bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma
Authors: Colomo Lluı́s , López-Guillermo Armando , Perales Marı́a , Rives Susana , Martı́nez Antonio , Bosch Francesc , Colomer Dolors , Falini Brunangelo , Montserrat Emili , Campo Elı́as 
Published: December 2002

AbstractTo analyze the relationship between immunophenotyping profile and main clinicopathological features and outcome in diffuse large B-cell lymphoma (DLBCL), we studied 128 patients (59 men, 69 women; median age 65 years) consecutively diagnosed with de novo DLBCL in a single institution. Cells from each patient were immunostained with CD20, CD79a, CD5, CD10, bcl-6, MUM1, CD138, bcl-2, p53, p27, and Ki-67 antibodies. Four immunophenotyping profiles were distinguished according to the pattern of differentiation: germinal center–CD10+ (GC-CD10+; CD10+/Bcl-6+/MUM1−/CD138−), germinal center–CD10− (GC-CD10−; CD10−/Bcl-6+/ MUM1−/CD138−), post–germinal center (pGC; CD10−/bcl-6±/ MUM1+/CD138−), and plasmablastic (CD10−/bcl-6−/MUM1+/CD138+). Rearrangement of bcl-2 was studied by polymerase chain reaction (PCR) in 57 patients. Single-antigen expression was as follows: CD5, 2%; CD10, 21%; bcl-6, 72%; MUM1, 54%; CD138, 2%; bcl-2, 59%; p53, 28%; p27, 40%. Distribution according to differentiation profiles was as follows: GC-CD10+, 24 patients, GC-CD10-, 30 patients; pGC, 60 patients; plasmablastic, 2 patients; other patterns, 12 patients. The pGC profile was associated with primary nodal presentation and immunoblastic morphology, whereas GC-CD10+ tumors showed disseminated disease, centroblastic morphology, bcl-2 rearrangement, and lower Ki-67 proliferative index. GC-CD10− patients more often presented with primary extranodal origin, early stage, normal lactic acid dehydrogenase (LDH) levels, and low or low/intermediate International Prognostic Index (IPI) scores than the others. However, no significant difference was found in terms of response or overall survival (OS) according to these profiles. Expression of bcl-2 was associated with advanced stage, high or high-intermediate IPI, and poor OS. Expression of bcl-2 maintained predictive value in multivariate analysis, with stage and LDH. In conclusion, differentiation profile was associated with particular clinicopathological features but was not essential to predicting outcome in DLBCL patients.
The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia
Authors: Vangala Rajani K. , Heiss-Neumann Marion S. , Rangatia Janki S. , Singh Sheo M. , Schoch Claudia , Tenen Daniel G. , Hiddemann Wolfgang , Behre Gerhard 
Published: December 2002

AbstractThe transcription factor PU.1 plays a pivotal role in normal myeloid differentiation. PU.1−/− mice exhibit a complete block in myeloid differentiation. Heterozygous PU.1 mutations were reported in some patients with acute myeloid leukemia (AML), but not in AML with translocation t(8;21), which gives rise to the fusion geneAML1-ETO. Here we report a negative functional impact of AML1-ETO on the transcriptional activity of PU.1. AML1-ETO physically binds to PU.1 in t(8;21)+ Kasumi-1 cells. AML1-ETO binds to the β3β4 region in the DNA-binding domain of PU.1 and displaces the coactivator c-Jun from PU.1, thus down-regulating the transcriptional activity of PU.1. This physical interaction of AML1-ETO and PU.1 did not abolish the DNA-binding capacity of PU.1. AML1-ETO down-regulates the transactivation capacity of PU.1 in myeloid U937 cells, and the expression levels of PU.1 target genes in AML French-American-British (FAB) subtype M2 patients with t(8;21) were lower than in patients without t(8;21). Conditional expression of AML1-ETO causes proliferation in mouse bone marrow cells and inhibits antiproliferative function of PU.1. Overexpression of PU.1, however, differentiates AML1-ETO–expressing Kasumi-1 cells to the monocytic lineage. Thus, the function of PU.1 is down-regulated by AML1-ETO in t(8;21) myeloid leukemia, whereas overexpression of PU.1 restores normal differentiation.
Thrombogenicity of β2-glycoprotein I–dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster
Authors: Jankowski Milosz , Vreys Ingrid , Wittevrongel Christine , Boon Doris , Vermylen Jos , Hoylaerts Marc. F. , Arnout Jef 
Published: December 2002

