bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired hematopoiesis in mice lacking the transcription factor Sp3
Authors: van Loo Pieter Fokko , Bouwman Peter , Ling Kam-Wing , Middendorp Sabine , Suske Guntram , Grosveld Frank , Dzierzak Elaine , Philipsen Sjaak , Hendriks Rudolf W. 
Published: April 2003

AbstractAs the zinc-finger transcription factor specificity protein 3 (Sp3) has been implicated in the regulation of many hematopoietic-specific genes, we analyzed the role of Sp3 in hematopoiesis. At embryonic day 18.5 (E18.5), Sp3-/- mice exhibit a partial arrest of T-cell development in the thymus and B-cell numbers are reduced in liver and spleen. However, pre–B-cell proliferation and differentiation into immunoglobulin M–positive (IgM+) B cells in vitro are not affected. At E14.5 and E16.5, Sp3-/- mice exhibit a significant delay in the appearance of definitive erythrocytes in the blood, paralleled by a defect in the progression of differentiation of definitive erythroid cells in vitro. Perinatal death of the null mutants precludes the analysis of adult hematopoiesis in Sp3-/- mice. We therefore investigated the ability of E12.5 Sp3-/- liver cells to contribute to the hematopoietic compartment in an in vivo transplantation assay. Sp3-/- cells were able to repopulate the B- and T-lymphoid compartment, albeit with reduced efficiency. In contrast, Sp3-/- cells showed no significant engraftment in the erythroid and myeloid lineages. Thus, the absence of Sp3 results in cell-autonomous hematopoietic defects, affecting in particular the erythroid and myeloid cell lineages.
SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V: localization of SHIP-2 to the activated platelet actin cytoskeleton
Authors: Dyson Jennifer M. , Munday Adam D. , Kong Anne M. , Huysmans Richard D. , Matzaris Maria , Layton Meredith J. , Nandurkar Harshal H. , Berndt Michael C. , Mitchell Christina A. 
Published: April 2003

AbstractThe platelet receptor for the von Willebrand factor (VWF) glycoprotein Ib-IX-V (GPIb-IX-V) complex mediates platelet adhesion at sites of vascular injury. The cytoplasmic tail of the GPIbα subunit interacts with the actin-binding protein, filamin, anchoring the receptor in the cytoskeleton. In motile cells, the second messenger phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3) induces submembraneous actin remodeling. The inositol polyphosphate 5-phosphatase, Src homology 2 domain-containing inositol polyphosphate 5-phosphatase-2 (SHIP-2), hydrolyzes PtdIns(3,4,5)P3 forming phosphatidylinositol 3,4 bisphosphate (PtdIns(3,4)P2) and regulates membrane ruffling via complex formation with filamin. In this study we investigate the intracellular location and association of SHIP-2 with filamin, actin, and the GPIb-IX-V complex in platelets. Immunoprecipitation of SHIP-2 from the Triton-soluble fraction of unstimulated platelets demonstrated association between SHIP-2, filamin, actin, and GPIb-IX-V. SHIP-2 associated with filamin or GPIb-IX-V was active and demonstrated PtdIns(3,4,5)P3 5-phosphatase activity. Following thrombin or VWF-induced platelet activation, detection of the SHIP-2, filamin, and receptor complex decreased in the Triton-soluble fraction, although in control studies the level of SHIP-2, filamin, or GPIb-IX-V immunoprecipitated by their respective antibodies did not change following platelet activation. In activated platelets spreading on a VWF matrix, SHIP-2 localized intensely with actin at the central actin ring and colocalized with actin and filamin at filopodia and lamellipodia. In spread platelets, GPIb-IX-V localized to the center of the platelet and showed little colocalization with filamin at the plasma membrane. These studies demonstrate a functionally active complex between SHIP-2, filamin, actin, and GPIb-IX-V that may orchestrate the localized hydrolysis of PtdIns(3,4,5)P3 and thereby regulate cortical and submembraneous actin.
Factor VII gene intronic mutation in a lethal factor VII deficiency: effects on splice-site selection
Authors: Borensztajn Keren , Sobrier Marie-Laure , Fischer Anne-Marie , Chafa Ouerdia , Amselem Serge , Tapon-Bretaudiére Jacqueline 
Published: April 2003

