bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical management of thrombophilia-related placental vascular complications
Authors: Brenner Benjamin 
Published: February 2004

AbstractPregnancy is a hypercoagulable state with an increased thrombotic risk throughout gestation and the postpartum period. Women with thrombophilia may have a further increased risk of placental vascular complications, including pregnancy loss, preeclampsia, intrauterine growth restriction, and placental abruption. Preliminary data suggest that maternal antithrombotic prophylaxis may result in improved gestational outcome. Randomized trials are under way and hopefully will optimize maternal and neonatal outcome.
Effect of chronic cytokine therapy on clonal dynamics in nonhuman primates
Authors: Kuramoto Ken , Follmann Dean A. , Hematti Peiman , Sellers Stephanie , Agricola Brian A. , Metzger Mark E. , Donahue Robert E. , von Kalle Christof , Dunbar Cynthia E. 
Published: February 2004

AbstractHematopoietic cytokines such as filgrastim are used extensively to stimulate granulocyte production or to mobilize hematopoietic progenitors into the circulation; however, their effect on more primitive hematopoietic progenitor and stem cells in vivo is unknown, particularly in large animals or humans. In particular, there is concern that chronic therapy with cytokines could result in stem cell exhaustion or clonal dominance; however, direct assessment of the dynamics of individual stem and progenitor cell clones in vivo has not been previously reported. A number of models can be proposed regarding the mechanisms by which the marrow responds to cytokine stimulation, including recruitment of previously quiescent clones, stimulation of proliferation of already active clones, or prevention of apoptosis of more mature progenitors from all clones. Using retroviral marking and comprehensive insertion site tracking of individual stem and progenitor cell clones in 2 rhesus macaques, we analyzed the effect of chronic administration of granulocyte colony-stimulating factor (G-CSF), or a combination of G-CSF plus stem cell factor (SCF). The overall number of contributing clones remained constant, and the relative output from each clone did not change significantly during or following cytokine treatments. These results suggest that individual transduced stem or progenitor cells can contribute to hematopoiesis for prolonged periods, with no evidence for an effect of G-CSF or G-CSF/SCF on the number, the lifespan, or the relative activity of individual stem or progenitor cell clones. These relevant large animal studies are reassuring regarding clinical applications of cytokines and provide new insights into their mechanisms of action.
Engraftment of NOD/SCID-β2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome
Authors: Thanopoulou Eleni , Cashman Johanne , Kakagianne Theodora , Eaves Allen , Zoumbos Nicholas , Eaves Connie 
Published: February 2004

AbstractThe development of immunodeficient mouse xenograft models has greatly facilitated the investigation of some human hematopoietic malignancies, but application of this approach to the myelodysplastic syndromes (MDSs) has proven difficult. We now show that cells from most MDS patients (including all subtypes) repopulate nonobese diabetic-severe combined immunodeficient (scid)/scid-β2 microglobulin null (NOD/SCID-β2m-/-) mice at least transiently and produce abnormal differentiation patterns in this model. Normal marrow transplants initially produce predominantly erythroid cells and later predominantly B-lymphoid cells in these mice, whereas most MDS samples produced predominantly granulopoietic cells. In 4 of 4 MDS cases, the regenerated cells showed the same clonal markers (trisomy 8, n = 3; and 5q-, n = 1) as the original sample and, in one instance, regenerated trisomy 8+ B-lymphoid as well as myeloid cells were identified. Interestingly, the enhanced growth of normal marrow obtained in NOD/SCID-β2m-/- mice engineered to produce human interleukin-3, granulocyte-macrophage colony-stimulating factor, and Steel factor was seen only with 1 of 7 MDS samples. These findings support the concept that human MDS originates in a transplantable multilineage hematopoietic stem cell whose genetic alteration may affect patterns of differentiation and responsiveness to hematopoietic growth factors. They also demonstrate the potential of this new murine xenotransplant model for future investigations of MDS. (Blood. 2004;103:4285-4293)
Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease
Authors: Reddy Vijay , Iturraspe Jose A. , Tzolas Alessandra C. , Meier-Kriesche Herwig-Ulf , Schold Jesse , Wingard John R. 
Published: February 2004

