bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel antimalarial antibodies highlight the importance of the antibody Fc region in mediating protection
Authors: Pleass Richard J. , Ogun Solabomi A. , McGuinness David H. , van de Winkel Jan G. J. , Holder Anthony A. , Woof Jenny M. 
Published: July 2003

AbstractParasite drug resistance and difficulties in developing effective vaccines have precipitated the search for alternative therapies for malaria. The success of passive immunization suggests that immunoglobulin (Ig)-based therapies are effective. To further explore the mechanism(s) by which antibody mediates its protective effect, we generated human chimeric IgG1 and IgA1 and a single-chain diabody specific for the C-terminal 19-kDa region of Plasmodium yoelii merozoite surface protein 1 (MSP119), a major target of protective immune responses. These novel human reagents triggered in vitro phagocytosis of merozoites but, unlike their parental mouse IgG2b, failed to protect against parasite challenge in vivo. Therefore, the Fc region appears critical for mediating protection in vivo, at least for this MSP119 epitope. Such antibodies may serve as prototype therapeutic agents, and as useful tools in the development of in vitro neutralization assays with Plasmodium parasites. (Blood. 2003;102:4424-4430)
RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements
Authors: Puig-Kröger Amaya , Sánchez-Elsner Tilman , Ruiz Natividad , Andreu Enrique J. , Prosper Felipe , Jensen Uffe B. , Gil Juana , Erickson Paul , Drabkin Harry , Groner Yoram , Corbí Angel L. 
Published: July 2003

AbstractThe CD11a/CD18 (leukocyte function-associated antigen 1 [LFA-1]) integrin mediates critical leukocyte adhesive interactions during immune and inflammatory responses. The CD11a promoter directs CD11a/CD18 integrin expression, and its activity in lymphoid cells depends on a functional RUNX1/AML-1–binding site (AML-110) within the MS7 sequence. We now report that MS7 contains a C/EBP-binding site (C/EBP-100), which overlaps with AML-110 and is bound by C/EBP factors in myeloid cells. C/EBP and RUNX/AML factors compete for binding to their respective cognate elements and bind to the CD11a promoter MS7 sequence in a cell lineage- and differentiation-dependent manner. In myeloid cells MS7 is primarily recognized by C/EBP factors in proliferating cells whereas RUNX/AML factors (especially RUNX3/AML-2) bind to MS7 in differentiated cells. RUNX3/AML-2 binding to the CD11a promoter correlates with increased RUNX3/AML-2 protein levels and enhanced CD11a/CD18 cell surface expression. The relevance of the AML-110 element is underscored by the ability of AML-1/ETO to inhibit CD11a promoter activity, thus explaining the low CD11a/CD18 expression in t(8;21)–containing myeloid leukemia cells. Therefore, the expression of the CD11a/CD18 integrin in myeloid cells is determined through the differential occupancy of the CD11a proximal promoter by transcription factors implicated in the pathogenesis of myeloid leukemia.
Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist
Authors: Liles W. Conrad , Broxmeyer Hal E. , Rodger Elin , Wood Brent , Hübel Kai , Cooper Scott , Hangoc Giao , Bridger Gary J. , Henson Geoffrey W. , Calandra Gary , Dale David C. 
Published: July 2003

Abstract
Stromal cell-derived factor 1 (SDF1/CXCL12) and its cognate receptor, CXCR4, play key regulatory roles in CD34+ cell trafficking. We investigated whether AMD3100, a selective CXCR4 antagonist, could mobilize hematopoietic progenitor cells from marrow to peripheral blood in healthy human volunteers. Initially, 10 persons each received a single dose of AMD3100 (80 μg/kg subcutaneously), which induced rapid, generalized leukocytosis associated with an increase in peripheral blood CD34+ cells, representing pluripotent hematopoietic progenitors by in vitro colony-forming unit assays, from 3.8 ± 0.5/μL to 20.7 ± 3.5/μL at 6 hours. Subsequent dose-response studies showed a maximum increase in circulating CD34+ cells from 2.6 ± 0.3/μL to 40.4 ± 3.4/μL at 9 hours after 240 μg/kg AMD3100. Serial administration of AMD3100 (80 μg/kg/d for 3 days) resulted in consistent, reversible increases in peripheral blood CD34+ cells. AMD3100 was well tolerated and caused only mild, transient toxicity. These findings suggest potential clinical application of AMD3100 for CD34+ cell mobilization and collection for hematopoietic stem cell transplantation.
Gadd45β mediates the protective effects of CD40 costimulation against Fas-induced apoptosis
Authors: Zazzeroni Francesca , Papa Salvatore , Algeciras-Schimnich Alicia , Alvarez Kellean , Melis Tiziana , Bubici Concetta , Majewski Nathan , Hay Nissim , De Smaele Enrico , Peter Marcus E. , Franzoso Guido 
Published: July 2003

