bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients
Authors: Markert M. Louise , Sarzotti Marcella , Ozaki Daniel A. , Sempowski Gregory D. , Rhein Maria E. , Hale Laura P. , Le Deist Francoise , Alexieff Marilyn J. , Li Jie , Hauser Elizabeth R. , Haynes Barton F. , Rice Henry E. , Skinner Michael A. , Mahaffey Samuel M. , Jaggers James , Stein Leonard D. , Mill Michael R. 
Published: April 2003

AbstractComplete DiGeorge syndrome is a fatal condition in which infants have no detectable thymus function. The optimal treatment for the immune deficiency of complete DiGeorge syndrome has not been determined. Safety and efficacy of thymus transplantation were evaluated in 12 infants with complete DiGeorge syndrome who had less than 20-fold proliferative responses to phytohemagglutinin. All but one had fewer than 50 T cells/mm3. Allogeneic postnatal cultured thymus tissue was transplanted. T-cell development was followed by flow cytometry, lymphocyte proliferation assays, and T-cell receptor Vβ (TCRBV) repertoire evaluation. Of the 12 patients, 7 are at home 15 months to 8.5 years after transplantation. All 7 survivors developed T-cell proliferative responses to mitogens of more than 100 000 counts per minute (cpm). By one year after transplantation, 6 of 7 patients developed antigen-specific proliferative responses. The TCRBV repertoire showed initial oligoclonality that progressed to polyclonality within a year. B-cell function developed in all 3 patients tested after 2 years. Deaths were associated with underlying congenital problems. Risk factors for death included tracheostomy, long-term mechanical ventilation, and cytomegalovirus infection. Adverse events in the first 3 months after transplantation included eosinophilia, rash, lymphadenopathy, development of CD4-CD8- peripheral T cells, elevated serum immunoglobulin E (IgE), and possible pulmonary inflammation. Adverse events related to the immune system occurring more than 3 months after transplantation included thrombocytopenia in one patient and hypothyroidism and alopecia in one other patient. Thymic transplantation is efficacious, well tolerated, and should be considered as treatment for infants with complete DiGeorge syndrome.
Ex vivo targeting of p21Cip1/Waf1 permits relative expansion of human hematopoietic stem cells
Authors: Stier Sebastian , Cheng Tao , Forkert Randolf , Lutz Christoph , Dombkowski David M. , Zhang Jie Lin , Scadden David T. 
Published: April 2003

AbstractRelative quiescence is a defining characteristic of hematopoietic stem cells. Reasoning that inhibitory tone dominates control of stem cell cycling, we previously showed that mice engineered to be deficient in the cyclin-dependent kinase inhibitor, p21Cip1/Waf1 (p21), have an increased stem cell pool under homeostatic conditions. Since p21 was necessary to maintain stem cell quiescence and its absence sufficient to permit increased murine stem cell cycling, we tested whether reduction of p21 alone in human adult–derived stem cells could affect stem cell proliferation. We demonstrate here that interrupting p21 expression ex vivo resulted in expanded stem cell number and in vivo stem cell function compared with control, manipulated cells. Further, we demonstrate full multilineage reconstitution capability in cells where p21 expression was knocked down. Therefore, lifting the brake on cell proliferation by altering cell cycle checkpoints provides an alternative paradigm for increasing hematopoietic stem cell numbers. This approach may be useful for relative ex vivo human stem cell expansion.
IgE alone stimulates mast cell adhesion to fibronectin via pathways similar to those used by IgE + antigen but distinct from those used by Steel factor
Authors: Lam Vivian , Kalesnikoff Janet , Lee Corinna W. K. , Hernandez-Hansen Valerie , Wilson Bridget S. , Oliver Janet M. , Krystal Gerald 
Published: April 2003

