bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arsenic trioxide–induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL
Authors: Liu Qun , Hilsenbeck Susan , Gazitt Yair 
Published: May 2003

AbstractArsenic trioxide (ATO) has been shown to induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells concomitant with down-regulation of the PML-RARα fusion protein, a product of the t(15:17) translocation characteristic of APL leukemic cells. However, ATO is also a potent inducer of apoptosis in a number of other cancer cells lacking the t(15:17) translocation. The exact mechanism of ATO-induced apoptosis in these cells is not yet clear. We tested the effect of ATO on 7 myeloma cell lines with varying p53 status and report that in cells with mutated p53, ATO induced rapid and extensive (more than 90%) apoptosis in a time- and dose-dependent manner concomitant with arrest of cells in G2/M phase of the cell cycle. Myeloma cells with wild-type (wt) p53 were relatively resistant to ATO with maximal apoptosis of about 40% concomitant with partial arrest of cells in G1 and up-regulation of p21. The use of caspase blocking peptides, fluorescence-tagged caspase-specific substrate peptides, and Western immunoblotting confirmed the involvement of primarily caspase-8 and -3 in ATO-induced apoptosis in myeloma cells with mutated p53 and primarily caspase-9 and -3 in cells expressing wt p53. We also observed up-regulation by ATO of R1 and R2 APO2/TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) receptors. Most important, however, we observed a synergy between ATO and APO2/TRAIL in the induction of apoptosis in the partially resistant myeloma cell lines and in myeloma cells freshly isolated from myeloma patients. Our results justify the use of the combination of these 2 drugs in clinical setting in myeloma patients.
Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1
Authors: Reca Ryan , Mastellos Dimitrios , Majka Marcin , Marquez Leah , Ratajczak Janina , Franchini Silvia , Glodek Aleksandra , Honczarenko Marek , Spruce Lynn A. , Janowska-Wieczorek Anna , Lambris John D. , Ratajczak Mariusz Z. 
Published: May 2003

AbstractComplement has recently been implicated in developmental pathways and noninflammatory processes. The expression of various complement components and receptors has been shown in a wide range of circulating myeloid and lymphoid cells, but their role in normal hematopoiesis and stem cell homing has not yet been investigated. We report that normal human CD34+ cells and lineage-differentiated hematopoietic progenitors express the complement anaphylatoxin C3a receptor (C3aR) and respond to C3a. Moreover, C3a, but not the biologically inactive desArg-C3a, induces calcium flux in these cells. Furthermore, we found that C3 is secreted by bone marrow stroma and that, although C3a does not influence directly the proliferation/survival of hematopoietic progenitors, it (1) potentiates the stromal cell–derived factor 1 (SDF-1)–dependent chemotaxis of human CD34+ cells and lineage-committed myeloid, erythroid, and megakaryocytic progenitors; (2) primes SDF-1–dependent trans-Matrigel migration; and (3) stimulates matrix metalloproteinase-9 secretion and very late antigen 4 (VLA-4)–mediated adhesion to vascular cell adhesion molecule 1 (VCAM-1). Furthermore, we found that murine Sca-1+ cells primed by C3a engrafted faster in lethally irradiated animals. These results indicate that normal human hematopoietic stem and progenitor cells express functional C3aR and that the C3aR-C3a axis sensitizes the responses of these cells to SDF-1 and thus may be involved in promoting their homing into the bone marrow via cross talk with the SDF–CXC chemokine receptor-4 (CXCR4) signaling axis. C3a is the first positive regulator of this axis to be identified.
Targeting of the collagen-binding site on glycoprotein VI is not essential for in vivo depletion of the receptor
Authors: Schulte Valerie , Rabie Tamer , Prostredna Miroslava , Aktas Barsom , Grüner Sabine , Nieswandt Bernhard 
Published: May 2003

