may offer a highly selective means of modifying T-cell behavior, thus allowing the development of more specific immunosuppressive therapies.
Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells
Authors: Zhang Cheng Cheng , Lodish Harvey F. 
Published: November 2003

AbstractHematopoietic stem cells (HSCs) undergo dramatic expansion during fetal liver development, but attempts to expand their numbers ex vivo have failed. We hypothesized that unidentified fetal liver cells produce growth factors that support HSC proliferation. Here we describe a novel population of CD3+ and Ter119- day-15 fetal liver cells that support HSC expansion in culture, as determined by limiting dilution mouse reconstitution analyses. DNA array experiments showed that, among other proteins, insulin-like growth factor 2 (IGF-2) is specifically expressed in fetal liver CD3+ cells but not in several cells that do not support HSCs. Treatment of fetal liver CD3+Ter119- cells with anti–IGF-2 abrogated their HSC supportive activity, suggesting that IGF-2 is the key molecule produced by these cells that stimulates HSC expansion. All mouse fetal liver and adult bone marrow HSCs express receptors for IGF-2. Indeed, when combined with other growth factors, IGF-2 supports a 2-fold expansion of day-15 fetal liver Lin-Sca-1+c-Kit+ long-term (LT)–HSC numbers. Thus, fetal liver CD3+Ter119- cells are a novel stromal population that is capable of supporting HSC expansion, and IGF-2, produced by these cells, is an important growth factor for fetal liver and, as we show, adult bone marrow HSCs.
Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential
Authors: Peister Alexandra , Mellad Jason A. , Larson Benjamin L. , Hall Brett M. , Gibson Laura F. , Prockop Darwin J. 
Published: November 2003

AbstractFor reasons that are not apparent, it has been difficult to isolate and expand the adult stem cells referred to as mesenchymal stem cells or marrow stromal cells (MSCs) from murine bone marrow. We developed a protocol that provides rapidly expanding MSCs from 5 strains of inbred mice. The MSCs obtained from 5 different strains of mice were similar to human and rat MSCs in that they expanded more rapidly if plated at very low density, formed single-cell–derived colonies, and readily differentiated into either adipocytes, chondrocytes, or mineralizing cells. However, the cells from the 5 strains differed in their media requirements for optimal growth, rates of propagation, and presence of the surface epitopes CD34, stem cell antigen-1 (Sca-1), and vascular cell adhesion molecule 1 (VCAM-1). The protocol should make it possible to undertake a large number of experiments with MSCs in transgenic mice that have previously not been possible. The differences among MSCs from different strains may explain some of the conflicting data recently published on the engraftment of mouse MSCs or other bone marrow cells into nonhematopoietic tissues.
Erythrocyte detergent-resistant membrane proteins: their characterization and selective uptake during malarial infection
Authors: Murphy Sean C. , Samuel Benjamin U. , Harrison Travis , Speicher Kaye D. , Speicher David W. , Reid Marion E. , Prohaska Rainer , Low Philip S. , Tanner Michael J. , Mohandas Narla , Haldar Kasturi 
Published: November 2003

AbstractInfection of human erythrocytes by the apicomplexan malaria parasite Plasmodium falciparum results in endovacuolar uptake of 4 host proteins that reside in erythrocyte detergent-resistant membranes (DRMs). Whether this vacuolar transport reflects selective uptake of host DRM proteins remains unknown. A further complication is that DRMs of vastly different protein and cholesterol contents have been isolated from erythrocytes. Here we show that isolated DRMs containing the highest cholesterol-to-protein ratio have low protein mass. Liquid chromatography, mass spectrometry, and antibody-based studies reveal that the major DRM proteins are band 3, flotillin-1 and -2, peroxiredoxin-2, and stomatin. Band 3 and stomatin, which reflect the bulk mass of erythrocyte DRM proteins, and all tested non-DRM proteins are excluded from the vacuolar parasite. In contrast, flotillin-1 and -2 and 8 minor DRM proteins are recruited to the vacuole. These data suggest that DRM association is necessary but not sufficient for vacuolar recruitment and there is active, vacuolar uptake of a subset of host DRM proteins. Finally, the 10 internalized DRM proteins show varied lipid and peptidic anchors indicating that, contrary to the prevailing model of apicomplexan vacuole formation, DRM association, rather than lipid anchors, provides the preferred criteria for protein recruitment to the malarial vacuole.
Local irradiation enhances congenic donor pluripotent hematopoietic stem cell engraftment similarly in irradiated and nonirradiated sites
Authors: Ito Hiroshi , Takeuchi Yasuo , Shaffer Juanita , Sykes Megan 
Published: November 2003

