bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells
Authors: Takeya Hiroyuki , Gabazza Esteban C. , Aoki Shinya , Ueno Hikaru , Suzuki Koji 
Published: May 2003

AbstractSphingosine 1-phosphate (S1P), a bioactive lipid, is produced and stored in platelets and is released from activated platelets during blood coagulation activation. Thrombin, which is also generated during blood coagulation, has been shown to induce tissue factor (TF), the initiator of blood coagulation, in endothelial cells (ECs); however, the effect of S1P on this process is not evaluated. Here we demonstrated that S1P strongly potentiated thrombin-induced TF expression in ECs and that S1P itself did not induce TF expression. Among signaling lipids, platelet-activating factor slightly enhanced thrombin-induced TF expression; other lipids, including lysophosphatidic acid, lysophosphatidylcholine, sphingosine, and C2-ceramide exert no effect on TF expression. S1P enhanced TF expression at the transcriptional level, possibly via promoting the activation of transcription factors nuclear factor–κB (NF-κB) and Egr-1. Thrombin weakly and S1P strongly activated extracellular signal–regulated kinase 1/2 (ERK1/2) mitogen-activated protein (MAP) kinase and, in the presence of both stimulants, enhanced and sustained activation of this kinase was observed. The ERK1/2-specific inhibitor PD98059 significantly inhibited enhanced TF expression induced by both stimulants but only weakly inhibited thrombin-induced TF expression, thus indicating the requirement of the ERK1/2 pathway in synergistic induction of TF expression. In addition, we found that thrombin and S1P rapidly up-regulated the expression of S1P receptors, endothelial differentiation gene-1 (EDG-1) and EDG-3, thereby suggesting that the effect of S1P on TF expression and other EC functions may be enhanced by thrombin and S1P itself. The present data reveal the synergistic effect of S1P on thrombin-induced TF expression in ECs, which may promote further thrombin and S1P generation, thus propagating a positive feedback reaction.
Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3
Authors: Teixeira Christine , Stang Stacey L. , Zheng Yong , Beswick Naomi S. , Stone James C. 
Published: May 2003

AbstractMembers of the RasGRP family of Ras activators have C1 domains that bind diacylglycerol (DAG) and DAG analogs such as the tumor-promoting phorbol esters. RasGRP members could be responsible for some of the DAG signaling processes that have previously been attributed to protein kinase C (PKC). We found that RasGRP3 is selectively expressed in B cells, suggesting that RasGRP3 might function downstream of the B-cell receptor (BCR). Indeed, stimulation of Ramos B cells with the DAG analog phorbol ester myristate (PMA) results in the association of RasGRP3 with the membrane fraction. However, we also made the unexpected observation that RasGRP3 is phosphorylated, coincident with Ras activation after stimulation. When inhibitors of PKC are present, Ras activation is attenuated, and this attenuation correlates with an inhibition of RasGRP3 phosphorylation. RasGRP3 is phosphorylated in vitro by PKC-θ and PKC-β2. When ectopically coexpressed in HEK-293 cells, a dominant-activated mutant of PKC-θ phosphorylates RasGRP3 and enhances Ras-Erk signaling. These results provide the first indication for a functional interaction between a RasGRP family member and a dissimilar DAG binding protein. A convergent DAG signaling system could be important in fine-tuning Ras signaling during B-cell development or during the humoral immune response.
Microsatellite polymorphism in heme oxygenase-1 gene promoter is associated with susceptibility to oxidant-induced apoptosis in lymphoblastoid cell lines
Authors: Hirai Hisao , Kubo Hiroshi , Yamaya Mutsuo , Nakayama Katsutoshi , Numasaki Muneo , Kobayashi Seiichi , Suzuki Satoshi , Shibahara Shigeki , Sasaki Hidetada 
Published: May 2003