Abstract
Glycoprotein (GP) VI is an essential collagen receptor on platelets and may serve as an attractive target for antithrombotic therapy. We have previously shown that a monoclonal antibody (mAb) against the major collagen-binding site on mouse GPVI (JAQ1) induces irreversible down-regulation of the receptor and, consequently, long-term antithrombotic protection in vivo. To determine whether this unique in vivo effect of JAQ1 is based on its interaction with the ligand-binding site on GPVI, we generated new mAbs against different epitopes on GPVI (JAQ2, JAQ3) and tested their in vitro and in vivo activity. We show that none of the mAbs inhibited platelet activation by collagen or the collagen-related peptide in vitro. Unexpectedly, however, injection of either antibody induced depletion of GPVI with the same efficacy and kinetics as JAQ1. Importantly, this effect was also seen with monovalent F(ab) fragments of JAQ2 and JAQ3, excluding the involvement of the Fc part or the dimeric form of anti-GPVI antibodies in this process. This indicates that anti-GPVI agents, irrespective of their binding site may generally induce down-regulation of the receptor in vivo.
Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor
Authors: Tönnies Holger , Huber Stefanie , Kühl Jörn-Sven , Gerlach Antje , Ebell Wolfram , Neitzel Heidemarie 
Published: May 2003

Abstract
Fanconi anemia (FA) is a condition that induces susceptibility to bone marrow failure, myelodysplastic syndrome (MDS), and leukemia. We report on a high incidence of expanding clonal aberrations with partial trisomies and tetrasomies of chromosome 3q in bone marrow cells of 18 of 53 FA patients analyzed, detected by conventional and molecular cytogenetics. To determine the clinical relevance of these findings, we compared the cytogenetic data, the morphologic features of the bone marrow, and the clinical course of these patients with those of 35 FA patients without clonal aberrations of 3q. The 2 groups did not differ significantly with respect to age, sex, or complementation group. There was a significant survival advantage of patients without abnormalities of chromosome 3q. Even more pronounced was the risk assessment of patients with gains of 3q material with respect to the development of morphologic MDS and acute myeloid leukemia (AML). Thus, our data from 18 patients with 3q aberrations reveal that gains of 3q are strongly associated with a poor prognosis and represent an adverse risk factor in FA.
166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials
Authors: Giralt Sergio , Bensinger William , Goodman Mark , Podoloff Donald , Eary Janet , Wendt Richard , Alexanian Raymond , Weber Donna , Maloney David , Holmberg Leona , Rajandran Joseph , Breitz Hazel , Ghalie Richard , Champlin Richard 
Published: May 2003

AbstractHolmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation. (Blood. 2003;102:2684-2691)
Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice
Authors: Beider Katia , Nagler Arnon , Wald Ori , Franitza Suzanna , Dagan-Berger Michal , Wald Hanna , Giladi Hilla , Brocke Stefan , Hanna Jacob , Mandelboim Ofer , Darash-Yahana Merav , Galun Eithan , Peled Amnon 
Published: May 2003

Abstract
Human natural killer (NK) and NK T cells play an important role in allogeneic bone marrow (BM) transplantation and graft-versus-leukemia (GVL) effect. The mechanisms by which these cells home to the BM and spleen are not well understood. Here we show that treatment of these cells with pertussis toxin and neutralizing antibodies to the chemokine receptor CXCR4 inhibited homing of the cells to the BM, but not the spleen, of NOD/SCID mice. The retention of NK and NK T cells within the spleen and BM was dependent on Gαi signaling and CXCR4 function. The chemokine receptors CXCR4 and CXCR3 are expressed predominantly on the cell surface of NK T cells. Following activation with interleukin-2 (IL-2), the levels of CXCR4 on NK and NK T cells decreased significantly. Treatment of cells with IL-2 inhibited their migration in response to CXCL12 and their homing and retention in the BM and spleen of NOD/SCID mice. In contrast to CXCR4, the expression levels of the chemokine receptor CXCR3 and the migration of cells in response to CXCL9 and CXCL10 increased after IL-2 treatment. Thus, down-regulation of CXCR4 and up-regulation of CXCR3 may direct the trafficking of cells to the site of inflammation, rather than to hematopoietic organs, and therefore may limit their alloreactive potential.
Transgenic sickle mice have vascular inflammation
Authors: Belcher John D. , Bryant Christopher J. , Nguyen Julia , Bowlin Paul R. , Kielbik Miroslaw C. , Bischof John C. , Hebbel Robert P. , Vercellotti Gregory M. 
Published: May 2003