AbstractIn a patient with lethal factor VII (FVII) deficiency, 2 homozygous nucleotide substitutions were identified in the F7 gene: a IVS7+2T&gt;G transversion involving the IVS7 donor splice site, followed by a mutation at nucleotide 10588 that would result in a missense variation (Arg224Gln). The mutated splice site, located within the first repeat of a minisatellite, is followed by a variable number of pseudo-sites, normally silent. To investigate the consequences of this mutation on F7 splicing, we designed normal and mutant minigenes, spanning exons 5 to 8. In cells transfected with the mutant construct, no normal splicing occurred. Only spliced transcripts including the first minisatellite repeat were observed, resulting from the activation of the most proximal wild-type pseudo-site, which would generate a truncated protein (stop codon upstream of nucleotide 10588). These findings, which suggest the existence of a mechanism selecting one single splice site among multiple cryptic sites, explain the patient's phenotype.
Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells
Authors: Bornhäuser Martin , Storer Barry , Slattery John T. , Appelbaum Frederick R. , Deeg H. Joachim , Hansen John , Martin Paul J. , McDonald George B. , Nichols W. Garrett , Radich Jerald , Woolfrey Ann , Jenke Andreas , Schleyer Eberhard , Thiede Christian , Ehninger Gerhard , Anasetti Claudio 
Published: April 2003

Abstract
A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The conditioning regimen consisted of 30 mg/m2 intravenous fludarabine daily from day -9 to day -6, and oral busulfan given at 1 mg/kg 4 times a day every 6 hours from day -5 to day -2, with doses adjusted to target plasma levels of 900 ± 100 ng/mL at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Enrolled were 42 patients with high-risk CML (n = 4) or MDS (n = 38). The median patient age was 52 years (range, 12-65 years). Mobilized blood stem cells were obtained from HLA-compatible siblings (n = 16) or unrelated donors (n = 26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 months (range, 13-27 months), the probabilities of overall survival, disease-free survival, and nonrelapse mortality were 42.4%, 34.9%, and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard-risk patients.
Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features
Authors: Guarini Anna , Gaidano Gianluca , Mauro Francesca Romana , Capello Daniela , Mancini Francesca , De Propris Maria Stefania , Mancini Marco , Orsini Enrica , Gentile Massimo , Breccia Massimo , Cuneo Antonio , Castoldi Gianluigi , Foa Robert 
Published: April 2003

Abstract
Different biologic features have been associated with a more or less aggressive clinical course in chronic lymphocytic leukemia (CLL). In the present study, 20 patients with highly stable CLL observed at a single institution over a period of 10 to 23 years and who never required treatment were extensively characterized. The aim was to identify a distinct and reproducible biologic profile associated with disease stability that may be used to recognize at presentation CLL patients who are likely to have a very benign clinical course and for whom treatment is not indicated. The results obtained indicate that numerous parameters are closely associated with disease stability: a typical CLL morphology and immunophenotype, the lack of expression of the CD38 antigen, the mutated immunoglobulin (Ig) heavy (H) chain variable (V) pattern, the absence of p53 mutations, a CD4/CD8 ratio more than 1, the lack of 17p and 11q deletions and of complex karyotypic aberrations, and the occurrence of the 13q14 deletion. No case displayed the VH3-21 gene, linked in mutated CLL with a poor outcome. In addition, the VH1-69 gene associated with unmutated CLL cases was never detected. These biologic features were coupled with an indolent clinical course characterized by an unmodified clinical stage over time, and by lack of autoimmune phenomena and of major infections requiring parental antibiotics. At a time when aggressive therapeutic strategies are always more frequently used in the management of CLL, the distinctive features of patients with long-lived stable disease should be prospectively identified at presentation.
Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells
Authors: Hinds Kathleen A. , Hill Jonathan M. , Shapiro Erik M. , Laukkanen Mikko O. , Silva Alfonso C. , Combs Christian A. , Varney Timothy R. , Balaban Robert S. , Koretsky Alan P. , Dunbar Cynthia E. 
Published: April 2003

