bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyaluronan is synthesized by primitive hemopoietic cells, participates in their lodgment at the endosteum following transplantation, and is involved in the regulation of their proliferation and differentiation in vitro
Authors: Nilsson Susan K. , Haylock David N. , Johnston Hayley M. , Occhiodoro Teresa , Brown Tracey J. , Simmons Paul J. 
Published: January 2003

AbstractThe localization of adult hemopoiesis to the marrow involves developmentally regulated interactions between hemopoietic stem cells and the stromal cell–mediated hemopoietic microenvironment. Although primitive hemopoietic cells exhibit a broad repertoire of adhesion molecules, little is known about the molecules influencing the site of cell lodgment within the marrow following transplantation. However, our recent studies indicate that hierarchically dependent patterns of migration of transplanted hemopoietic cells result in the retention of primitive cells within the endosteal and lineage-committed cells in the central marrow regions. Herein, we now demonstrate that these 2 subpopulations exhibit a striking difference in the expression of a cell surface adhesion molecule, with populations enriched for murine and human hemopoietic stem cells expressing the carbohydrate hyaluronic acid (HA). Furthermore, the presence of this glycosaminoglycan appears critical for the spatial distribution of transplanted stem cells in vivo. In addition, we also demonstrate that the binding of HA by a surrogate ligand results in marked inhibition of primitive hemopoietic cell proliferation and granulocyte differentiation. Collectively, these data describe an important yet previously unrecognized role for HA in the biology of primitive hemopoietic progenitor cells.
Nocturnal oxygen saturation and painful sickle cell crises in children
Authors: Hargrave Darren R. , Wade Angie , Evans Jane P. M. , Hewes Deborah K. M. , Kirkham Fenella J. 
Published: January 2003

Abstract
The pathogenesis of acute painful crisis in children with sickle cell disease is poorly understood; suggested risk factors include sickle cell type, severity of anemia, fetal hemoglobin concentration, and hypoxemia from upper airway obstruction. In a cohort study of 95 patients the relationship between clinical, laboratory, and sleep study data and frequency of painful crisis was investigated. Both univariate and multiple regression modeling showed that low nocturnal oxygen saturation was highly significantly associated with a higher rate of painful crisis in childhood (P < .0001). Screening and treatment for hypoxemia may reduce the frequency of this and other complications of the disease.
Chemoattractant receptor–stimulated F-actin polymerization in the human neutrophil is signaled by 2 distinct pathways
Authors: Chodniewicz David , Zhelev Doncho V. 
Published: January 2003

AbstractWe characterized the overall rate of F-actin polymerization in the pseudopod region by measuring the rate of extension of single pseudopods stimulated by f-Met-Leu-Phe. The rate of pseudopod extension was measured in the presence of inhibitors for signaling molecules that are known to be involved in motility. Our data show the existence of 2 distinct signaling pathways of actin polymerization in the pseudopod region: a phosphoinositide 3-kinase γ (PI3Kγ)–dependent and –independent pathway. The PI3Kγ dependent signaling of F-actin polymerization also depends on protein kinase C ζ and protein kinase B (Akt/PKB). The PI3Kγ-independent pathway depends on GTPase RhoA, the RhoA ROCK kinase, Src family tyrosine kinases, and NADPH, and is modulated by cAMP.
Cancer incidence in persons with Fanconi anemia
Authors: Rosenberg Philip S. , Greene Mark H. , Alter Blanche P. 
Published: January 2003

Abstract
Fanconi anemia (FA) is an autosomal recessive condition associated with congenital abnormalities, progressive pancytopenia, and a predisposition to leukemia and solid tumors. We studied a retrospective cohort of North American patients with FA. We calculated relative risks of cancer compared to the general population and cause-specific hazards of the first major adverse outcomes of FA: bone marrow transplantation (BMT) for marrow complications, acute myeloid leukemia (AML), solid tumors, or death from bone marrow failure. We also estimated the cumulative incidence of each adverse event in the presence of the competing risks. Among 145 patients with FA, 9 developed leukemia and 14 developed a total of 18 solid tumors. The ratio of observed to expected cancers (O/E ratio) was 50 for all cancers, 48 for all solid tumors, and 785 for leukemia; these increased risks were statistically significant. The highest solid tumor O/E ratios were 4317 for vulvar cancer, 2362 for esophageal cancer, and 706 for head and neck cancer. Cause-specific hazards of both death and AML peaked at 1%/y in teenage years; the hazard of BMT peaked at 4%/y at age 7. In contrast, the hazard of a solid tumor approached 8%/y by age 40 years. The cumulative incidence to age 48 was 10% for leukemia, 11% for death from marrow failure, 29% for a solid tumor, and 43% for BMT. The risk of a solid tumor may become even higher as death from aplastic anemia is reduced and as patients survive longer after BMT.
Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: up-regulation of cIAP2 by granulocyte colony-stimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia
Authors: Hasegawa Taro , Suzuki Kenichi , Sakamoto Chikahiko , Ohta Kensuke , Nishiki Saori , Hino Masayuki , Tatsumi Noriyuki , Kitagawa Seiichi 
Published: January 2003