AbstractInflammation may play an essential role in vaso-occlusion in sickle cell disease. Sickle patients have high white counts and elevated levels of serum C-reactive protein (CRP), cytokines, and adhesion molecules. In addition, circulating endothelial cells, leukocytes, and platelets are activated. We examined 4 transgenic mouse models expressing human α- and sickle β-globin genes to determine if they mimic the inflammatory response seen in patients. These mouse models are designated NY-S, Berk-SAntilles, NY-S/SAntilles (NY-S × Berk-SAntilles), and Berk-S. The mean white counts were elevated 1.4- to 2.1-fold (P ≤ .01) in the Berk-SAntilles, NY-S/SAntilles, and Berk-S mice, but not in the NY-S mice compared with controls. Serum amyloid P-component (SAP), an acute-phase response protein with 60% to 70% sequence homology to CRP, was elevated 8.5- to 12.1-fold (P ≤ .001) in transgenic sickle mice. Similarly, serum interleukin-6 (IL-6) was elevated 1.6- to 1.9-fold (P ≤ .05). Western blots, confirming immunohistochemical staining, showed vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and platelet-endothelial cell adhesion molecule (PECAM) were up-regulated 3- to 5-fold (P ≤ .05) in the lungs of sickle mice. Ribonuclease protection assays (RPAs) demonstrated VCAM mRNA also was elevated in sickle mice 1.2- to 1.4-fold (P ≤ .01). Nuclear factor κB (NF-κB), a transcription factor critical for the inflammatory response, was elevated 1.9-fold (P ≤ .006) in NY-S sickle mouse lungs. We conclude that transgenic sickle mice are good models to study vascular inflammation and the potential benefit of anti-inflammatory therapies to prevent vaso-occlusion in sickle cell disease.
The heat-shock protein receptor CD91 is up-regulated in monocytes of HIV-1–infected “true” long-term nonprogressors
Authors: Stebbing Justin , Gazzard Brian , Kim Louise , Portsmouth Simon , Wildfire Adrian , Teo Ian , Nelson Mark , Bower Mark , Gotch Frances , Shaunak Sunil , Srivastava Pramod , Patterson Steve 
Published: May 2003

AbstractA small proportion of patients with human immunodeficiency virus type 1 (HIV-1) remains asymptomatic for a long period after infection. It is thought that a vigorous immune response may contribute to long-term nonprogression, though studies are confounded by heterogeneity among patients. We studied the levels of HIV-1 receptors, costimulatory T-cell molecules, and dendritic cell (DC) numbers in 18 patients with long-term infection, CD4 counts greater than 400 cells/mm3, and HIV-1 viral loads lower than 50 copies/mL. These patients were further differentiated through the presence or absence of 2-LTR DNA circles, a possible marker for residual ongoing HIV-1 replication. A statistically significant increase in levels of CD91, the heat-shock protein (HSP) receptor, was observed in therapy-naive patients who had no evidence of ongoing viral replication (P = .01). This difference was most notable on their monocytes. High levels of CD91 may be a host factor that contributes to the maintenance of long-term nonprogression. The ability of CD91 to internalize α-defensins and to cross-present exogenous antigen to cytotoxic T lymphocytes through major histocompatibility complex (MHC) class 1 may maintain CD8+ responses in these patients.
β2-Microglobulin as a negative regulator of the immune system: high concentrations of the protein inhibit in vitro generation of functional dendritic cells
Authors: Xie Jin , Wang Ying , Freeman Muta E. , Barlogie Bart , Yi Qing 
Published: May 2003