AbstractDendritic cells (DCs) are key antigen-presenting cells with a potential role in tumor vaccines. We investigated the hypothesis that early reconstitution of DCs after allogeneic hematopoietic stem cell transplantation (SCT) improves survival. We also correlated DC reconstitution with complications of relapse and acute graft-versus-host disease (aGVHD). Fifty patients underwent transplantation between February 2000 and March 2003, with a median follow-up of 501 days (range, 136-1263 days). Most (92%) received blood stem cells, and the remainder received bone marrow from HLA-matched sibling donors for predominantly high-risk hematologic malignancies. Around the time of engraftment, peripheral blood underwent flow cytometry analysis for DCs, and the cells were divided as DC1 and DC2. Using Kaplan-Meier analysis, patients with lower DC counts (&lt; 4.97 cells/μL) were found to have significantly worse survival (P = .002), increased incidence of relapse (P = .002), higher incidence of aGVHD onset (P = .0005), and a composite end point of relapse or death (P = .0017). A Cox proportional hazards multivariate model adjusted for important covariates confirmed that low DC count is independently associated with death (hazard ratio [HR], 3.8; P = .02), time to relapse (HR, 11.6; P = .001), and aGVHD (HR, 3.3; P = .04). Sensitivity and specificity rates for low DC count in predicting death or relapse are 73% and 75%, respectively. Low numbers of circulating DCs significantly increase the risk for relapse and acute GVHD and predict death after allogeneic SCT. (Blood. 2004;103:4330-4335)
Immunoglobulin class-switch recombination in mice devoid of any Sμ tandem repeat
Authors: Khamlichi Ahmed Amine , Glaudet Florence , Oruc Zeliha , Denis Vincent , Le Bert Marc , Cogné Michel 
Published: February 2004

AbstractImmunoglobulin heavy-chain class-switch recombination (CSR) occurs between highly repetitive switch sequences located upstream of the constant region genes. However, the role of these sequences remains unclear. Mutant mice were generated in which most of the Iμ-Cμ intron was deleted, including all the repeats. Late B-cell development was characterized by a severe impairment, but not a complete block, in class switching to all isotypes despite normal germ line transcription. Sequence analysis of the Iμ-Cμ intron in in vitro activated–mutant splenocytes did not reveal any significant increase in activation-induced cytidine deaminase (AID)–induced somatic mutations. Analysis of switch junctions showed that, in the absence of any Sμ repeat, the Iμ exon was readily used as a substrate for CSR. In contrast to the sequence alterations downstream of the switch junctions, very few, if any, mutations were found upstream of the junction sites. Our data suggest that the core Eμ enhancer could be the boundary for CSR-associated somatic mutations. We propose that the core Eμ enhancer plays a central role in the temporal dissociation of somatic hypermutation from class switching.
Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells
Authors: Brun Ann C. M. , Björnsson Jon Mar , Magnusson Mattias , Larsson Nina , Leveén Per , Ehinger Mats , Nilsson Eva , Karlsson Stefan 
Published: February 2004

AbstractEnforced expression of Hoxb4 dramatically increases the regeneration of murine hematopoietic stem cells (HSCs) after transplantation and enhances the repopulation ability of human severe combined immunodeficiency (SCID) repopulating cells. Therefore, we asked what physiologic role Hoxb4 has in hematopoiesis. A novel mouse model lacking the entire Hoxb4 gene exhibits significantly reduced cellularity in spleen and bone marrow (BM) and a subtle reduction in red blood cell counts and hemoglobin values. A mild reduction was observed in the numbers of primitive progenitors and stem cells in adult BM and fetal liver, whereas lineage distribution was normal. Although the cell cycle kinetics of primitive progenitors was normal during endogenous hematopoiesis, defects in proliferative responses of BM Lin- Sca1+ c-kit+ stem and progenitor cells were observed in culture and in vivo after the transplantation of BM and fetal liver HSCs. Quantitative analysis of mRNA from fetal liver revealed that a deficiency of Hoxb4 alone changed the expression levels of several other Hox genes and of genes involved in cell cycle regulation. In summary, the deficiency of Hoxb4 leads to hypocellularity in hematopoietic organs and impaired proliferative capacity. However, Hoxb4 is not required for the generation of HSCs or the maintenance of steady state hematopoiesis.
Probiotic effects on experimental graft-versus-host disease: let them eat yogurt
Authors: Gerbitz Armin , Schultz Michael , Wilke Andrea , Linde Hans-Jörg , Schölmerich Jürgen , Andreesen Reinhard , Holler Ernst 
Published: February 2004