AbstractHuman neutrophils were found to express members of the inhibitor of apoptosis (IAP) family, namely cellular IAP1 (cIAP1), cIAP2, and X-linked IAP. Among these members, cIAP2 expression was selectively up-regulated by stimulation with granulocyte colony-stimulating factor (G-CSF), but not with granulocyte-macrophage CSF. The increased expression of cIAP2 mRNA was detected as early as 30 minutes after in vitro stimulation with G-CSF, and the elevated level of cIAP2 protein was detected at 1 hour. The elevated level of cIAP2 protein was also detected in peripheral blood neutrophils obtained from healthy donors receiving G-CSF administration. G-CSF–induced up-regulation of cIAP2 mRNA and protein, phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the antiapoptotic effects were inhibited by pretreatment of cells with AG490, a specific inhibitor of Janus kinase 2 (JAK2). Mature neutrophils from a patient with chronic neutrophilic leukemia exhibited remarkable overexpression of cIAP2 mRNA and prolongation of survival, whereas cIAP2 mRNA expression and survival in mature neutrophils from patients with chronic myelogenous leukemia were essentially similar to those in normal neutrophils. These findings suggest that cIAP2 expression is up-regulated by G-CSF through activation of the JAK2-STAT3 pathway, and increased expression of cIAP2 protein may contribute to G-CSF–mediated antiapoptosis. In addition, overexpression of cIAP2 may be partly responsible for sustained neutrophilia at least in some cases of chronic neutrophilic leukemia.
Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival
Authors: Astier Anne Laurence , Xu Ronghui , Svoboda Marek , Hinds Esther , Munoz Olivier , de Beaumont Rosalie , Crean Colin Daniel , Gabig Theodore , Freedman Arnold Stephen 
Published: January 2003

AbstractThe physical interactions between B cells and stromal cells from the lymphoid tissue microenvironment are critical to the survival of normal and malignant B cells. They are principally mediated by integrins expressed on B cells and counterreceptors on stromal cells. Specifically, α4β1 integrin engagement rescues B cells from physiological or drug-induced apoptosis. Therefore, in order to understand the mechanisms by which integrins prevent apoptosis in leukemia B cells, we compared the temporal gene expression profiles induced by β1-integrin ligation with fibronectin (Fn) or adhesion by poly-L-Lysine in serum-starved precursor B leukemia cells. Among the 38 selected differentially expressed genes, 6 genes involved in adhesion (VAV2, EPB41L1, CORO1A), proliferation (FRAP1, CCT4), and intercellular communication (GJB3) were validated by real-time quantitative polymerase chain reaction (RT-Q-PCR). Gene expression modulation could also be validated at the protein level for 5 other genes. We show that integrin stimulation up-regulated FBI-1 expression but inhibited CD79a, Requiem, c-Fos, and caspase 7 induction when the cells underwent apoptosis. We further demonstrate that Fn stimulation also inhibits caspase 3 activation but increases XIAP and survivin expression. Moreover, integrin stimulation also prevents caspase activation induced by doxorubicin. Therefore, we identified genes modulated by adhesion of human precursor B leukemia cells that regulate proliferation and apoptosis, highlighting new pathways that might provide insights into future therapy aiming at targeting apoptosis of leukemia cells.
Expression of B-cell–attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma
Authors: Smith Justine R. , Braziel Rita M. , Paoletti Samantha , Lipp Martin , Uguccioni Mariagrazia , Rosenbaum James T. 
Published: January 2003