AbstractHeme oxygenase-1 (HO-1) confers cytoprotection against oxidative stress. A (GT)n dinucleotide repeat in the 5′-flanking region of human HO-1 gene shows length polymorphism, which was classified into S (&lt; 27 GT), M (27-32 GT), and L alleles (≥ 33 GT). Polymorphism in the HO-1 gene promoter was shown to be associated with susceptibility to pulmonary emphysema and restenosis after angioplasty. However, the biologic mechanism underlying these associations is still unclear. To examine this issue, we established lymphoblastoid cell lines (LCLs) from subjects possessing S/S or L/L genotypes. HO-1 mRNA expressions and HO activities induced by oxidative stress were significantly higher in LCLs with S/S than those with L/L. Furthermore, LCLs with S/S were significantly more resistant to oxidant-induced apoptosis than those with L/L. These findings suggested that the polymorphism of the HO-1 gene is associated with the strength of antiapoptotic effects of HO-1, resulting in an association with susceptibility to oxidative stress–mediated diseases.
Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation
Authors: Soverini Simona , Cavo Michele , Cellini Claudia , Terragna Carolina , Zamagni Elena , Ruggeri Deborah , Testoni Nicoletta , Tosi Patrizia , de Vivo Antonio , Amabile Marilina , Grafone Tiziana , Ottaviani Emanuela , Giannini Barbara , Cangini Delia , Bonifazi Francesca , Neri Antonino , Fabris Sonia , Tura Sante , Baccarani Michele , Martinelli Giovanni 
Published: May 2003

AbstractWe used a sensitive real-time reverse transcription–polymerase chain reaction assay to quantify cyclin D1 mRNA levels in bone marrow samples collected at diagnosis from 74 newly diagnosed multiple myeloma (MM) patients who were randomized to undergo either single or double autologous peripheral blood stem cell transplantation as part of first-line therapy for their malignancy. In 46 cases, fluorescence in situ hybridization (FISH) analysis and/or conventional cytogenetics were performed to detect chromosome 11 abnormalities. Patients with the t(11;14) or trisomy 11 significantly overexpressed cyclin D1 (P &lt; .0001) in comparison with patients without 11q abnormalities, who had cyclin D1 mRNA levels similar to healthy donors. Overall, 32 (43%) of 74 patients showed cyclin D1 overexpression. No difference was found between cyclin D1–positive (group A) and cyclin D1–negative (group B) patients with respect to presenting clinical and laboratory characteristics, including chromosome 13 abnormalities, as well as to response to therapy and overall survival, both of which were calculated on an intent-to-treat basis. Patients who overexpressed cyclin D1 had significantly longer duration of remission in comparison with patients who did not (41 vs 26 months, respectively; P = .02). As a result, median event-free survival (EFS) was longer in group A than in group B (33 vs 24 months, respectively; P = .055). We concluded that cyclin D1 overexpression is closely associated with 11q abnormalities and identifies a subset of MM patients who are more likely to have prolonged duration of remission and EFS following autologous transplantation.
The nonenzymatic subunit of pseutarin C, a prothrombin activator from eastern brown snake (Pseudonaja textilis) venom, shows structural similarity to mammalian coagulation factor V
Authors: Rao Veena S. , Swarup Sanjay , Kini R. Manjunatha 
Published: May 2003

AbstractPseutarin C is a group C prothrombin activator from the venom of the eastern brown snake Pseudonaja textilis. It is a multi-subunit protein complex consisting of catalytic and nonenzymatic subunits similar to coagulation factor Xa and factor Va, respectively. Here we describe the complete sequence of the nonenzymatic subunit. Based on the partial amino acid sequence of the nonenzymatic subunit, degenerate primers were designed. Using a “walking” strategy based on sequentially designed primers, we determined the complete cDNA sequence of the nonenzymatic subunit. The cDNA encodes a protein of 1461 amino acid residues, which includes a 30-residue signal peptide, a mature protein of 1430 amino acid residues, and a stop codon. cDNA blot analysis showed a single transcript of approximately 4.6 kb. The deduced amino acid sequence shows approximately 50% identity to mammalian factor V and by homology has a similar domain structure consisting of domains A1-A2-B-A3-C1-C2. Interestingly, the B domain of pseutarin C is shorter than that of mammalian factor V (FV). Although most of the proteolytic activation sites are conserved, 2 of 3 proteolytic sites cleaved by activated protein C are mutated, and thus activated protein C is not able to inactivate this procoagulant toxin. The predicted posttranslational modifications, including disulfide bonds, N-glycosylation, phosphorylation, and sulfation, in pseutarin C are significantly different compared with bovine factor V. Thus, our data demonstrate that the nonenzymatic subunit of group C prothrombin activators is structurally similar to mammalian FV.
Murine GPVI stimulates weak integrin activation in PLCγ2–/– platelets: involvement of PLCγ1 and PI3-kinase
Authors: Suzuki-Inoue Katsue , Inoue Osamu , Frampton Jon , Watson Steve P. 
Published: May 2003