Abstract
Acute graft-versus-host disease (aGVHD) often limits feasibility and outcome of allogeneic bone marrow transplantation. Current pathophysiologic concepts of aGVHD involve conditioning regimens, donor-derived T cells, proinflammatory cytokines, and bacterial lipopolysaccharide (LPS) as a major trigger for aGVHD. LPS derives mostly from gram-negative bacteria and can enter circulation through the impaired mucosal barrier after the conditioning regimen. Probiotic microorganisms have been shown to alter the composition of the intestinal microflora and thereby mediate anti-inflammatory effects. We hypothesized that modifying the enteric flora using the probiotic microorganism Lactobacillus rhamnosus GG, would ameliorate aGVHD. Here we show that oral administration of Lactobacillus rhamnosus GG before and after transplantation results in improved survival and reduced aGVHD. Furthermore, subculturing of mesenteric lymph node tissue revealed a reduced translocation of enteric bacteria. Our findings suggest that alteration of the intestinal microflora plays an important role in the initiation of experimental aGVHD. (Blood. 2004;103:4365-4367)
The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin
Authors: Walter Roland B. , Raden Brian W. , Cronk Michelle R. , Bernstein Irwin D. , Appelbaum Frederick R. , Banker Deborah E. 
Published: February 2004

AbstractThe antibody-targeted therapeutic, gemtuzumab ozogamicin (GO, Mylotarg), is approved for treatment of relapsed acute myeloid leukemia (AML). We previously showed that AML blasts from GO refractory patients frequently express the drug transporters P-glycoprotein (Pgp) and/or multidrug resistance protein (MRP). We also previously reported that inhibition of drug transport by the Pgp modulator, cyclosporine A (CSA), can increase GO sensitivity in Pgp+ AML cells and that the peripheral benzodiazepine receptor ligand, PK11195, sensitizes AML cells to standard chemotherapeutics both by inhibiting Pgp-mediated efflux and by promoting mitochondrial apoptosis. We now show that PK11195 also can overcome multiple resistance mechanisms to increase GO sensitivity in AML cells, including resistance associated with expression of drug transporters and/or antiapoptotic proteins. PK11195 substantially increases GO cytotoxicity in AML cells from many different cell lines and primary patient samples, often more effectively than CSA. We also show that PK11195 is nontoxic in NOD/SCID mice and can sensitize xenografted human AML cells to GO. Since PK11195 is well tolerated in humans as a single agent, its further study as a multifunctional chemosensitizer for anti-AML therapies, including GO-based therapies, is warranted. (Blood. 2004;103:4276-4284)
Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83
Authors: Sénéchal Brigitte , Boruchov Adam M. , Reagan John L. , Hart Derek N. J. , Young James W. 
Published: February 2004

AbstractWe have studied the mechanisms by which human cytomegalovirus (HCMV) infection of monocyte-derived dendritic cells (moDCs) contribute to immune suppression. Unlike infection of immature moDCs, infection of mature moDCs is not lytic and results in minimally decreased surface major histocompatibility complex (MHC) and costimulatory molecule expression. The presence of a small percentage of CMV-infected mature moDCs, or the transfer of supernatant from infected moDCs depleted of infectious virions, is nevertheless sufficient to cause marked inhibition of immunostimulation by normal uninfected moDCs. Neither viral nor human interleukin 10 (IL-10) nor transforming growth factor-β-1 (TGF-β-1) could account for this inhibition. In contrast, we show that infected mature moDCs lose surface CD83 while maintaining intracellular protein expression. Soluble CD83 accumulates in the supernatants of CMV-infected mature moDCs, and CD83 immunodepletion removes the inhibitory effect of these supernatants on normal DC immunostimulation. We have thus discovered a new mechanism by which HCMV infection may establish a nonlytic reservoir in mature moDCs that inhibits DC-mediated T-cell responses. (Blood. 2004;103:4207-4215)
Human B lymphoblastoid cells contain distinct patterns of cathepsin activity in endocytic compartments and regulate MHC class II transport in a cathepsin S-independent manner
Authors: Lautwein Alfred , Kraus Marianne , Reich Michael , Burster Timo , Brandenburg J , Overkleeft Herman S , Schwarz Gerold , Kammer Winfried , Weber Ekkehard , Kalbacher Hubert , Nordheim Alfred , Driessen Christoph 
Published: February 2004