AbstractIn B lymphocytes, induction of apoptosis or programmed cell death (PCD) by Fas (CD95/APO-1) is suppressed by the triggering of CD40. This suppression controls various aspects of the humoral immune response, including antibody affinity maturation. The opposing effects of these receptors are also crucial to B-cell homeostasis, autoimmune disease, and cancer. Cytoprotection by CD40 involves activation of protective genes mediated by NF-κB transcription factors; however, its basis remains poorly understood. Here, we report that, in B cells, Gadd45β is induced by CD40 through a mechanism that requires NF-κB and that this induction suppresses Fas-mediated killing. Importantly, up-regulation of Gadd45β by CD40 precedes Fas-induced caspase activation, as well as up-regulation of other NF-κB–controlled inhibitors of apoptosis such as Bcl-xL and c-FLIPL. In the presence of Gadd45β, the Fas-induced apoptotic cascade is halted at mitochondria. However, in contrast to Bcl-xL, Gadd45β is unable to hamper the “intrinsic” pathway for apoptosis and in fact appears to block Fas cytotoxicity herein by suppressing a mitochondria-targeting mechanism activated by this receptor. These findings identify Gadd45β as a critical mediator of the prosurvival response to CD40 stimulation and provide important new insights into the apoptotic mechanism that is triggered by Fas in B cells.
Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation
Authors: Dubois Bertrand , Chapat Ludivine , Goubier Anne , Papiernik Martine , Nicolas Jean-François , Kaiserlian Dominique 
Published: July 2003

AbstractTo elucidate the role of CD4+CD25+ regulatory T cells in oral tolerance, we used the model of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene (DNFB), which is mediated by CD8+ Tc1 effector cells independently of CD4+ T-cell help. Conversely to normal mice, invariant chain knock-out (KO) (Ii°/°) mice, which are deficient in CD4+ T cells, cannot be orally tolerized and develop a chronic hapten-specific CHS response. Transfer of naive CD4+ T cells before hapten gavage into Ii°/° mice restores oral tolerance by a mechanism independent of interleukin-10 (IL-10) production by CD4+ T cells. That naturally occurring CD4+CD25+ T cells are critical for oral tolerance induction is demonstrated by the finding that (1) transfer of CD4+CD25+ but not CD4+CD25– T cells into Ii°/° recipients completely prevents the CHS response and skin infiltration by CD8+ T cells, by blocking development of hapten-specific CD8+ T cells; (2) in vivo depletion of CD4+CD25+ cells by antibody treatment in normal mice impairs oral tolerance; and (3) CD4+CD25+ T cells inhibit hapten-specific CD8+ T-cell proliferation and interferon γ (IFNγ) production, in vitro. These data show that naturally occurring CD4+CD25+ T cells are instrumental for orally induced tolerance and are key actors for the control of antigen-specific CD8+ T-cell effectors mediating skin inflammation.
Inducible expression of BCR/ABL using human CD34 regulatory elements results in a megakaryocytic myeloproliferative syndrome
Authors: Huettner Claudia S. , Koschmieder Steffen , Iwasaki Hiromi , Iwasaki-Arai Junko , Radomska Hanna S. , Akashi Koichi , Tenen Daniel G. 
Published: July 2003