AbstractPrimary central nervous system lymphoma (PCNSL) is a rare but often rapidly fatal form of non-Hodgkin B-cell lymphoma that arises within the central nervous system (CNS) and has a low propensity to metastasize. We performed immunohistochemistry on formalin-fixed, paraffin-embedded brain biopsy specimens from 24 patients with PCNSL to investigate the expression of B cell–attracting chemokine 1 (BCA-1, CXCL13), a lymphoid chemokine involved in B-cell compartmental homing within secondary lymphoid organs and recently implicated in the pathogenesis of inflammatory and malignant lymphocyte-mediated diseases. Whereas BCA-1 was not detected in normal human brain, all 24 brain biopsy specimens containing PCNSL were positive for BCA-1. Double immunostaining on selected specimens localized BCA-1 to malignant B lymphocytes and vascular endothelium. In contrast, 2 chemokines implicated particularly in T-cell movement, secondary lymphoid tissue chemokine (SLC, CCL21) and Epstein-Barr virus–induced molecule 1 ligand chemokine (ELC, CCL19), were expressed only by occasional stromal cells in 2 and 4 of the 24 specimens, respectively. Tumor cells stained positively for CXCR5, the primary receptor for BCA-1. In situ hybridization verified the expression of BCA-1 mRNA by malignant B cells, but not vascular endothelium, within the tumor mass, suggesting that vascular endothelial BCA-1 expression may be consequent to transcytosis. In PCNSL, expression of BCA-1 by malignant lymphocytes and vascular endothelium may influence tumor development and localization to CNS.
Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases
Authors: Christopherson Kent W. , Hood Antoinette F. , Travers Jeffrey B. , Ramsey Heather , Hromas Robert A. 
Published: January 2003

AbstractThe signals that mediate T-cell infiltration during T-cell autoimmune diseases are poorly understood. The chemokine CCL21 (originally isolated by us and others as Exodus-2/6Ckine/SLC/TCA4) is highly potent and highly specific for stimulating T-cell migration. However, it is thought to be expressed only in secondary lymphoid organs, directing naive T cells to areas of antigen presentation. It is not thought to play a role in T-cell effector function during a normal immune response. In this study we tested the expression of T-cell chemokines and their receptors during T-cell autoimmune infiltrative skin diseases. By using immunohistology it was found that the expression of CCL21 but not CCL19 or 20 was highly induced in endothelial cells of T-cell autoimmune diseases. The receptor for CCL21, CCR7, was also found to be highly expressed on the infiltrating T cells, most of which expressed the memory CD45Ro phenotype. These data imply that the usual loss of CCL21 responsiveness in the normal development of memory T-cell effector function does not hold for autoimmune skin diseases.
cAMP inhibits both Ras and Rap1 activation in primary human T lymphocytes, but only Ras inhibition correlates with blockade of cell cycle progression
Authors: Grader-Beck Thomas , van Puijenbroek Andre A. F. L. , Nadler Lee M. , Boussiotis Vassiliki A. 
Published: January 2003

AbstractCyclic adenosine monophosphate (cAMP) is a negative regulator of T-cell activation. However, the effects of cAMP on signaling pathways that regulate cytokine production and cell cycle progression remain unclear. Here, using primary human T lymphocytes in which endogenous cAMP was increased by the use of forskolin and 3-isobutyl-1-methylxanthine (IBMX), we show that increase of cAMP resulted in inhibition of T-cell receptor (TCR)/CD3 plus CD28–mediated T-cell activation and cytokine production and blockade of cell cycle progression at the G1 phase. Increase of cAMP inhibited Ras activation and phosphorylation of mitogen-induced extracellular kinase (MEK) downstream targets extracellular signal–related kinase 1/2 (ERK1/2) and phosphatidylinositol-3-kinase (PI3K) downstream target protein kinase B (PKB; c-Akt). These functional and biochemical events were secondary to the impaired activation of ZAP-70 and phosphorylation of LAT and did not occur when cells were stimulated with phorbol ester, which bypasses the TCR proximal signaling events and activates Ras. Increase of cAMP also inhibited activation of Rap1 mediated by TCR/CD3 plus CD28. Importantly, inhibition of Rap1 activation by cAMP was also observed when cells were stimulated with phorbol ester, although under these conditions Ras was activated and cells progressed into the cell cycle. Thus, TCR plus CD28–mediated activation of ERK1/2 and PKB, cytokine production, and cell cycle progression, all of which are inhibited by cAMP, require activation of Ras but not Rap1. These results indicate that signals that regulate cAMP levels after encounter of T cells by antigen will likely determine the functional fate toward clonal expansion or repression of primary T-cell responses.
Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes
Authors: Kietzmann Thomas , Samoylenko Anatoly , Roth Ulrike , Jungermann Kurt 
Published: January 2003