AbstractEndocytic proteolysis represents a major functional component of the major histocompatibility complex class II antigen-presentation machinery. Although transport and assembly of class II molecules in the endocytic compartment are well characterized, we lack information about the pattern of endocytic protease activity along this pathway. Here, we used chemical tools that visualize endocytic proteases in an activity-dependent manner in combination with subcellular fractionation to dissect the subcellular distribution of the major cathepsins (Cat) CatS, CatB, CatH, CatD, CatC, and CatZ as well as the asparagine-specific endoprotease (AEP) in human B-lymphoblastoid cells (BLC). Endocytic proteases were distributed in two distinct patterns: CatB and CatZ were most prominent in early and late endosomes but absent from lysosomes, and CatH, CatS, CatD, CatC, and AEP distributed between late endosomes and lysosomes, suggesting that CatB and CatZ might be involved in the initial proteolytic attack on a given antigen. The entire spectrum of protease activity colocalized with human leukocyte antigen-DM and the C-terminal and N-terminal processing of invariant chain (Ii) in late endosomes. CatS was active in all endocytic compartments. Surprisingly and in contrast with results from dendritic cells, inhibition of CatS activity by leucine–homophenylalanine–vinylsulfone-phenol prevented N-terminal processing of Ii but did not alter the subcellular trafficking or surface delivery of class II complexes, as deferred from pulse-chase analysis in combination with subcellular fractionation and biotinylation of cell-surface protein. Thus, BLC contain distinct activity patterns of proteases in endocytic compartments and regulate the intracellular transport and surface-delivery of class II in a CatS-independent manner.
Diesel exhaust particles increase LPS-stimulated COX-2 expression and PGE2 production in human monocytes
Authors: Hofer Thomas P J , Bitterle Ellen , Beck-Speier Ingrid , Maier Konrad L , Frankenberger Marion , Heyder Joachim , Ziegler-Heitbrock Löms 
Published: February 2004

AbstractLittle is known about health effects of ultrafine particles (UFP) found in ambient air, but much of their action may be on cells of the lung, including cells of the monocyte/macrophage lineage. We have analyzed the effects of diesel exhaust particles (DEP; SRM1650a) on human monocytes in vitro. DEP, on their own, had little effect on cyclooxygenase (COX)-2 gene expression in the Mono Mac 6 cell line. However, when cells were preincubated with DEP for 1 h, then stimulation with the Toll-like receptor 4 (TLR4) ligand lipopolysaccharide (LPS) induced an up-to fourfold-higher production of COX-2 mRNA with an average twofold increase. This costimulatory effect of DEP led to enhanced production of COX-2 protein and to increased release of prostaglandin E2 (PGE2). The effect was specific in that tumor necrosis factor gene expression was not enhanced by DEP costimulation. Furthermore, costimulation with the TLR2 ligand Pam3Cys also led to enhanced COX-2 mRNA. DEP and LPS showed similar effects on COX-2 mRNA in primary blood mononuclear cells, in highly purified CD14-positive monocytes, and in monocyte-derived macrophages. Our data suggest that UFP such as DEP may exert anti-inflammatory effects mediated by enhanced PGE2 production.
Streptococcus pyogenesandLactobacillus rhamnosusdifferentially induce maturation and production of Th1-type cytokines and chemokines in human monocyte-derived dendritic cells
Authors: Veckman Ville , Miettinen Minja , Pirhonen Jaana , Sirén Jukka , Matikainen Sampsa , Julkunen Ilkka 
Published: February 2004