AbstractWe recently demonstrated that immunoglobulin E (IgE), in the absence of cross-linking agents, activates signaling pathways in healthy murine bone marrow–derived mast cells (BMMCs) and that this activation enhances BMMC survival, at least in part, via secretion of autocrine-acting cytokines. We report herein that IgE alone also triggers the adhesion of both BMMCs and connective tissue mast cells (CTMCs) to the connective tissue component, fibronectin (FN). This adhesion occurs to the same extent as that triggered by optimal levels of Steel factor (SF) or IgE + antigen (IgE + Ag) and is mediated by an increased avidity of the integrin very late antigen 5 (VLA-5). Moreover, this IgE-induced adhesion, which is prolonged compared with that elicited by SF or IgE + Ag, requires phosphatidylinositol 3-kinase (PI3K), phospholipase C γ (PLCγ), and extracellular calcium but not extracellular-regulated kinase (Erk) or p38. Interestingly, we found, using the calcium channel blocker, 2-APB (2-aminoethoxydiphenyl borate) and Lyn–/– BMMCs that both IgE- and IgE + Ag-induced adhesion to FN require extracellular calcium entry, whereas SF does not. Furthermore, our data suggest that FN acts synergistically with IgE to prolong intracellular phosphorylation events and to enhance IgE-induced inflammatory cytokine production and BMMC survival.
Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry
Authors: Percy Melanie J. , McMullin Mary Frances , Jowitt Simon N. , Potter Michael , Treacy Marilyn , Watson William H. , Lappin Terence R. J. 
Published: April 2003

Abstract
The Chuvash form of polycythemia is an autosomal recessive disorder common to a large number of families in central Russia. Affected individuals have been reported to be homozygous for an Arg200Trp mutation in the von Hippel–Lindau (VHL) gene. We have screened 78 patients with erythrocytosis and found 8 of Bangladeshi and Pakistani origin to be homozygous for the Arg200Trp mutation and another of English descent to be heterozygous. Of these patients, 5 have elevated serum erythropoietin (Epo) levels, while the other 4 have Epo values in the normal range. The heterozygous patient does not fulfill the Chuvash criterion for homozygosity of the Arg200Trp mutation and consequently may harbor a further, as yet uncharacterized, mutation. This mutation has a wider geographic distribution than originally presumed and haplotype analysis suggests a common origin of the Arg200Trp mutation in the 4 families, but it still remains to be established if it has arisen independently of the Chuvash population.
Molecular and functional analysis of Shiga toxin–induced response patterns in human vascular endothelial cells
Authors: Matussek Andreas , Lauber Joerg , Bergau Anna , Hansen Wiebke , Rohde Manfred , Dittmar Kurt E. J. , Gunzer Matthias , Mengel Michael , Gatzlaff Patricia , Hartmann Maike , Buer Jan , Gunzer Florian 
Published: April 2003

AbstractEnterohemorrhagic Escherichia coli (EHEC) is the major cause of hemolyticuremic syndrome (HUS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. EHEC produces one or more Shiga toxins (Stx1 and Stx2), and it was assumed that Stx's only relevant biologic activity was cell destruction through inhibition of protein synthesis. However, recent data indicate that in vivo the cytokine milieu may determine whether endothelial cells survive or undergo apoptosis/necrosis when exposed to Stxs. In this study, we analyzed the genome-wide expression patterns of human endothelial cells stimulated with subinhibitory concentrations of Stxs in order to characterize the genomic expression program involved in the vascular pathology of HUS. We found that Stxs elicited few, but reproducible, changes in gene expression. The majority of genes reported in this study encodes for chemokines and cytokines, which might contribute to the multifaceted inflammatory response of host endothelial cells observed in patients suffering from EHEC disease. In addition, our data provide for the first time molecular insights into the epidemiologically well-established higher pathogenicity of Stx2 over Stx1.
CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma
Authors: Robillard Nelly , Avet-Loiseau Hervé , Garand Richard , Moreau Philippe , Pineau Danielle , Rapp Marie-Josée , Harousseau Jean-Luc , Bataille Régis 
Published: April 2003

Abstract
CD20 has been reinvestigated in 66 patients with multiple myeloma (MM). Twelve of the patients (18%) expressed CD20, including 5 of 50 patients at diagnosis presenting 100% CD20+ cells. Seven (58%) of 12 CD20+ patients with MM had a small mature plasma cell morphology as opposed to 4 (7%) of 54 with CD20- MM (P = .0001). Of note, 10 (83%) of 12 patients with CD20+ MM had t(11;14) as opposed to 5 of 54 (9%) CD20- patients (P &lt; .001). All the patients with 100% CD20+ cells presented with t(11;14) and 4 of 5 with a small mature plasma cell morphology. Thus, 66% of the patients with t(11;14) expressed CD20, whereas only 4% of the 51 patients lacking such translocation expressed CD20 (P &lt; .0001). In conclusion, CD20 expression is associated with small mature plasma cell morphology and with t(11;14) in patients with MM.
Survival of acute myeloid leukemia cells requires PI3 kinase activation
Authors: Xu Qing , Simpson Serge-Emile , Scialla Timothy J. , Bagg Adam , Carroll Martin 
Published: April 2003