AbstractThe expression of the plasminogen activator inhibitor-1(PAI-1) gene is enhanced by insulin both in vivo and in various cell types. Because insulin exerts a number of its biologic activities via the phosphatidylinositol 3-kinase and protein kinase B (PI3K/PKB) signaling pathway, it was the aim of the present study to investigate the role of the PI3K/PKB pathway in the expression of the PAI-1 gene and to identify the insulin responsive promoter sequences. It was shown that the induction of PAI-1 mRNA and protein expression by insulin and mild hypoxia could be repressed by the PI3K inhibitor wortmannin. Overexpression of a constitutively active PKB led to induction of PAI-1 mRNA expression and of luciferase (Luc) activity from a gene construct containing 766 bp of the rat PAI-1 promoter. Mutation of the hypoxia response elements (HRE-1 and HRE-2) in rat PAI-1 promoter, which could bind hypoxia inducible factor-1 (HIF-1), abolished the induction of PAI-1 by insulin and PKB. Insulin and the constitutive active PKB also induced Luc expression in cells transfected with the pGl3EPO-HRE Luc construct, containing 3 copies of the HRE from the erythropoietin gene in front of the SV40 promoter. Furthermore, insulin and the active PKB enhanced all 3 HIF α-subunit protein levels and HIF-1 DNA-binding activity, as shown by electrophoretic mobility shift assays (EMSAs). Thus, the insulin-dependent activation of the PAI-1 gene expression can be mediated via the PI3K/PKB pathway and the transcription factor HIF-1 binding to the HREs in the PAI-1 gene promoter.
Circulating peripheral blood plasma cells as a prognostic indicator in patients with primary systemic amyloidosis
Authors: Pardanani Animesh , Witzig Thomas E. , Schroeder Georgene , McElroy Edwin A. , Fonseca Rafael , Dispenzieri Angela , Lacy Martha Q. , Lust John A. , Kyle Robert A. , Greipp Philip R. , Gertz Morie A. , Rajkumar S. Vincent 
Published: January 2003

Abstract
This study examined the prognostic value of circulating peripheral blood plasma cells (PBPCs) in patients with primary systemic amyloidosis (AL). A sensitive slide-based immunofluorescence technique was used to assess 147 patients for circulating PBPCs. Circulating monoclonal plasma cells were quantified as a percentage of circulating cytoplasmic immunoglobulin-positive cells (PBPC%). The absolute circulating plasma cell count was also determined. When analyzed retrospectively, 24 (16%) of 147 patients were found to have detectable circulating PBPCs. Overall survival for patients with high PBPC%'s (> 1%) was poorer (median survival, 10 vs 29 months;P = .002). Similarly, overall survival for patients with high PBPC counts (> 0.5 × 106/L) was significantly poorer (median, 13 vs 31 months;P = .003). Increased percentages of bone marrow plasma cells (BMPC%; P = .0004), increased levels of serum β2-microglobulin (P = .04), and dominant cardiac amyloid involvement (P = .03) also predicted poorer survival. The combined consideration of circulating PBPCs and BMPC% identified low-, intermediate-, and high-risk groups with median survivals of 37.5, 15.5, and 10 months, respectively (P = .0003). Multivariate analysis revealed circulating PBPCs and BMPC% to be independent prognostic factors for survival. Patients with PBPC%'s of 2% or higher were significantly more likely to have a coexisting clinical diagnosis of multiple myeloma (50% vs 12%, P = .008). The prognostic value of circulating PBPCs may help select treatment for patients with AL.
Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development
Authors: Zhan Fenghuang , Tian Erming , Bumm Klaus , Smith Ruston , Barlogie Bart , Shaughnessy John 
Published: January 2003