AbstractDendritic cells (DCs) are the most efficient antigen-presenting cells and thus, have a major role in regulating host immune responses. In the present study, we have analyzed the ability of Gram-positie, pathogenic Streptococcus pyogenes and nonpathogenic Lactobacillus rhamnosus to induce the maturation of human monocyte-derived DCs. Stimulation of DCs with S. pyogenes resulted in strong expression of DC costimulatory molecules CD80, CD83, and CD86 accompanied with a T helper cell type 1 (Th1) cytokine and chemokine response. S. pyogenes also induced interleukin (IL)-2 and IL-12 production at mRNA and protein levels. In addition, IL-23 and IL-27 subunits p40, p19, p28, and EBI3 were induced at mRNA level. In contrast, L. rhamnosus-stimulated DCs showed only moderate expression of costimulatory molecules and produced low levels of cytokines and chemokines. Furthermore, no production of IL-2 or IL-12 family cytokines was detected. Bacteria-induced DC maturation and especially cytokine and chemokine production were reduced when bacteria were heat-inactivated. Our results show that human monocyte-derived DCs respond differently to different Gram-positive bacteria. Although pathogenic S. pyogenes induced a strong Th1-type response, stimulation with nonpathogenic L. rhamnosus resulted in development of semi-mature DCs characterized by moderate expression of costimulatory molecules and low cytokine production.
TGF-β: the perpetrator of immune suppression by regulatory T cells and suicidal T cells
Authors: Wahl Sharon M , Swisher Jennifer , McCartney-Francis Nancy , Chen Wanjun 
Published: February 2004

AbstractInnate and adaptive immunity function to eliminate foreign invaders and respond to injury while enabling coexistence with commensal microbes and tolerance against self and innocuous agents. Although most often effective in accomplishing these objectives, immunologic processes are not fail-safe and may underserve or be excessive in protecting the host. Checks and balances to maintain control of the immune system are in place and are becoming increasingly appreciated as targets for manipulating immunopathologic responses. One of the most recognized mediators of immune regulation is the cytokine transforming growth factor-β (TGF-β), a product of immune and nonimmune cells. Emerging data have unveiled a pivotal role for TGF-β as a perpetrator of suppression by CD4+CD25+ regulatory T (Treg) cells and in apoptotic sequelae. Through its immunosuppressive prowess, TGF-β effectively orchestrates resolution of inflammation and control of autoaggressive immune reactions by managing T cell anergy, defining unique populations of Treg cells, regulating T cell death, and influencing the host response to infections.
Annexin 1 and the biology of the neutrophil
Authors: Perretti Mauro , Flower Roderick John 
Published: February 2004

AbstractThis overview will focus on one aspect of neutrophil biology, which is the selective activation of the annexin 1 system in relation to the process of cell extravasation. Besides the current view about the biochemistry of annexin 1 and annexin 1 receptor(s) up-regulation within the microenvironment of the adherent neutrophils, we will also comment on the final result achieved by activation of the system, which is inhibition of neutrophil recruitment. In view of the historical link between annexin 1 and glucocorticoids, the potential for the annexin 1 system in mediating at least some of the anti-inflammatory actions of these powerful drugs is also discussed.
Cannabinoid receptor-mediated regulation of intracellular calcium by Δ9-tetrahydrocannabinol in resting T cells
Authors: Rao Gautham K , Zhang Wei , Kaminski Norbert E 
Published: February 2004

AbstractCannabinoids exhibit broad immune modulating activity by targeting many cell types within the immune system, including T cells, which exhibit sensitivity, as evidenced by altered activation, proliferation, and cytokine expression. As a result of the critical role calcium plays in T cell function coupled with previous findings demonstrating disruption of the calcium-regulated transcription factor, nuclear factor of activated T cells, by cannabinoid treatment the objective of the present investigation was to perform an initial characterization of the role of the cannabinoid receptors in the regulation of the intracellular calcium concentration ([Ca2+]i) by Δ9-tetrahydrocannabinol (Δ9-THC) in T lymphocytes. Here, we demonstrate that Δ9-THC robustly elevates [Ca2+]i in purified murine splenic T cells and in the human peripheral blood acute lymphoid leukemia (HPB-ALL) human T cell line but only minimally elevates [Ca2+]i in Jurkat E6-1 (dysfunctional cannabinoid receptor 2-expressing) human T cells. Removal of extracellular calcium severely attenuated the Δ9-THC-mediated rise in [Ca2+]i in murine splenic T cells and HPB-ALL cells. Pretreatment with cannabinoid receptor antagonists, SR144528 and/or SR141716A, led to an attenuation of Δ9-THC-mediated elevation in [Ca2+]i in splenic T cells and HPB-ALL cells but not in Jurkat E6-1 cells. Furthermore, pretreatment of HPB-ALL cells with SR144528 antagonized the small rise in [Ca2+]i elicited by Δ9-THC in the absence of extracellular calcium. These findings suggest that Δ9-THC induces an influx of extracellular calcium in resting T cells in a cannabinoid receptor-dependent manner.