AbstractThe mechanisms that regulate the growth and survival of acute myeloid leukemia (AML) cells are largely unknown. We hypothesized that constitutive activation of phosphatidyl-inositide 3 kinase (PI3 kinase) could regulate survival in primary cells from patients with AML. Here we demonstrate that Akt, a critical substrate of PI3 kinase, is activated in AML blasts. In a short-term culture system, most AML patient samples showed a dose-dependent decrease in survival after incubation with the PI3 kinase inhibitor LY294002. This decrease in survival was partially due to the induction of apoptosis. Furthermore, we have shown that p70 S6 kinase and 4EBP-1, downstream mediators of Akt signaling, also are phosphorylated in AML blasts. Phosphorylation of these proteins is inhibited by the mTOR inhibitor RAD001. Incubation of AML blasts with RAD001 induces only a small decrease in survival of the cells; however, when combined with Ara-C, RAD001 enhances the toxicity of Ara-C. These results demonstrate that constitutive activation of the PI3 kinase pathway is necessary for the survival of AML blasts and that targeting of this pathway with pharmacologic inhibitors may be of clinical benefit in treatment of AML.
Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization
Authors: Heeschen Christopher , Aicher Alexandra , Lehmann Ralf , Fichtlscherer Stephan , Vasa Mariuca , Urbich Carmen , Mildner-Rihm Christiane , Martin Hans , Zeiher Andreas M. , Dimmeler Stefanie 
Published: April 2003

AbstractIncreasing evidence suggests that postnatal neovascularization involves the recruitment of circulating endothelial progenitor cells (EPCs). Hematopoietic and endothelial cell lineages share common progenitors. Cytokines formerly thought to be specific for the hematopoietic system have only recently been shown to affect several functions in endothelial cells. Accordingly, we investigated the stimulatory potential of erythropoietin (Epo) on EPC mobilization and neovascularization. The bone marrow of Epo-treated mice showed a significant increase in number and proliferation of stem and progenitor cells as well as in colony-forming units. The number of isolated EPCs and CD34+/flk-1+ precursor cells was significantly increased in spleen and peripheral blood of Epo-treated mice compared with phosphate-buffered saline–treated mice. In in vivo models of postnatal neovascularization, Epo significantly increased inflammation- and ischemia-induced neovascularization. The physiologic relevance of these findings was investigated in patients with coronary heart disease. In a multivariate regression model, serum levels of Epo and vascular endothelial growth factor were significantly associated with the number of stem and progenitor cells in the bone marrow as well as with the number and function of circulating EPCs. In conclusion, the present study suggests that Epo stimulates postnatal neovascularization at least in part by enhancing EPC mobilization from the bone marrow. Epo appears to physiologically regulate EPC mobilization in patients with ischemic heart disease. Thus, Epo serum levels may help in identifying patients with impaired EPC recruitment capacity.
Plasminogen activator inhibitor type–1 deficiency does not influence the outcome of murine pneumococcal pneumonia
Authors: Rijneveld Anita W. , Florquin Sandrine , Bresser Paul , Levi Marcel , de Waard Vivian , Lijnen Roger , Van der Zee Jaring S. , Speelman Peter , Carmeliet Peter , van der Poll Tom 
Published: April 2003