Abstract
Tracking transplanted stem cells using magnetic resonance imaging (MRI) could offer biologic insight into homing and engraftment. Ultrasmall dextran-coated iron oxide particles have previously been developed for uptake into cells to allow MRI tracking. We describe a new application of much larger, micron-scale, iron oxide magnetic particles with enhanced MR susceptibility, which enables detection of single cells at resolutions that can be achieved in vivo. In addition, these larger particles possess a fluorophore for histologic confirmation of cell distribution. We demonstrate highly efficient, nontoxic, endosomal uptake of these particles into hematopoietic CD34+ cells and mesenchymal stem cells documented by confocal and electron microscopy. Labeled cells retain biologic activity with preservation of colony-forming ability and differentiation capacity. MRI studies could detect labeled CD34+ cells and mesenchymal stem cells (MSCs) at single cell resolution. This appears to be a promising tool for serial noninvasive monitoring of in vivo cell homing and localization using MRI.
Polyclonal hematopoiesis maintained in patients with bone marrow failure harboring a minor population of paroxysmal nocturnal hemoglobinuria–type cells
Authors: Ishiyama Ken , Chuhjo Tatsuya , Wang Hongbo , Yachie Akihiro , Omine Mitsuhiro , Nakao Shinji 
Published: April 2003

Abstract
Although a minor population of paroxysmal nocturnal hemoglobinuria (PNH)–type blood cells is often detected in patients with aplastic anemia (AA) and refractory anemia (RA), the significance of such cells in the pathophysiology of bone marrow (BM) failure remains obscure. We therefore examined clonality in peripheral blood granulocytes from 118 female patients with AA or myelodysplastic syndrome using the X chromosome inactivation pattern. Clonality, defined as a clonal population accounting for 35% or more of total granulocytes, was confirmed in 22 of 68 (32.4%) AA patients, in 13 of 44 (29.5%) RA patients, in all 4 RA with excess blasts (RAEB) patients, and in 4 patients with PNH. When the frequency of patients with granulocyte clonality was compared with respect to the presence of increased PNH-type cells, the frequency was significantly lower in AA patients with (PNH+; 21.2%) than without (PNH–; 42.9%) increased numbers of PNH-type cells (P = .049). Clonality was absent in granulocytes from the 15 PNH+ RA patients but present in 13 of 29 (44.8%) PNH– RA patients (P = .0013). The absence of clonality in AA and RA patients before treatment was strongly associated with positive response to immunosuppressive therapy (without clonality, 74.4%; with clonality, 33.3%; P = .0031) in all patients as well as in PNH+ patients (without clonality, 96.2%; with clonality, 66.6%, P = .026). These results suggest that AA and RA with a minor population of PNH-type cells are benign types of BM failure with immune pathophysiology that have little relationship to clonal disorders such as RAEB or acute myeloid leukemia.
Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity
Authors: Rollinson Sara , Levene Adam P. , Mensah Fiona K. , Roddam Philippa L. , Allan James M. , Diss Tim C. , Roman Eve , Jack Andrew , MacLennan Kenneth , Dixon Michael F. , Morgan Gareth J. 
Published: April 2003

Abstract
Gastric marginal zone lymphoma (GMZL) is strongly associated with Helicobacter pylori infection, which induces a chronic inflammatory response. Inflammation can result in DNA damage related to its severity, the cellular antioxidant capacity, and the integrity of DNA repair mechanisms. Interleukin-1 (IL-1) polymorphisms have been shown to be important mediators of inflammation, while glutathione S-transferase GST T1 and GST M1 polymorphisms are believed to affect cellular antioxidant capacity. We aimed to determine whether polymorphisms at the IL-1 and GST T1 and GST M1 loci modulate the risk of developing GMZL. Blood and biopsy samples were obtained for a historical series of 66 GMZL cases, whereas blood samples were available from 163 healthy controls. Genotypes were obtained for GST T1, GST M1, IL-1 RN, and IL-1B-31 using PCR-based techniques. H pylori infection was found in 86.0% of cases, whereas in the control population only 37.4% tested positive. The IL-1 RN 2/2 genotype was significantly associated with risk of GMZL (odds ratio [OR], 5.51; 95% confidence interval [CI] 2.16-14.07), but not the IL-1B-31 genotype. Likewise, the GST T1 null genotype was strongly associated with risk of GMZL (OR, 9.51; 95% CI 4.57-19.81), but not the GST M1 genotype. Evidence was found of effect modification between the IL-1 RN and GST T1 genotypes (P =.02). The combination of the IL-1 RN 2/2 and GST T1 null genotype was most strongly associated with risk of GMZL (OR, 32.29; 95% CI 6.92-150-63). These results support the hypothesis that the risk of developing GMZL is influenced by inter-individual variation in the cellular inflammatory immune responses to H pylori infection, and to antioxidative capacity.
Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness
Authors: Klion Amy D. , Noel Pierre , Akin Cem , Law Melissa A. , Gilliland D. Gary , Cools Jan , Metcalfe Dean D. , Nutman Thomas B. 
Published: April 2003