Abstract
We previously showed that β2-glycoprotein I (β2GPI)–dependent lupus anticoagulants (LAs) form bivalent antigen-antibody complexes with high affinity for phospholipids; these complexes are responsible for their in vitro anticoagulant effect. We now studied the role of these bivalent complexes in arterial thrombosis in the hamster. Three monoclonal antibodies (mAbs) raised against human β2GPI were selected on the basis of their cross-reactivity with hamster β2GPI. Two of these, one with LA activity, 5H2, and one with only anticardiolipin properties, 11E8, were infused at 0 to 10 mg/kg prior to photochemically induced vessel damage. 5H2 promoted thrombus formation dose dependently, raising the thrombus size from 6.0 arbitrary units (AU) in controls (n = 9) to 65.0 AU in the high-dose group (10 mg/kg, n = 6, P = .007). The LA−mAb 11E8 and mAb 27A8, reactive with human β2GPI exclusively, did not significantly promote thrombus formation. In a second set of experiments, intact mAb 5H2 was compared to its fragments. Intact mAb 5H2 at 3.3 mg/kg and the equimolar dose of F(ab′)2 fragments (2.2 mg/kg) promoted thrombus formation equally well (55.8 AU, n = 8 and 62.5 AU, n = 7, respectively); mAb 5H2-derived Fab′ fragments were inactive. Immunohistochemical analysis showed platelet-rich thrombi, with 5H2 or its F(ab′)2fragments mainly bound to individual platelets. Our results indicate that bivalent immune complex formation plays an important role in the genesis of arterial thrombosis by certain antiphospholipid antibodies. Cellular activation via the Fc portion of these immune complexes, however, is not essential, because F(ab′)2 fragments of 5H2 still promote thrombus formation.
A novel rapid single nucleotide polymorphism (SNP)–based method for assessment of hematopoietic chimerism after allogeneic stem cell transplantation
Authors: Hochberg Ephraim P. , Miklos David B. , Neuberg Donna , Eichner Daniel A. , McLaughlin Stephen F. , Mattes-Ritz Alex , Alyea Edwin P. , Antin Joseph H. , Soiffer Robert J. , Ritz Jerome 
Published: December 2002

Abstract
A major end point of nonmyeloablative hematopoietic stem cell transplantation is the attainment of either mixed chimerism or full donor hematopoiesis. Because the majority of human genetic disparity is generated by single nucleotide polymorphisms (SNPs), direct measurement of SNPs should provide a robust tool for the detection and quantitation of chimerism. Using pyrosequencing, a rapid quantitative sequencing technology, we developed a SNP-based assay for hematopoietic chimerism. Based on 14 SNPs with high allele frequencies, we were able to identify at least 1 informative SNP locus in 55 patients with HLA-identical donors. The median number of informative SNPs in related pairs was 5 and in unrelated pairs was 8 (P &lt; .0001). Assessment of hematopoietic chimerism in posttransplantation DNA was shown to be quantitative, accurate, and highly reproducible. The presence of 5% donor cells was reliably detected in replicate assays. Compared with current measures of engraftment based on identification of short tandem repeats (STRs), variable number of tandem repeats (VNTRs), or microsatellite polymorphisms, this SNP-based method provides a more rapid and quantitative assessment of chimerism. A large panel of SNPs enhances the ability to identify an informative marker in almost all patient/donor pairs and also facilitates the simultaneous use of multiple markers to improve the statistical validity of chimerism measurements. The inclusion of SNPs that encode minor histocompatibility antigens or other genetic polymorphisms that may influence graft-versus-host disease or other transplantation outcomes can provide additional clinically relevant data. SNP-based assessment of chimerism is a promising technique that will assist in the analysis of outcomes following transplantation.
Exogenous stress proteins enhance the immunogenicity of apoptotic tumor cells and stimulate antitumor immunity
Authors: Feng Hanping , Zeng Yi , Graner Michael W. , Likhacheva Anna , Katsanis Emmanuel 
Published: December 2002