AbstractLong-term multilineage chimerism is achieved in CD45 congenic mice receiving high bone marrow doses with or without mediastinal irradiation (MI). Increased donor chimerism results in MI-treated compared with nonirradiated animals, suggesting that MI makes “space” for engraftment of donor pluripotent hematopoietic stem cells (PHSCs). We have now examined whether space is systemic or whether increased engraftment of donor marrow in locally irradiated mice is confined to the irradiated bones. While increased donor chimerism was observed in irradiated bones compared with nonirradiated bones of MI-treated animals 4 weeks following bone marrow transplantation (BMT), these differences were minimal by 40 weeks. MI-treated chimeras contained more adoptively transferable donor PHSCs in the marrow of both irradiated and distant bones compared with non-MI–treated chimeras. Similar proportions of donor PHSCs were present in irradiated and nonirradiated bones of locally irradiated mice at both 4 and 40 weeks. Irradiated bones contained more donor short-term repopulating cells than distant bones at 4 weeks, but not 40 weeks, after BMT. Our study suggests that local proliferation of donor PHSCs in mice receiving local irradiation rapidly leads to a systemic increase in donor PHSC engraftment.
Acquired somatic ATRX mutations in myelodysplastic syndrome associated with α thalassemia (ATMDS) convey a more severe hematologic phenotype than germline ATRX mutations
Authors: Steensma David P. , Higgs Douglas R. , Fisher Chris A. , Gibbons Richard J. 
Published: November 2003

Abstract
Acquired somatic mutations in ATRX, an X-linked gene encoding a chromatin-associated protein, were recently identified in 4 patients with the rare subtype of myelodysplastic syndrome (MDS) associated with α thalassemia (ATMDS). Here we describe a series of novel point mutations in ATRX detected in archival DNA samples from marrow and/or blood of patients with ATMDS by use of denaturing high-performance liquid chromatography (DHPLC), a technique sensitive to low-level mosaicism. Two of the new mutations result in changes in amino acids altered in previously described pedigrees with germ line ATRX mutations (ATR-X syndrome), but the hematologic abnormalities were much more severe in the patients with ATMDS than in the corresponding constitutional cases. In one ATMDS case where DNA samples from several time points were available, the proportion of ATRX-mutant subclones correlated with changes in the amount of hemoglobin H. This study strengthens the link between acquired, somatic ATRX mutations and ATMDS, illustrates how molecular defects associated with MDS and other hematologic malignancies masked by somatic mosaicism may be detected by DHPLC, and shows that additional factors increase the severity of the hematologic phenotype of ATRX mutations in ATMDS.
Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2
Authors: Urosevic Mirjana , Kamarashev Jivko , Burg Günter , Dummer Reinhard 
Published: November 2003

Abstract
Primary cutaneous lymphomas constitute a spectrum of diseases characterized by a clonal accumulation of lymphocytes in the skin. Cutaneous T-cell lymphomas of the cytotoxic phenotype, including CD8+ and CD56+ lymphomas, are rare entities that have only been recently recognized and characterized. These lymphomas often show an aggressive clinical course. We investigated the expression of human leukocyte antigen G (HLA-G) and interleukin 10 (IL-10) in conjunction with expression of HLA-G killer-cell inhibitory receptor ligand immunoglobulin-like transcript 2 (ILT2) in 3 CD56+CD4+ and 4 CD8+ cutaneous T-cell lymphomas. HLA-G expression was detected in 2 of 3 lymphomas of the CD56+CD4+ type and in all lymphomas of CD8+ type. It is of note that CD56+CD4+ lymphomas displayed stronger HLA-G reactivity. The expression of IL-10 matched the expression of HLA-G. Together with the expression of IL-10, HLA-G might be one of the factors accounting for the evasion of immunosurveillance, thus contributing to aggressive phenotype of these lymphoma entities.
Expression of MRP8 and MRP14 by macrophages is a marker for severe forms of glomerulonephritis
Authors: Frosch Michael , Vogl Thomas , Waldherr Rüdiger , Sorg Clemens , Sunderkötter Cord , Roth Johannes 
Published: November 2003