AbstractTo identify genes linked to normal plasma cell (PC) differentiation and to classify multiple myeloma (MM) with respect to the expression patterns of these genes, we analyzed global mRNA expression in CD19-enriched B cells (BCs) from 7 tonsils, CD138-enriched PCs from 11 tonsils, 31 normal bone marrow samples, and 74 MM bone marrow samples using microarrays interrogating 6800 genes. Hierarchical clustering analyses with 3288 genes clearly segregated the 4 cell types, and chi-square and Wilcoxin rank sum tests (P < .0005) identified 359 and 500 previously defined and novel genes that distinguish tonsil BCs from tonsil PCs (early differentiation genes [EDGs]), and tonsil PCs from bone marrow PCs (late differentiation genes [LDGs]), respectively. MM as a whole was found to have dramatically variable expression of EDGs and LDGs, and one-way analysis of variance (ANOVA) was used to identify the most variable EDGs (vEDGs) and LDGs (v1LDG and v2LDG). Hierarchical cluster analysis with these genes revealed that previously defined MM gene expression subgroups (MM1-MM4) could be linked to one of the 3 normal cell types. Clustering with 30 vEDGs revealed that 13 of 18 MM4 cases clustered with tonsil BCs (P = .000 05), whereas 14 of 15 MM3 cases clustered with tonsil PCs when using 50 v1LDG (P = .000 008), and 14 of 20 MM2 cases clustered with bone marrow PCs when using 50 v2LDG (P = .000 09). MM1 showed no significant linkage with normal cell types studied. Thus, genes whose expression is linked to distinct transitions in late-stage B-cell differentiation can be used to classify MM.
Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts
Authors: Cragg Mark S. , Morgan Suzanne M. , Chan H. T. Claude , Morgan B. Paul , Filatov A. V. , Johnson Peter W. M. , French Ruth R. , Glennie Martin J. 
Published: January 2003

AbstractDespite the clinical success of anti-CD20 monoclonal antibody (mAb) in the treatment of lymphoma, there remains considerable uncertainty about its mechanism of action. Here we show that the ability of mAbs to translocate CD20 into low-density, detergent-insoluble membrane rafts appears to control how effectively they mediate complement lysis of lymphoma cells. In vitro studies using a panel of anti–B-cell mAbs revealed that the anti-CD20 mAbs, with one exception (B1), are unusually effective at recruiting human complement. Differences in complement recruitment could not be explained by the level of mAb binding or isotype but did correlate with the redistribution of CD20 in the cell membrane following mAb ligation. Membrane fractionation confirmed that B1, unlike 1F5 and rituximab, was unable to translocate CD20 into lipid rafts. In addition, we were able to drive B1 and a range of other anti–B-cell mAbs into a detergent-insoluble fraction of the cell by hyper–cross-linking with an F(ab′)2 anti-Ig Ab, a treatment that also conferred the ability to activate lytic complement. Thus, we have shown that an important mAb effector function appears to be controlled by movement of the target molecule into membrane rafts, either because a raft location favors complement activation by mAbs or because rafts are more sensitive to complement penetration.
Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors
Authors: Tehranchi Ramin , Fadeel Bengt , Forsblom Ann-Mari , Christensson Birger , Samuelsson Jan , Zhivotovsky Boris , Hellstrom-Lindberg Eva 
Published: January 2003

Abstract
Low-risk myelodysplastic syndromes (MDS), including refractory anemia and sideroblastic anemia, are characterized by increased apoptotic death of erythroid progenitors. The signaling pathways that elicit this pathologic cell death in MDS have, however, remained unclear. Treatment with erythropoietin in combination with granulocyte colony-stimulating factor (G-CSF) may synergistically improve the anemia in patients with MDS, with a concomitant decrease in the number of apoptotic bone marrow precursors. Moreover, we have previously reported that G-CSF inhibits Fas-induced caspase activation in sideroblastic anemia (RARS). The present data demonstrate that almost 50% of erythroid progenitor cells derived from patients with MDS exhibit spontaneous release of cytochrome c from mitochondria with ensuing activation of caspase-9, whereas normal erythroid progenitors display neither of these features. G-CSF significantly inhibited cytochrome c release and suppressed apoptosis, most noticeably in cells from patients with sideroblastic anemia. Furthermore, inhibition of caspase-9 suppressed both spontaneous and Fas-mediated apoptosis of erythroid progenitors in all low-risk MDS cases studied. We propose that the increased sensitivity of MDS progenitor cells to death receptor stimulation is due to a constitutive activation of the mitochondrial axis of the apoptotic signaling pathway in these cells. These studies yield a mechanistic explanation for the beneficial clinical effects of growth factor administration in patients with MDS, and provide a model for the study of growth factor–mediated suppression of apoptosis in other bone marrow disorders.