AbstractWe have previously reported that apoptotic tumor cells can be either immunogenic or nonimmunogenic in vivo, depending on whether or not these cells are heat stressed before induction of apoptosis. Stressed apoptotic cells express heat shock proteins on their plasma membranes and dendritic cells are capable of distinguishing them from nonstressed apoptotic cells. Here we provide evidence that when purified heat shock protein 70 or chaperone-rich cell lysate (CRCL) from syngeneic normal tissue is used as an adjuvant with nonimmunogenic apoptotic tumor cells in vaccination, potent antitumor immunity can be generated. This antitumor immunity is mediated by T cells because antitumor effects are not observed in either severe combined immunodeficiency or T cell–depleted mice. We further demonstrate that vaccination of mice with apoptotic tumor cells mixed with liver-derived CRCL as adjuvant were capable of enhancing the production of TH1 cytokines, inducing specific cytotoxic T lymphocytes and eliciting long-lasting antitumor immunity. Stress proteins from autologous normal tissue components therefore can serve as danger signals to enhance the immunogenicity of apoptotic tumor cells and stimulate tumor-specific immunity
Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias
Authors: Jensen Peter D. , Jensen Finn T. , Christensen Thorkil , Nielsen Johan L. , Ellegaard Joergen 
Published: December 2002

Abstract
The role of iron overload as cause of liver dysfunction has never been studied in detail in patients without concomitant hepatotropic infections who receive multiple transfusions. We therefore investigated the relationship between the extent of hepatocellular injury as reflected by serum levels of aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and several iron status indices in 39 anti–hepatitis C virus-negative (HCV−) nonthalassemic patients with transfusional iron overload owing to acquired anemias. In 12 patients, we monitored aminotransferase levels and indices of iron status during iron chelation treatment. Before treatment, elevated aminotransferase activity was seen only at liver iron concentrations more than 300 μM/g. During treatment all aminotransferase values were normal if the liver iron concentration returned below 350 μM/g. At the start of treatment, ALT (R2 = 0.64, P = .006) and AST activity (R2 = 0.57,P = .01) were closely related to urinary iron excretion, reflecting the size of the chelatable or the labile iron pool. During treatment, a comparable pattern was seen and the urinary iron excretion was also directly related to the liver iron concentration at concentrations above approximately 400 μM/g. All elevated ALT values were associated with a urinary iron excretion more than 15 mg/24 h. In conclusion, our data suggest the existence of a critical liver iron concentration range, above which hepatocellular injury is seen. The extent of the injury seems to be determined mainly by the size of the chelatable or labile iron pool, supporting the concept of the labile iron pool as the compartment directly involved in iron toxicity. Our findings may be helpful in establishing criteria for safety from complications of transfusional iron overload.
Noninvasive measurement of iron: report of an NIDDK workshop
Authors: Brittenham Gary M. , Badman David G. 
Published: December 2002

Abstract
An international workshop on the noninvasive measurement of iron was conducted by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) on April 17, 2001, to assess the current state of the science and to identify areas needing further investigation. The workshop concluded that a clear clinical need is evident for quantitative, noninvasive, safe, accurate, and readily available means of measuring body storage iron to improve the diagnosis and management of patients with iron overload from such disorders as hereditary hemochromatosis, thalassemia major, sickle cell disease, aplastic anemia, and myelodysplasia, among others. Magnetic resonance imaging (MRI) potentially provides the best available technique for examining the 3-dimensional distribution of excess iron in the body, but further research is needed to develop means of making measurements quantitative. Biomagnetic susceptometry provides the only noninvasive method to measure tissue iron stores that has been calibrated, validated, and used in clinical studies, but the complexity, cost, and technical demands of the liquid-helium–cooled superconducting instruments required at present have restricted clinical access to the method. The workshop identified basic and clinical research opportunities for deepening our understanding of the physical properties of iron and iron toxicity, for further investigation of MRI as a method for quantitative determinations of tissue iron, especially in liver, heart and brain, and for development of improved methods and more widely available instrumentation for biomagnetic susceptometry.
Recombinant PfEMP1 peptide inhibits and reverses cytoadherence of clinical Plasmodium falciparum isolates in vivo
Authors: Yipp Bryan G. , Baruch Dror I. , Brady Ciaran , Murray Allan G. , Looareesuwan Sornchai , Kubes Paul , Ho May 
Published: December 2002