AbstractCollagen stimulates platelet activation through a tyrosine kinase–based pathway downstream of the glycoprotein VI (GPVI)–Fc receptor (FcR) γ-chain complex. Genetic ablation of FcR γ-chain results in a complete inhibition of aggregation to collagen. In contrast, a steady increase in light transmission is induced by collagen in phospholipase Cγ2–deficient (PLCγ2–/–) platelets in a Born aggregometer, indicating a weak level of activation. This increase is inhibited partially in the presence of an α2β1-blocking antibody or an αIIbβ3 antagonist and completely by a combination of the 2 inhibitors. It is also abolished by the Src kinase inhibitor PP1 and reduced in the presence of the phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. The GPVI-specific agonists convulxin and collagen-related peptide (CRP) also stimulate weak aggregation in PLCγ2–/– platelets, which is inhibited by wortmannin and PP1. Collagen and CRP stimulate tyrosine phosphorylation of PLCγ1 at its regulatory site, Tyr 783, in murine but not in human platelets through a Src kinase–dependent pathway. Adhesion of PLCγ2–/– platelets to a collagen monolayer is severely reduced at a shear rate of 800 s–1, relative to controls, whereas it is abolished in FcR γ-chain–/– platelets. These results provide strong evidence that engagement of GPVI stimulates limited integrin activation in PLCγ2–/– platelets via PLCγ1 and PI3-kinase.
Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia
Authors: Huntly Brian J. P. , Bench Anthony , Green Anthony R. 
Published: May 2003

Abstract
Chronic myeloid leukemia (CML) is characterized by formation of a BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Recently the development of new fluorescence insitu hybridization (FISH) techniques has allowed identification of unexpected deletions of the reciprocal translocation product, the derivative chromosome 9, in 10% to 15% of patients with CML. These deletions are large, span the translocation breakpoint, and occur at the same time as the Ph translocation. Such deletions therefore give rise to previously unsuspected molecular heterogeneity from the very beginning of this disease, and there is mounting evidence for similar deletions associated with other translocations. Several studies have demonstrated that CML patients who carry derivative chromosome 9 deletions exhibit a more rapid progression to blast crisis and a shorter survival. Deletion status is independent of, and more powerful than, the Sokal and Hasford/European prognostic scoring systems. The poor prognosis associated with deletions is seen in patients treated with hydroxyurea or interferon, and preliminary evidence suggests that patients with deletions may also have a worse outcome than nondeleted patients following stem cell transplantation or treatment with imatinib. Poor outcome cannot be attributed to loss of the reciprocal ABL-BCR fusion gene expression alone, and is likely to reflect loss of one or more critical genes within the deleted region. The molecular heterogeneity associated with the Philadelphia translocation provides a new paradigm with potential relevance to all malignancies associated with reciprocal chromosomal translocations and/or fusion gene formation.
Increased apoptosis in bone marrow B lymphocytes but not T lymphocytes in myelodysplastic syndrome
Authors: Amin Hesham M. , Jilani Iman , Estey Elihu H. , Keating Michael J. , Dey Amanda L. , Manshouri Taghi , Kantarjian Hagop M. , Estrov Zeev , Cortes Jorge E. , Thomas Deborah A. , Giles Francis J. , Albitar Maher 
Published: May 2003

AbstractThe hallmark of myelodysplastic syndrome (MDS) is enhanced apoptosis in myeloid, erythroid, and megakaryocytic cells in the bone marrow leading to ineffective hematopoiesis. Recent studies suggested that immunological and microenvironmental factors play a role in the pathophysiology of this disease. We report a significant increase in apoptosis in bone marrow B lymphocytes in MDS as compared to that found in acute myeloid leukemia and healthy controls. Furthermore, we demonstrate that patients with refractory anemia with excess blasts in transformation (RAEB-T) had apoptosis levels in lymphocytes similar to those seen in other subtypes of MDS. Our findings suggest that the alterations in B lymphocytes in the form of increased apoptosis can be seen in MDS and support the concept that immune modulation plays a role in the pathophysiology of MDS.
Classification of pediatric acute lymphoblastic leukemia by gene expression profiling
Authors: Ross Mary E. , Zhou Xiaodong , Song Guangchun , Shurtleff Sheila A. , Girtman Kevin , Williams W. Kent , Liu Hsi-Che , Mahfouz Rami , Raimondi Susana C. , Lenny Noel , Patel Anami , Downing James R. 
Published: May 2003