AbstractSince serum tryptase levels are elevated in some patients with myeloproliferative disorders, we examined their utility in identifying a subset of patients with hypereosinophilic syndrome (HES) and an underlying myeloproliferative disorder. Elevated serum tryptase levels (&gt; 11.5 ng/mL) were present in 9 of 15 patients with HES and were associated with other markers of myeloproliferation, including elevated B12 levels and splenomegaly. Although bone marrow biopsies in these patients showed increased numbers of CD25+ mast cells and atypical spindle-shaped mast cells, patients with HES and elevated serum tryptase could be distinguished from patients with systemic mastocytosis and eosinophilia by their clinical manifestations, the absence of mast cell aggregates, the lack of a somatic KIT mutation, and the presence of the recently described fusion of the Fip1–like 1 (FIP1L1) gene to the platelet-derived growth factor receptor α gene (PDGFRA). Patients with HES and elevated serum tryptase were more likely to develop fibroproliferative end organ damage, and 3 of 9 died within 5 years of diagnosis in contrast to 0 of 6 patients with normal serum tryptase levels. All 6 patients with HES and elevated tryptase treated with imatinib demonstrated a clinical and hematologic response. In summary, elevated serum tryptase appears to be a sensitive marker of a myeloproliferative variant of HES that is characterized by tissue fibrosis, poor prognosis, and imatinib responsiveness.
Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome
Authors: Yamaguchi Hiroki , Baerlocher Gabriela M. , Lansdorp Peter M. , Chanock Stephen J. , Nunez Olga , Sloand Elaine , Young Neal S. 
Published: April 2003

Abstract
Mutations in the human telomerase RNA (TERC) occur in autosomal dominant dyskeratosis congenita (DKC). Because of the possibility that TERC mutations might underlie seemingly acquired forms of bone marrow failure, we examined blood samples from a large number of patients with aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplasia (MDS). Only 3 of 210 cases showed heterozygous TERC mutations: both nucleotide 305 (n305) (G&gt;A) and n322 (G&gt;A) were within the conserved region (CR) 4–CR5 domain; n450 (G&gt;A) was localized to the boxH/ACA domain. However, only one patient (with a mutation at n305 [G&gt;A]) had clinical characteristics suggesting DKC; her blood cells contained short telomeres and her sister also suffered from bone marrow failure. Another 21 patients with short telomeres did not show TERC mutations. Our results suggest that cryptic DKC, at least secondary to mutations in the TERC gene, is an improbable diagnosis in patients with otherwise typical AA, PNH, and MDS.
Occupational and nonoccupational factors associated with high grade bronchial pre-invasive lesions
Authors: Paris C. , Benichou J. , Bota S. , Sagnier S. , Metayer J. , Eloy S. , Auliac J-B. , Nouvet G. , Thiberville L. 
Published: April 2003

Besides tobacco exposure, factors associated with the development of pre-invasive bronchial lesions are not known. Autofluorescence bronchoscopy was used to assess the prevalence of severe dysplasia and carcinomain situ(SD/CIS) of the proximal bronchial tree in relation to occupational or nonoccupational carcinogen exposure.Among the 241 individuals in this study, the overall prevalence of at least one SD/CIS was 9% (21 subjects). Multivariable analysis revealed significant and independent associations between presence of SD/CIS and: 1) active smoking, relative to former smokers; 2) presence of synchronous invasive lung cancer; 3) duration of asbestos exposure and; 4) exposure to other occupational carcinogens.The independent associations of synchronous lung cancer with severe dysplasia and carcinoma, after adjusting for both occupational and nonoccupational carcinogen exposures, suggest other mechanisms than a field cancerisation may be involved in the carcinogenesis of these pre-invasive lesions. Moreover, active smokers, patients with recently resected invasive lung cancer and workers occupationally exposed to bronchial carcinogens may represent a population of choice for early cancer endoscopic detection programmes in view of their high severe dysplasia and carcinoma prevalence.
Validity and interpretation of mortality, health service and survey data on COPD and asthma in England
Authors: Hansell A. , Hollowell J. , McNiece R. , Nichols T. , Strachan D. 
Published: April 2003