AbstractThe parasite ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and host endothelial receptors represent potential targets for antiadhesive therapy for cytoadherence. In the present study, the major host receptor CD36 was targeted in vitro and in vivo with a recombinant peptide, PpMC-179, corresponding to the minimal CD36-binding domain from the cysteine-rich interdomain region 1 (CIDR1) within the MCvar1 PfEMP1. The in vitro inhibitory effect of PpMC-179 on human dermal microvascular endothelial cells (HDMECs) expressing multiple relevant adhesion molecules was investigated using a parallel-plate flow chamber. Pretreatment of endothelial monolayers with PpMC-179 (2 μM) inhibited the adhesion of infected erythrocytes (IRBCs) from all clinical isolates tested by 84.4% on resting and 62.8% on tumor necrosis factor α (TNF-α)–stimulated monolayers. Adhesion to stimulated cells was further inhibited (90.4%) when PpMC-179 was administered with an inhibitory anti–intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody 84H10 (5 μg/mL). To determine the in vivo effectiveness of PpMC-179, we used a human/severe combined immunodeficiency (SCID) mouse chimeric model that allowed direct visualization of cytoadherence on intact human microvasculature. In unstimulated skin grafts, PpMC-179 inhibited adhesion by 86.3% and by 84.6% in TNF-α–stimulated skin grafts. More importantly, PpMC-179 administration resulted in the detachment of already adherent IRBCs by 80.7% and 83.3% on resting and stimulated skin grafts, respectively. The antiadhesive effect of PpMC-179 was rapid and sustained in vivo for at least 30 minutes. Our data indicate that targeting cytoadhesion in vivo is feasible and may offer a rapid antimalarial therapy.
A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility
Authors: Soria José Manuel , Almasy Laura , Souto Joan Carles , Buil Alfonso , Martı́nez-Sánchez Elisabeth , Mateo José , Borrell Montserrat , Stone William H. , Lathrop Mark , Fontcuberta Jordi , Blangero John 
Published: December 2002

AbstractActivated protein C resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20% to 60% of familial thrombophilia. A mutation in the F5 gene, factor V Leiden (FVL), is a major determinant of pathological APCR in some populations. However, APCR predicts risk for thrombosis independently of FVL. This suggests that other genetic factors may influence risk of thrombosis through quantitative variation in APCR. To search for these unknown loci, we conducted a genome-wide linkage screen for genes affecting normal variation in APCR in the 21 Spanish families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project. Conditional on FVL, the strongest linkage signal for APCR was found on chromosome 18 near D18S53. Bivariate linkage analyses with a genetically correlated trait, levels of clotting factor VIII, strengthened evidence for the chromosome 18 quantitative trait locus (QTL; logarithm of the odds [LOD], 4.5; P = 3.08 × 10−5). However, the region on chromosome 1 that contains the F5structural gene showed little evidence of linkage to APCR (LOD, &lt; 1). This indicates that apart from the FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 haplotype polymorphisms. A second bivariate analysis of APCR with thrombosis liability suggested that this QTL also influences the risk of thrombosis (P = .0016). These results indicate that a locus on chromosome 18 pleiotropically influences normal variation in the APCR phenotype and factor VIII (FVIII) levels as well as susceptibility to thrombosis. Importantly, there are no known thrombosis-related candidate genes in this region, implying that this QTL represents a completely novel thrombosis risk factor.
Acute sickle cell hepatopathy represents a potential contraindication for percutaneous liver biopsy
Authors: Zakaria Nada , Knisely Alex , Portmann Bernard , Mieli-Vergani Giorgina , Wendon Julia , Arya Roopen , Devlin John 
Published: December 2002

Abstract
After several complications following percutaneous liver biopsy in patients with sickle cell disease, we reviewed our experience. We examined 14 patients with sickle cell disease who underwent a percutaneous liver biopsy. Clinicopathologic findings were correlated with outcome. Of 14 patients, 5 (36%) suffered serious hemorrhage; 4 died (80%; 28% of all patients). None of the 9 patients without biopsy complications was in an acute sickling crisis at the time of biopsy; 4 of 5 patients with complications were in acute sickling crisis. Of the 5 patients with complications, 4 underwent biopsy for an emergency indication. Chronic venous outflow obstruction, marked hepatic sequestration of erythrocytes, and sinusoidal dilatation were strongly associated with complications. Data obtained by biopsy in group 1 were not of substantial value in clinical management, in contrast to group 2 (8/9; 89%). Acute hepatic disease complicating sickle cell anemia represents a newly identified contraindication to percutaneous liver biopsy.
Homeostasis of telomere length rather than telomere shortening after allogeneic peripheral blood stem cell transplantation
Authors: Roelofs Helene , de Pauw Elmar S. D. , Zwinderman Aeilko H. , Opdam Sonja M. , Willemze Roel , Tanke Hans J. , Fibbe Willem E. 
Published: December 2002