AbstractContemporary treatment of pediatric acute lymphoblastic leukemia (ALL) requires the assignment of patients to specific risk groups. We have recently demonstrated that expression profiling of leukemic blasts can accurately identify the known prognostic subtypes of ALL, including T-cell lineage ALL (T-ALL), E2A-PBX1, TEL-AML1, MLL rearrangements, BCR-ABL, and hyperdiploid karyotypes with more than 50 chromosomes. As the next step toward developing this methodology into a frontline diagnostic tool, we have now analyzed leukemic blasts from 132 diagnostic samples using higher density oligonucleotide arrays that allow the interrogation of most of the identified genes in the human genome. Nearly 60% of the newly identified subtype discriminating genes are novel markers not identified in our previous study, and thus should provide new insights into the altered biology underlying these leukemias. Moreover, a proportion of the newly selected genes are highly ranked as class discriminators, and when incorporated into class-predicting algorithms resulted in an overall diagnostic accuracy of 97%. The performance of an array containing the identified discriminating genes should now be assessed in frontline clinical trials in order to determine the accuracy, practicality, and cost effectiveness of this methodology in the clinical setting.
Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency
Authors: Chen Huijun , Su Trent , Attieh Zouhair K. , Fox Tama C. , McKie Andrew T. , Anderson Gregory J. , Vulpe Chris D. 
Published: May 2003

AbstractHephaestin is a membrane-bound multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation. Mice with sex-linked anemia (sla) have a mutant form of Hephaestin and a defect in intestinal basolateral iron transport, which results in iron deficiency and anemia. Ireg1 (SLC11A3, also known as Ferroportin1 or Mtp1) is the putative intestinal basolateral iron transporter. We compared iron levels and expression of genes involved in iron uptake and storage in sla mice and C57BL/6J mice fed iron-deficient, iron-overload, or control diets. Both iron-deficient wild-type mice and sla mice showed increased expression of Heph and Ireg1 mRNA, compared to controls, whereas only iron-deficient wild-type mice had increased expression of the brush border transporter Dmt1. Unlike iron-deficient mice, sla mouse enterocytes accumulated nonheme iron and ferritin. These results indicate that Dmt1 can be modulated by the enterocyte iron level, whereas Hephaestin and Ireg1 expression respond to systemic rather than local signals of iron status. Thus, the basolateral transport step appears to be the primary site at which the small intestine responds to alterations in body iron requirements.
Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations
Authors: Hetet Gilles , Devaux Isabelle , Soufir Nadem , Grandchamp Bernard , Beaumont Carole 
Published: May 2003

AbstractUnexplained hyperferritinemia is a common clinical finding, even in asymptomatic persons. When early onset bilateral cataracts are also present, the hereditary hyperferritinemia-cataract syndrome (HHCS), because of heterozygous point mutation in the L ferritin iron-responsive element (IRE) sequence, can be suspected. We sequenced the L ferritin exon 1 in 52 DNA samples from patients referred to us for molecular diagnosis of HHCS. We identified 24 samples with a point mutation/deletion in the IRE. For the 28 samples in which no IRE mutation was present, we also genotyped HFE mutations and sequenced both H ferritin and ferroportin genes. We found an increased frequency of His63Asp heterozygotes (12 of 28) but no H ferritin mutations. We identified 3 new ferroportin mutations, producing, respectively, Asp157Gly, Gln182His, and Gly323Val amino acid replacements, suggesting that these patients have dominant type 4 hemochromatosis. This study demonstrates that both L ferritin IRE and ferroportin mutations can account for isolated hyperferritinemia. The presence of cataract does not permit the unambiguous identification of patients with HHCS, although the existence of a family history of cataract was only encountered in these patients. This raises the intriguing possibility that lens ferritin accumulation might be a factor contributing to age-related cataract in the general population. Additional causes of isolated hyperferritinemia remain to be identified.
Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation
Authors: Antin Joseph H. , Kim Haesook T. , Cutler Corey , Ho Vincent T. , Lee Stephanie J. , Miklos David B. , Hochberg Ephraim P. , Wu Catherine J. , Alyea Edwin P. , Soiffer Robert J. 
Published: May 2003