AbstractExpression of two S100 proteins, myeloid related protein (MRP)8 and MRP14, as well as their complex formation indicate proinflammatory properties of macrophages. We analyzed if the different forms of glomerulonephritis (GN) are associated with the appearance of certain phenotypes of infiltrating macrophages characterized by expression of MRP8 and MRP14 as well as their complex formation. Immunohistochemical analysis of 89 renal biopsies with different forms of nephritis revealed that expression and complex formation of MRP8 and MRP14 by infiltrating macrophages in the glomeruli correlated with the severity of the inflammatory process. As such, MRP8/MRP14-expressing monocytes prevailed in highly proliferating forms of GN, i.e., systemic lupus erythematosus GN and extracapillary GN. In contrast, a high percentage of macrophages in the renal interstitium expressed MRP8 and MRP14 without concomitant formation of their complex, and they indicated a chronic type of inflammatory reaction in GN. Immunosuppressive drugs had no direct effects on the expression of MRP8 and MRP14 in macrophages in vitro. The correlation of MRP8 and MRP14 expression with disease activity indicates that these calcium-binding proteins are of pathophysiological relevance in GN. In addition, our findings reflect differences in the inflammatory mechanisms underlying the various forms of GN, as they revealed that distinct macrophage subpopulations prevail in the different forms of GN.
Shielding the double-edged sword: negative regulation of the innate immune system
Authors: Kobayashi Koichi S , Flavell Richard A 
Published: November 2003

AbstractThe innate immune system is evolutionarily conserved among all multicellular organisms and is the first line of defense against microorganisms. It enables the host not only to combat pathogenic organisms but also to cohabit with nonpathogenic microorganisms by balancing the host-microorganism interaction. The innate immune response is activated rapidly (within hours) compared with adaptive immunity. Activation of the innate immune system allows the activation of the adaptive immune response by production of proinflammatory cytokines and by providing stimulatory signals via major histocompatibility complex molecules and costimulatory molecules such as CD40, CD80, or CD86; together, these lead to the full activation of both immune systems to fight against pathogenic microorganisms. Activation of the innate immune system, however, can be a double-edged sword for the host. Proinflammatory cytokines mediate a positive feedback loop on the innate immune system, and overproduction of cytokines, if unchecked, is hazardous to the host and may cause severe outcomes such as hyperthermia, organ failure, and even death in extreme cases. Moreover, if the overproduction of proinflammatory cytokines persists, it may cause chronic inflammatory diseases. During evolution, the innate immune system has acquired complicated regulatory systems to control itself so that this “sword” will not kill the host. Various mechanisms including inhibition of Toll-like receptor signaling by interleukin-1 receptor-associated kinase-M have evolved for this purpose and are important not only to fight against pathogenic microorganisms efficiently but also are critical for the peaceful coexistence with commensal bacterial flora.
Mycobacterial heat shock protein 65 enhances antigen cross-presentation in dendritic cells independent of Toll-like receptor 4 signaling
Authors: Chen Kang , Lu Jinhua , Wang Lei , Gan Yunn-Hwen 
Published: November 2003

AbstractHeat shock proteins (HSP) have been shown to enhance antigen processing and presentation through their association with antigenic peptides and delivery of these moieties into major histocompatibility complex class I pathways. In this study, mycobacterial Hsp65 is demonstrated to have the ability to help cross-present an exogenous protein by dendritic cells (DC) to CD8 T cells without the need for complex formation between Hsp65 and the protein. This abilit of Hsp65 to enhance cross-presentation is independent of its weak stimulatory effect on DC, the latter seen only after prolonged incubation. When the effect of lipopolysaccharide contamination is abrogated, Hsp65 is unable to activate Toll-like receptor (TLR)4 in the presence of CD14 and MD2. This accounts for the inability of Hsp65 to drive maturation of DC and shows that Hsp65 is not a potent stimulator of DC. Thus, Hsp65 enhances the cross-presentation of a soluble, free antigen by DC, independent of TLR4 signaling and up-regulation of costimulatory molecules.
Trefoil peptide TFF2 treatment reduces VCAM-1 expression and leukocyte recruitment in experimental intestinal inflammation
Authors: Soriano-Izquierdo Antonio , Gironella Meritxell , Massaguer Anna , May Felicity E B , Salas Antonio , Sans Miquel , Poulsom Richard , Thim Lars , Piqué Josep M , Panés Julián 
Published: November 2003