AbstractHematopoietic reconstitution after stem cell transplantation requires excessive replicative activity because of the limited number of stem cells that are used for transplantation. Telomere shortening has been detected in hematopoietic cells after bone marrow transplantation. This has been thought to result from excessive replication of the stem cells, with putative concomitant reduction of their replicative potential. Hematopoietic stem cells from cytokine-mobilized peripheral blood are increasingly used for stem cell transplantation. These grafts contain higher numbers of hematopoietic stem cells, resulting in a faster hematopoietic reconstitution. We have performed a combined prospective and cross-sectional study of hematologic recovery and telomere length dynamics in the immediate reconstitution period after allogeneic T-cell–depleted blood stem cell transplantation. We analyzed hematologic recovery and telomere length of granulocytes, monocytes, B cells, and T-cell subsets in 30 donor/recipient combinations. We found fast recovery in combination with transient telomere shortening in the myeloid lineages. This initial reduction of telomere length was followed by an increase in telomere length to such an extent that 1 year after transplantation the telomere length in recipient cells was similar to the telomere length in donor-derived cells. Therefore, our data indicate telomere length homeostasis after peripheral blood stem cell transplantation, implying no loss of replicative capacity of the stem cells. Our data indicate that fast expansion is accompanied by a reduction of telomere length and that telomere length homeostasis is achieved by de novo generation of hematopoietic cells from stem cells without transplantation-related telomere loss.
HK Utrecht: missense mutation in the active site of human hexokinase associated with hexokinase deficiency and severe nonspherocytic hemolytic anemia
Authors: van Wijk Richard , Rijksen Gert , Huizinga Eric G. , Nieuwenhuis Hendrik K. , van Solinge Wouter W. 
Published: December 2002

Abstract
Hexokinase deficiency is a rare autosomal recessive disease with a clinical phenotype of severe hemolysis. We report a novel homozygous missense mutation in exon 15 (c.2039C&gt;G, HK [hexokinase] Utrecht) of HK1, the gene that encodes red blood cell–specific hexokinase-R, in a patient previously diagnosed with hexokinase deficiency. The Thr680Ser substitution predicted by this mutation affects a highly conserved residue in the enzyme's active site that interacts with phosphate moieties of adenosine diphosphate, adenosine triphosphate (ATP), and inhibitor glucose-6-phosphate. We correlated the molecular data to the severe clinical phenotype of the patient by means of altered enzymatic properties of partially purified hexokinase from the patient, notably with respect to Mg2+-ATP binding. These kinetic properties contradict those obtained from a recombinant mutant brain hexokinase-I with the same Thr680Ser substitution. This contradiction thereby stresses the valuable contribution of studying patients with hexokinase deficiency to achieve a better understanding of hexokinase's key role in glycolysis.
High-level expression of hemoglobin A in human thalassemic erythroid progenitor cells following lentiviral vector delivery of an antisense snRNA
Authors: Vacek Marla M. , Ma Hong , Gemignani Federica , Lacerra Giuseppina , Kafri Tal , Kole Ryszard 
Published: December 2002

AbstractMutations at nucleotides 654, 705, or 745 in intron 2 of the human β-globin gene activate aberrant 3′ and 5′ splice sites within the intron and prevent correct splicing of β-globin pre-mRNA, resulting in inhibition of β-globin synthesis and in consequence β-thalassemia. Transfection of HeLa cells expressing the 3 thalassemic mutants with modified U7 snRNA (U7.623), containing a sequence antisense to a region between the aberrant splice sites, reduced the incorrect splicing of pre-mRNA and led to increased levels of the correctly spliced β-globin mRNA and protein. A lentiviral vector carrying the U7.623 gene was effective in restoration of correct splicing in the model cell lines for at least 6 months. Importantly, the therapeutic value of this system was demonstrated in hematopoietic stem cells and erythroid progenitor cells from a patient with IVS2-745/IVS2-1 thalassemia. Twelve days after transduction of the patient cells with the U7.623 lentiviral vector, the levels of correctly spliced β-globin mRNA and hemoglobin A were approximately 25-fold over background. These results should be regarded as a proof of principle for lentiviral vector–based gene therapy for β-thalassemia.