AbstractWe studied the feasibility and activity of adding sirolimus to tacrolimus and low-dose methotrexate as graft-versus-host disease (GVHD) prophylaxis in recipients of alternative donor transplants. Forty-one patients with hematologic malignancies were conditioned with cyclophosphamide and total body irradiation. Marrow stem cells were from an HLA-A, -B, and -DR compatible, unrelated donor (n = 26, 68%), froma5of6 antigen-matched unrelated donor (n = 8, 20%), or from a 5 of 6 antigen-matched family member (n = 5, 12%). Therapeutic serum levels of sirolimus were attained in most patients. All evaluable patients engrafted. An absolute neutrophil count of 500/μL was achieved on day +18 (range, 11-32 days). Sustained platelet counts of more than 20 000/ μL were attained on day +29 (range, 14-98 days). Grades 0-I acute GVHD occurred in 75% of patients. Grades II, III, and IV acute GVHD occurred in 13%, 8%, and 5%, respectively (total grades II-IV GVHD, 26%). Median survival is 366 days (95% CI 185, not estimable) and actuarial survival at 1 year is 52%. Oral sirolimus is tolerable, adequate blood levels are achievable, and there is a low rate of acute GVHD compared with historical data in this high-risk population. This novel agent is worthy of further study in allogeneic transplantation.
CXCL12 expression by invasive trophoblasts induces the specific migration of CD16– human natural killer cells
Authors: Hanna Jacob , Wald Ori , Goldman-Wohl Debra , Prus Diana , Markel Gal , Gazit Roi , Katz Gil , Haimov-Kochman Ronit , Fujii Nobutaka , Yagel Simcha , Peled Amnon , Mandelboim Ofer 
Published: May 2003

AbstractIn the maternal decidua, natural killer (NK) cells, characterized by lack of CD16, are found in direct contact with the fetal extravillous trophoblasts (EVTs). It is yet unknown which factors contribute to the specific homing of this unique NK subset to the decidua. In this study we analyze the chemokine receptor repertoire on various NK populations derived from the peripheral blood and decidua. We show that CXCR4 and CXCR3 receptors are preferentially expressed on CD16– NK subsets derived either from the peripheral blood or the decidua and that these receptors are involved in migration of all NK subsets to their ligands. We further demonstrate in vivo that invading EVTs that eventually perform endovascular invasion express CXCL12, the ligand for CXCR4, but not ligands for CXCR3. Indeed, specific accumulation of the CD16– NK cells at the expense of CD16+ cells was observed only when in vitro migration was performed with ligands for CXCR4. Finally, incubation of the peripheral blood CD16– NK cells with cytokines present in the decidua, especially interleukin 15 (IL-15), resulted in the expression of chemokine receptor repertoire similar to that observed on decidual NK cells, suggesting an additional important regulatory effect of local decidual cytokines.
Syk activation is a leukotriene B4–regulated event involved in macrophage phagocytosis of IgG-coated targets but not apoptotic cells
Authors: Canetti Claudio , Hu Bin , Curtis Jeffrey L. , Peters-Golden Marc 
Published: May 2003

AbstractMacrophages are called upon to ingest both IgG-coated targets and apoptotic cells. Important roles for tyrosine kinase Syk and leukotriene B4 (LTB4) are recognized in FcγR-mediated phagocytosis. Here we evaluated the roles of Syk and LTB4 in macrophage phagocytosis of apoptotic thymocytes versus IgG-coated erythrocytes. Macrophage ingestion of apoptotic thymocytes was not influenced by exogenous or endogenous LTB4 nor associated with Syk activation (phosphorylation). By contrast, LTB4 dose-dependently amplified FcγR-mediated phagocytosis as well as Syk activation. Furthermore, a role for endogenous LTB4 in Syk activation during FcγR-mediated phagocytosis was demonstrated using pharmacologic and genetic abrogation of 5-lipoxygenase. LTB4 was unique among 5-lipoxygenase products in this regard, since LTD4 and 5-hydroxyeicosatetraenoic acid (HETE) were unable to amplify Syk activation in response to FcγR engagement. Ca2+ chelation studies revealed that FcγR-mediated Syk activation as well as LTB4 amplification thereof was Ca2+ regulated. These 2 parallel phagocytic processes therefore exhibit initial divergence in signal transduction events, with Syk activation being an LTB4-regulated event in FcγR-mediated but not apoptotic cell ingestion. As LTB4 is an important proinflammatory product of macrophages, we speculate that this divergence evolved to permit FcγR-mediated phagocytosis to proceed in an inflammatory milieu, while apoptotic cell clearance is noninflammatory.