AbstractThere is evidence for a beneficial effect of trefoil peptides in animal models of gastric damage and intestinal inflammation, but the optimal treatment strategy and the mechanistic basis have not been explored thoroughly. It has been suggested that these proteins may modulate the inflammatory response. The aims of this study were to compare the protective and curative value of systemic and topical trefoil factor family (TFF)2 administration in dextran sulfate sodium-induced experimental colitis and to investigate the relationship between the therapeutic effects of TFF2 and modulation of leukocyte recruitment and expression of cell adhesion molecules. Clinical and morphologic severity of colitis was evaluated at the end of the study (Day 10). Leukocyte–endothelial cell interactions were determined in colonic venules by fluorescence intravital microscopy. The expression of cell adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) was measured by the dual radiolabeled monoclonal antibody technique. Pretreatment with TFF2 by subcutaneous or intracolonic (ic) route ameliorated the clinical course of colitis, and the luminal route had a significantly superior effect. This beneficial effect was correlated with significant reductions in endothelial VCAM-1 but not MAdCAM-1 expression and leukocyte adhesion to intestinal venules, which returned to levels similar to those of controls. In established colitis, ic TFF2 treatment did not modify the severity of colonic lesions. In conclusion, TFF2 is useful in the treatment of colitis, and topical administration is superior to the systemic route. Reduction in adhesion molecule expression and leukocyte recruitment into the inflamed intestine contributes to the beneficial effect of this treatment.
Comparative evaluation of CC chemokine-induced migration of murine CD8α+ and CD8α− dendritic cells and their in vivo trafficking
Authors: Colvin Bridget L , Morelli Adrian E , Logar Alison J , Lau Audrey H , Thomson Angus W 
Published: November 2003

AbstractMurine CD11c+CD8α− and CD11c+CD8α+ dendritic cells (DCs) differentially regulate T cell responses. Although specific chemokines that recruit immature (i) or mature (m) CD8α− DCs have been identified, little is known about the influence of chemokines on CD8α+ DCs. iDCs and mDCs isolated from spleens of fms-like tyrosine kinase 3 ligand-treated B10 mice were compared directly for migratory responses to a panel of CC chemokines or following local or systemic administration. In vitro assays were performed using Transwell® chambers. iDCs did not respond to any CC chemokines tested. Both subsets of mDCs migrated to CCL19 and CCL21, with consistently lower percentages of CD8α+ DCs migrating. Chemokine receptor mRNA and protein expression were analyzed, but no correlation between expression and function was demonstrated. In vivo trafficking of fluorochrome-labeled DCs (B10; H2b) was assessed by immunohistochemistry and by rare-event flow cytometric analysis of allogeneic recipient (BALB/c; H2d) draining lymph node (DLN) and spleen cells. Twenty-four hours after intravenous injection, chloromethylfluorescein diacetate-positive CD8α+ and CD8α− mDCs were detected by immunohistochemistry in spleens in similar numbers (that decreased over time). Following subcutaneous injection, both DC subsets were detected in DLN at 24 h, but only CD8α− DCs were evident by flow analysis at 48 h. Although CD8α+ DCs migrate from peripheral tissues to T cell areas of (allogeneic) secondary lymphoid organs, they appear to mobilize as mDCs and less efficiently than CD8α− mDCs.
High-Dose Methotrexate-Based Chemotherapy Followed by Consolidating Radiotherapy in Non–AIDS-Related Primary Central Nervous System Lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962
Authors: Poortmans Philip M.P. , Kluin-Nelemans Hanneke C. , Haaxma-Reiche Hanny , Van’t Veer Mars , Hansen Mads , Soubeyran Pierre , Taphoorn Martin , Thomas José , Van den Bent Martin , Fickers Martin , Van Imhoff Gustaaf , Rozewicz Cynthia , Teodorovic Ivana , van Glabbeke Martine 
Published: November 2003

Purpose: To confirm the feasibility and estimate the efficacy of methotrexate (MTX), teniposide, carmustine, and methylprednisolone (MBVP) chemotherapy combined with radiotherapy (RT) for patients with non–AIDS-related primary CNS lymphoma (PCNSL) treated in a multicenter setting. Patients and Methods: Treatment consisted of two cycles of MBVP (MTX 3 g/m2 days 1 and 15, teniposide 100 mg/m2 days 2 and 3, carmustine 100 mg/m2 day 4, methylprednisolone 60 mg/m2 days 1 to 5, and two intrathecal injections of MTX 15 mg, cytarabine 40 mg, and hydrocortisone 25 mg) followed by 40 Gy of RT. Primary end points were response and safety of this regimen. Results: Twelve centers included 52 patients who were all analyzed on an intent-to-treat basis. Median follow-up of all patients was 27 months. One patient progressed and died before treatment, and five patients died during treatment. Four patients received RT after one cycle of chemotherapy, and 42 patients completed the entire treatment. Hematologic grade 3 and 4 toxicity was seen in 78% of patients for leukocytes and 24% of patients for platelets. The overall response rate of all 52 patients was 81%. Two patients who did not fulfill the criteria of objective response survived more than 1 year; one of them is still alive without disease. Eighteen patients died; 11 deaths were a result of tumor, five were probably treatment-related, one was caused by late leukoencephalopathy, and one was a result of intercurrent disease. Median estimated overall survival was 46 months. Conclusion: MBVP followed by RT for PCNSL has a high response rate. However, the 10% toxic death rate during treatment in a multicenter setting underlines the need for highly specialized care.