AbstractThe BCR/ABL fusion protein is found in more than 90% of patients with chronic myeloid leukemia (CML) as well as in a subset of patients with acute B-cell leukemia. We have previously described a transgenic model for an inducible and reversible acute B-cell leukemia caused by p210 BCR/ABL. Here, we describe a new model of an inducible BCR/ABL disease by directing the expression of the oncogene to megakaryocytic progenitor cells within the murine bone marrow using the tetracycline-responsive expression system under the control of human CD34 regulatory elements. The predominant feature was the development of a chronic thrombocytosis. The condition progressed with the development of splenomegaly accompanied by lymphadenopathy in some mice. Affected animals demonstrated a dramatic increase in the number of megakaryocytes in the bone marrow and the spleen. Immunohistochemistry demonstrated that the reporter gene was expressed in hematopoietic stem cells (HSCs), common myeloid progenitor (CMP) cells, as well as in megakaryocytic/erythroid progenitor cells (MEPs). Although these mice did not display the increase in granulopoiesis commonly found in chronic myeloid leukemia (CML), the phenotype closely resembles a myeloproliferative disorder affecting the megakaryocytic lineage observed in some patients with the BCR/ABL P210 translocation.
Signaling but not trafficking function of HIV-1 protein Nef is essential for Nef-induced defects in human intrathymic T-cell development
Authors: Stove Veronique , Naessens Evelien , Stove Christophe , Swigut Tomek , Plum Jean , Verhasselt Bruno 
Published: July 2003

AbstractThe HIV-1 gene nef is important for progression toward AIDS and cellular depletion of the infected thymus. Expression of the Nef protein alone impairs human thymopoiesis. Here, we performed a structure-function analysis of the Nef protein by comparing the effect on T-cell development of different nef alleles, either wild type or defective for selected functions, expressed by human thymocytes. We show that Nef-mediated impaired thymopoiesis is not due to altered surface marker trafficking, nor dependent on oligomerization of Nef. By contrast, mutations in the myristoylation site and in signaling sites of Nef, ie, sites important for interaction with phosphofurin acidic cluster sorting protein-1 (PACS-1), Src homology domain 3 (SH3) domains, and p21-activated kinase 2 (PAK2), were found to be critical for its effect on T-cell development. These results point to sites in Nef to target therapeutically for restoration of thymopoiesis in HIV infection.
Control of thrombus embolization and fibronectin internalization by integrin αIIbβ3 engagement of the fibrinogen γ chain
Authors: Ni Heyu , Papalia Jessie M. , Degen Jay L. , Wagner Denisa D. 
Published: July 2003

AbstractFibrin(ogen) deficiency (Fg-/-) was shown previously to be compatible with rapid thrombus growth within injured arterioles, but platelet fibronectin content was increased and newly formed thrombi were unstable. To further define the role of fibrin(ogen) in thrombus formation and stabilization, platelet biology was examined in mice expressing a form of fibrinogen that clots normally but lacks the γ chain C-terminal binding site for αIIbβ3 (FgγΔ5). Thrombus growth within the arterioles of FgγΔ5 mice appeared faster than in wild-type mice despite a far greater emboli formation. Unlike Fg-/- mice, the emboli were relatively small and released from the top of thrombi, rather than by fracture at the vessel wall. The fibronectin content in FgγΔ5 platelets was also dramatically increased through a β3 integrin-dependent mechanism. The following has been concluded: (1) Fibrin formation contributes to, but is not sufficient for, the stabilization of arterial thrombi. Platelet receptor engagement of the C-terminal of the Fg γ chain contributes to the stable incorporation of platelets into thrombi. (2) Alternative ligands to fibrinogen can support efficient thrombus growth. (3) Fibrinogen is internalized through αIIbβ3 engagement of the fibrinogen γ chain element, and this interaction secondarily controls the fibronectin content of platelets. (Blood. 2003;102: 3609-3614)
Thrombopoietin stimulates Hoxb4 expression: an explanation for the favorable effects of TPO on hematopoietic stem cells
Authors: Kirito Keita , Fox Norma , Kaushansky Kenneth 
Published: July 2003