AbstractUrokinase-type plasminogen activator (uPA) and its receptor uPAR are components of the fibrinolytic system and are important for an adequate immune response to respiratory tract infection, in part through their role in the migration of inflammatory cells. PA inhibitor–1 (PAI-1) is the predominant inhibitor of soluble and receptor-bound uPA. To determine the role of PAI-1 in host defense against pneumococcal pneumonia, the following studies were performed: (1) Patients with unilateral community-acquired pneumonia demonstrated elevated PAI-1 concentrations together with decreased PA activity in bronchoalveolar lavage fluid (BALF) obtained from the infected, but not from the contralateral, site. (2) Mice with Streptococcus pneumoniae pneumonia displayed elevated PAI-1 protein and mRNA levels in their lungs. (3) PAI-1 gene–deficient mice, however, had an unaltered immune response to pneumococcal pneumonia, as measured by cell recruitment into lungs, bacterial outgrowth, and survival. Furthermore, plasminogen-gene–deficient mice also had an unremarkable defense against pneumococcal pneumonia. These data indicate that pneumonia is associated with inhibition of the fibrinolytic system at the site of the infection secondary to increased production of PAI-1; an intact fibrinolytic response is not required for an adequate host response to respiratory tract infection, however, suggesting that the previously described role of uPA and uPAR are restricted to their function in cell migration.
Changes in the lymph node microenvironment induced by oncostatin M
Authors: Louis Isabelle , Dulude Gaël , Corneau Sophie , Brochu Sylvie , Boileau Catherine , Meunier Caroline , Côté Caroline , Labrecque Nathalie , Perreault Claude 
Published: April 2003

AbstractOncostatin M (OM) transforms the lymph node (LN) into a “super lymphoid organ” with 2 striking features: massive thymus-independent T-cell development and major expansion of the memory T-cell pool. We report that T-cell development in the LckOM LN is regulated by a cyclooxygenase-2 (COX-2)–dependent neoangiogenesis involving high endothelial venules (HEVs). That LN HEVs are particularlyrich in OM-receptor β-chain provides aplausible explanation for the fact that extrathymic T-cell development in LckOM mice is limited to the LN. Moreover, we found that increased production of the CCL20 chemokine by LN stromal cells was instrumental in the expansion of the memory phenotype CD4 T-cell pool in LckOM mice. The generality of the latter finding was demonstrated by the fact that CCL20/CCR6 interactions increase the basal proliferation rate of CD62Llo CD4 T cells irrespective of their thymic (in non–OM-transgenic mice) or extrathymic (in LckOM mice) origin. To our knowledge, CCL20 is the first molecule found to increase the proliferation of memory phenotype CD4 T cells. These findings identify potential targets for the creation of thymic substitutes (LN HEVs) and for expansion of the CD4 memory T-cell compartment (CCL20).
Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells
Authors: Chadwick Kristin , Wang Lisheng , Li Li , Menendez Pablo , Murdoch Barbara , Rouleau Anne , Bhatia Mickie 
Published: April 2003

AbstractHuman embryonic stem cells (hESCs) randomly differentiate into multiple cell types during embryoid body (EB) development. To date, characterization of specific factors capable of influencing hematopoietic cell fate from hESCs remains elusive. Here, we report that the treatment of hESCs during EB development with a combination of cytokines and bone morphogenetic protein-4 (BMP-4), a ventral mesoderm inducer, strongly promotes hematopoietic differentiation. Hematopoietic progenitors of multiple lineages were generated from EBs and were found to be restricted to the population of progeny expressing cell surface CD45. Addition of BMP-4 had no statistically significant effect on hematopoietic differentiation but enabled significant enhancement in progenitor self-renewal, independent of cytokine treatment. Hematopoietic commitment was characterized as the temporal emergence of single CD45+ cells first detectable after day 10 of culture and was accompanied by expression of hematopoietic transcription factors. Despite the removal of cytokines at day 10, hematopoietic differentiation of hESCs continued, suggesting that cytokines act on hematopoietic precursors as opposed to differentiated hematopoietic cells. Our study establishes the first evidence for the role of cytokines and BMP-4 in promoting hematopoietic differentiation of hESC lines and provides an unprecedented system to study early developmental events that govern the initiation of hematopoiesis in the human.
Anisotropic inversion of seismic data for stressed media: Theory and a physical modeling study on Berea Sandstone
Authors: Sarkar Debashish , Bakulin Andrey , Kranz Robert L. 
Published: April 2003