The comparability of asthma and chronic obstructive pulmonary disease (COPD) epidemiology in different English routine data sources was examined to explore their use and validity in investigating environmental influences on respiratory health.National data were obtained for mortality, emergency hospital admissions, general practitioner contacts and symptoms in the early 1990s. Age/sex patterns, seasonal variations and regional and urban/rural age/sex standardised event ratios were examined. Spearman rank correlations were used to describe consistency of regional rankings across data sets.Asthma showed inconsistent disease patterns in different data sources and weak correlations for regional rankings but COPD was notably consistent. Unmeasured confounders may partly explain the findings, but individual level adjustment for social class and smoking (possible for symptoms) only partially attenuated the higher COPD rates in northern and urban areas and did not affect findings for asthma.When epidemiological patterns are consistent across data sources as with chronic obstructive pulmonary disease in England, healthcare use is likely to reflect the underlying prevalence and severity of disease and can be used to study environmental influences. When patterns vary, as with asthma, the validity of the data in relation to its intended use must be carefully considered.
Acute exacerbation of idiopathic pulmonary fibrosis: report of a series
Authors: Ambrosini V. , Cancellieri A. , Chilosi M. , Zompatori M. , Trisolini R. , Saragoni L. , Poletti V. 
Published: April 2003

This study describes five cases presenting an acute clinical course of pulmonary fibrosis, in the absence of specific precipitating factors.A retrospective chart review of five patients with histologically proved usual interstitial pneumonia was carried out in 2001–2002. Clinical data, bronchoalveolar lavage (BAL) findings, high resolution computed tomography and histological features were reported.On admission all cases presented hypoxemia and dyspnoea, while some showed an increase of carbohydrate antigen 19.9 or laboratory tests typical of infection, although appropriate cultures were all negative. Altogether, four subjects died and only one is on follow-up. A pattern of diffuse ground-glass or alveolar opacification superimposed on reticular and linear findings was evident on lung imaging in all cases. Marked neutrophilia, together with type II reactive cells hyperplasia, was detected on BAL.Histological findings, from open lung biopsy or autopsy, showed all the aspects of usual interstitial pnemonia with superimposed features of acute lung injury, such as diffuse alveolar damage, with or without hyaline membranes, type II reactive cells hyperplasia and numerous fibroblastic foci. This study also underlines the diagnostic value of bronchoalveolar lavageversusopen lung biopsy.
Induced sputum for diagnosingPneumocystis cariniipneumonia in HIV patients: new data, new issues
Authors: Turner D. , Schwarz Y. , Yust I. 
Published: April 2003

The complexity of bronchoalveolar lavage (BAL) has motivated the search for noninvasive methodology to retrieve specimens for detecting the presence of various pulmonary diseases. Induced sputum (IS) has been shown to be a reliable tool in terms of sensitivity and specificity comparable to BAL. Investigators from institutions worldwide have published several reports providing evidence in support of one or the other or a combination of both approaches. Among them are studies demonstrating the sensitivity and specificity of IS in diagnosingPneumocystis cariniipneumonia (PCP) in patients with acquired immunodeficiency syndrome (AIDS). In 1996, highly active antiretroviral therapy was introduced for routine use and the morbidity from opportunistic infections decreased sharply.An earlier study showed that cost-effectiveness depends on the prevalence of a given condition in the population. More recent studies have confirmed that prophylaxis against PCP can be stopped after increasing the CD4 cell count, thus reducing the attractiveness of IS as a preferred method for monitoring the course of disease.This review presents a brief description of the evolution of the bronchoalveolar lavageversusinduced sputum controversy and reconsiders the strengths and weaknesses of the earlier arguments in light of newer data that have emerged with regard toPneumocystis cariniipneumonia in acquired immunodeficiency syndrome.