Abstract
Thrombopoietin (TPO), the primary regulator of platelet production, also plays an important role in hematopoietic stem cell (HSC) biology. In previous studies we demonstrated that the self-renewal and expansion of HSCs is 10 to 20 times less robust in tpo–/– mice than in controls. To explore the molecular basis of this effect, we postulated that Hoxb4 might mediate at least part of the TPO effect on these cells. We first analyzed the effects of TPO on Hoxb4 expression in primitive hematopoietic cell lines; TPO increased expression of the gene 2- to 3-fold in EML and UT-7/TPO cells. We also compared Hoxb4 levels in a candidate HSC population derived from tpo–/– and control mice; Hoxb4 expression was 2- to 5-fold lower in null HSCs. Of the numerous signal transduction molecules induced by TPO, we found that p38 mitogen-activated protein kinase (MAPK) was responsible for the TPO-induced Hoxb4 elevation. We also demonstrated that upstream stimulating factor 1 (USF-1), a transcription factor previously shown to regulate Hoxb4 expression, is also induced by TPO in a p38-dependent manner. Together, these data provide a molecular pathway by which a growth factor can modulate a transcription factor and thereby help direct a critical developmental process.
Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels
Authors: van de Donk Niels W. C. J. , Kamphuis Marloes M. J. , van Kessel Berris , Lokhorst Henk M. , Bloem Andries C. 
Published: July 2003

AbstractHMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma.
Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis
Authors: Freie Brian , Li Xiaxin , Ciccone Samantha L. M. , Nawa Kathy , Cooper Scott , Vogelweid Catherine , Schantz Laurel , Haneline Laura S. , Orazi Attilio , Broxmeyer Hal E. , Lee Suk-Hee , Clapp D. Wade 
Published: July 2003

AbstractFanconi anemia (FA) is a recessive genomic instability syndrome characterized by developmental defects, progressive bone marrow failure, and cancer. FA is genetically heterogeneous, however; the proteins encoded by different FA loci interact functionally with each other and with the BRCA1, BRCA2, and ATM gene products. Although patients with FA are highly predisposed to the development of myeloid leukemia and solid tumors, the alterations in biochemical pathways responsible for the progression of tumorigenesis in these patients remain unknown. FA cells are hypersensitive to a range of genotoxic and cellular stresses that activate signaling pathways mediating apoptosis. Here we show that ionizing radiation (IR) induces modestly elevated levels of p53 in cells from FA type C (Fancc) mutant mice and that inactivation of Trp53 rescues tumor necrosis factor α-induced apoptosis in myeloid cells from Fancc-/- mice. Further, whereas Fancc-/- mice failed to form hematopoietic or solid malignancies, mice mutant at both Fancc and Trp53 developed tumors more rapidly than mice mutant at Trp53 alone. This shortened latency was associated with the appearance of tumor types that are found in patients with FA but not in mice mutant at Trp53 only. Collectively, these data demonstrate that p53 and Fancc interact functionally to regulate apoptosis and tumorigenesis in Fancc-deficient cells. (Blood. 2003;102:4146-4152)
Bcl2 retards G1/S cell cycle transition by regulating intracellular ROS
Authors: Deng Xingming , Gao Fengqin , May W. Stratford 
Published: July 2003

AbstractBcl2's antiapoptotic function is regulated by phosphorylation. Bcl2 also regulates cell cycle progression, but the molecular mechanism is unclear. Bcl2 is functionally expressed in mitochondria where it can act as an antioxidant that may regulate intracellular reactive oxygen species (ROS). Since ROS have been reported to act as second messengers in cell signaling, we tested whether Bcl2 phosphorylation regulates ROS and cell cycle progression. G1 → S transition and ROS levels were measured in cells expressing either the gain of function phosphomimetic Bcl2 mutants S70E and T69E/S70E/S87E (EEE) or the nonphosphorylatable and survival-deficient mutants S70A and T69A/S70A/S87A (AAA). Expression of S70E and EEE but not the A-containing Bcl2 mutants retards G1 → S transition by 35% to 50% and significantly slows cell growth in association with reduced levels of intracellular ROS. In addition to expression of the phosphomimetic Bcl2 mutants, either interleukin-3 withdrawal or treatment of cells with the antioxidant pyrrolidine dithiocarbamate (PDTC) also reduces intracellular ROS levels in association with up-regulation of p27 and accumulation of cells in G0/G1. Retardation of G1 → S transition can be overridden by directly adding H2O2 to the cells in a mechanism that involves down-regulation of p27 and activation of Cdk2. Thus, Bcl2 may regulate G1 → S transition by a novel signaling mechanism that couples regulation of intracellular ROS with p27 and Cdk2. Furthermore, phosphorylation of Bcl2 may functionally link its antiapoptotic, cell cycle retardation, and antioxidant properties.
Primitive erythropoiesis is regulated by Smad-dependent signaling in postgastrulation mesoderm
Authors: Schmerer Matthew , Evans Todd 
Published: July 2003