Nonhydrostatic stress, an often‐ignored source of seismic anisotropy, is universally present in the subsurface and may be as common as intrinsic or fracture‐induced anisotropy. Nonhydrostatic stress, applied to an initially transversely isotropic solid with vertical symmetry axis (VTI), results in an effective medium having almost orthorhombic symmetry (provided that one of the principal stresses is aligned with the symmetry axis). The symmetry planes observed in this orthorhombic medium are aligned with the orientations of the principal stresses, and anisotropic parameters (ε(1,2), δ(1,2,3), and γ(1,2)) can reveal information about the stress magnitudes. Thus, time‐lapse monitoring of changes in anisotropy potentially can provide information on temporal variations in the stress field.We use nonlinear elasticity theory to relate the anisotropic parameters to the magnitudes of the principal stresses and verify these relationships in a physical modeling study. Under the assumption of weak background and stress‐induced anisotropy, each effective anisotropic parameter reduces to the sum of the corresponding Thomsen parameter for the unstressed VTI background and the corresponding parameter associated with the nonhydrostatic stress. The stress‐related anisotropic parameters depend only on the differences between the magnitudes of principal stresses; therefore, principal stresses can influence anisotropic parameters only if their magnitudes differ in the symmetry plane in which the anisotropic parameters are defined.We test these predictions on a physical modeling data set acquired on a block of Berea Sandstone exhibiting intrinsic VTI anisotropy. Uniaxial stress, applied normal to the VTI symmetry axis, i.e., horizontally, produces an effective medium that is close to orthorhombic. We use two different methods to estimate the anisotropic parameters and study their variation as a function of stress. The first method utilizes conventional measurements of transmission velocities along the principal axes of the sample. The second method uses PP and PS reflection data acquired along seven different azimuths on the surface of the block.In accordance with theoretical predictions, the anisotropic parameters in the vertical plane normal to the stress are almost insensitive to the magnitude of the stress. In contrast, anisotropic parameters in the vertical plane of the applied stress increase approximately in a linear fashion with increasing stress. Except for the parameter δ(1), comparison of the measured values of anisotropic parameters with theoretical predictions shows satisfactory agreement.Despite some documented discrepancies, we believe that nonlinear elasticity may provide a suitable framework for estimating pore pressure and 3D stresses from seismic data.
Human Type 3 3α-Hydroxysteroid Dehydrogenase (Aldo-Keto Reductase 1C2) and Androgen Metabolism in Prostate Cells
Authors: Rižner Tea Lanišnik , Lin Hsueh K. , Peehl Donna M. , Steckelbroeck Stephan , Bauman David R. , Penning Trevor M. 
Published: April 2003

AbstractHuman aldo-keto reductases (AKRs) of the AKR1C subfamily function in vitro as 3-keto-, 17-keto-, and 20-ketosteroid reductases or as 3α-, 17β-, and 20α-hydroxysteroid oxidases. These AKRs can convert potent sex hormones (androgens, estrogens, and progestins) into their cognate inactive metabolites or vice versa. By controlling local ligand concentration AKRs may regulate steroid hormone action at the prereceptor level. AKR1C2 is expressed in prostate, and in vitro it will catalyze the nicotinamide adenine dinucleotide (NAD+)-dependent oxidation of 3α-androstanediol (3α-diol) to 5α-dihydrotestosterone (5α-DHT). This reaction is potently inhibited by reduced NAD phosphate (NADPH), indicating that the NAD+: NADPH ratio in cells will determine whether AKR1C2 makes 5α-DHT. In transient COS-1-AKR1C2 and in stable PC-3-AKR1C2 transfectants, 5α-DHT was reduced by AKR1C2. However, the transfected AKR1C2 oxidase activity was insufficient to surmount the endogenous 17β-hydroxysteroid dehydrogenase (17β-HSD) activity, which eliminated 3α-diol as androsterone. PC-3 cells expressed retinol dehydrogenase/3α-HSD and 11-cis-retinol dehydrogenase, but these endogenous enzymes did not oxidize 3α-diol to 5α-DHT. In stable LNCaP-AKR1C2 transfectants, AKR1C2 did not alter androgen metabolism due to a high rate of glucuronidation. In primary cultures of epithelial cells, high levels of AKR1C2 transcripts were detected in prostate cancer, but not in cells from normal prostate. Thus, in prostate cells AKR1C2 acts as a 3-ketosteroid reductase to eliminate 5α-DHT and prevents activation of the androgen receptor. AKR1C2 does not act as an oxidase due to either potent product inhibition by NADPH or because it cannot surmount the oxidative 17β-HSD present. Neither AKR1C2, retinol dehydrogenase/3α-HSD nor 11-cis-retinol dehydrogenase is a source of 5α-DHT in PC-3 cells.