AbstractThe bone morphogenetic proteins (BMPs) are required for the development of ventral mesoderm, which contributes to the ventral blood island and primitive (yolk sac stage) hematopoiesis. Primitive erythropoiesis is defective when BMP signaling is blocked during gastrulation of Xenopus embryos. This phenotype might be attributed to changes in mesoderm patterning leading indirectly to altered erythropoiesis. We developed an inducible system in order to block BMP signaling in a controlled fashion at later time points in development. For this purpose, an inhibitory Smad, xSmad6, was fused to the estrogen receptor ligand-binding domain. We show that ER-xSmad6 is inactive when expressed in developing embryos, but its activity is induced by estradiol. When induced early in development, ER-xSmad6 causes a dorsalized phenotype, equivalent to overexpression of native xSmad6. When ER-xSmad6 is induced after gastrulation, there is a specific defect in primitive erythropoiesis without any apparent effect on axial patterning. Our results identify an embryonic signal that is Smad-dependent, is required for maintaining expression of GATA-1, and functions within mesoderm and not the overlying ectoderm. Thus, BMP signaling is necessary both during mesoderm patterning and also following early specification events for proper regulation of the primitive erythroid lineage.
Inhibition of HIV-1 infection by a CCR5-binding cyclophilin from Toxoplasma gondii
Authors: Golding Hana , Aliberti Julio , King Lisa R. , Manischewitz Jody , Andersen John , Valenzuela Jesus , Landau Nathaniel R. , Sher Alan 
Published: July 2003

AbstractThe activation of murine dendritic cells by Toxoplasma gondii has recently been shown to depend on a parasite protein that signals through the chemokine receptor CCR5. Here we demonstrate that this molecule, cyclophilin-18 (C-18), is an inhibitor of HIV-1 cell fusion and infection with cell-free virus. T gondii C-18 efficiently blocked syncytium formation between human T cells and effector cells expressing R5 but not X4 envelopes. Neither human nor Plasmodium falciparum cyclophilins possess such inhibitory activity. Importantly, C-18 protected peripheral blood leukocytes from infection with multiple HIV-1 R5 primary isolates from several clades. C-18 bound directly to human CCR5, and this interaction was partially competed by the β-chemokine macrophage inflammatory protein 1β (MIP-1β) and by HIV-1 R5 gp120. In contrast to several other antagonists of HIV coreceptor function, C-18 mediated inhibition did not induce β-chemokines or cause CCR5 downmodulation, suggesting direct blocking of envelope binding to the receptor. These data support the further development of C-18 derivatives as HIV-1 inhibitors for preventing HIV-1 transmission and for postexposure prophylaxis.
The murine platelet and plasma factor V pools are biosynthetically distinct and sufficient for minimal hemostasis
Authors: Sun Hongmin , Yang Tony L. , Yang Angela , Wang Xixi , Ginsburg David 
Published: July 2003

AbstractCoagulation factor V (FV) is a central regulator of the coagulation cascade. Circulating FV is found in plasma and within platelet α granules. The specific functions of these distinct FV pools are uncertain. We now report the generation of transgenic mice with FV gene expression restricted to either the liver or megakaryocyte/platelet lineage using bacterial artificial chromosome (BAC) constructs. Six of 6 independent albumin BAC transgenes rescue the neonatal lethal hemorrhage of FV deficiency. Rescued mice all exhibit liver-specific Fv expression at levels ranging from 6% to 46% of the endogenous Fv gene, with no detectable FV activity within the platelet pool. One of the 3 Pf4 BAC transgenes available for analysis also rescues the lethal FV null phenotype, with FV activity restricted to only the platelet pool (approximately 3% of the wild-type FV level). FV-null mice rescued by either the albumin or Pf4 BAC exhibit nearly normal tail bleeding times. These results demonstrate that Fv expression in either the platelet or plasma FV pool is sufficient for basal hemostasis. In addition, these findings indicate that the murine platelet and plasma FV pools are biosynthetically distinct, in contrast to a previous report demonstrating a plasma origin for platelet FV in humans.