AbstractTwo common features in human immunodeficiency virus infection and acquired immunodeficiency syndrome, rheumatoid arthritis, and hematologic malignancies including multiple myeloma are elevated serum levels of β2-microglobulin (β2M) and activation or inhibition of the immune system. We hypothesized that β2M at high concentrations may have a negative impact on the immune system. In this study, we examined the effects of β2M on monocyte-derived dendritic cells (MoDCs). The addition of β2M (more than 10 μg/mL) to the cultures reduced cell yield, inhibited the up-regulation of surface expression of human histocompatibility leukocyte antigen (HLA)–ABC, CD1a, and CD80, diminished their ability to activate T cells, and compromised generation of the type-1 T-cell response induced in allogeneic mixed-lymphocyte reaction. Compared with control MoDCs, β2M-treated cells produced more interleukin-6 (IL-6), IL-8, and IL-10. β2M-treated cells expressed significantly fewer surface CD83, HLA-ABC, costimulatory molecules, and adhesion molecules and were less potent at stimulating allospecific T cells after an additional 48-hour culture in the presence of tumor necrosis factor-α and IL-1β. During cell culture, β2M down-regulated the expression of phosphorylated mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), and mitogen-induced extracellular kinase (MEK), inhibited nuclear factor-κB (NF-κB), and activated signal transducer and activator of transcription-3 (STAT3) in treated cells, all of which are involved in cell differentiation and proliferation. Thus, our study demonstrates that β2M at high concentrations retards the generation of MoDCs, which may involve down-regulation of major histocompatibility complex class I molecules, inactivation of Raf/MEK/ERK cascade and NF-κB, and activation of STAT3, and it merits further study to elucidate the underlying mechanisms.
Cell context–specific effects of the BCR-ABL oncogene monitored in hematopoietic progenitors
Authors: Wong Stephane , McLaughlin Jami , Cheng Donghui , Witte Owen N. 
Published: May 2003

AbstractAcute BCR-ABL expression during in vitro hematopoietic development of embryonic stem (ES) cells causes expansion of multipotent and myeloid progenitors with a concomitant reduction in differentiation toward erythroblasts. Progenitor cell expansion is due to a rapid, cell autonomous, suppression of programmed cell death with an increase in expression of the antiapoptotic molecule BCL-XL. Other antiapoptotic effectors, including AKT, STAT5, and BCL-2 are not up-regulated by BCR-ABL in this system. In addition, the proapoptotic p38 mitogen–activated protein kinase (MAPK) pathway is suppressed by BCR-ABL expression in ES-derived hematopoietic progenitors. Inhibition of p38 MAPK by the small molecule inhibitor SB203580 expanded ES-derived hematopoietic progenitors by an antiapoptotic mechanism and is sufficient to expand ES-derived hematopoietic progenitors to levels approaching 80% of that seen following BCR-ABL expression. In the cellular context of ES-derived hematopoietic progenitors, BCR-ABL expression expands cells by suppressing programmed cell death with a set of antiapoptotic pathways distinct from those previously reported in continuous cell line studies.
Leukocyte antiadhesive actions of annexin 1: ALXR- and FPR-related anti-inflammatory mechanisms
Authors: Gavins Felicity N. E. , Yona Simon , Kamal Ahmad M. , Flower Roderick J. , Perretti Mauro 
Published: May 2003

AbstractRecent investigations conducted with human neutrophils have indicated an involvement for the receptor for formylated peptides, termed FPR, and its analog FPRL1 (or ALXR because it is the receptor for the endogenous ligand lipoxin A4) in the in vitro inhibitory actions of the glucocorticoid-regulated protein annexin 1 and its peptidomimetics. To translate these findings in in vivo settings, we have used an ischemia/reperfusion (I/R) procedure to promote leukocyte-endothelium interactions in the mouse mesenteric microcirculation. In naive mice, the annexin 1 mimetic peptide Ac2-26 (20 to 100 μg administered intravenously prior to reperfusion) abolished I/R-induced cell adhesion and emigration, but not cell rolling. In FPR-deficient mice, peptide Ac2-26 retained significant inhibitory actions (about 50% of the effects in naive mice), and these were blocked by an FPR antagonist, termed butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe, or Boc2. In vitro, neutrophils taken from these animals could be activated at high concentrations of formyl-Met-Leu-Phe (30 μM; fMLP), and this effect was blocked by cell incubation with peptide Ac2-26 (66 μM) or Boc2 (100 μM). FPR-deficient neutrophils expressed ALXR mRNA and protein. Both ALXR agonists, lipoxin A4 and peptide Ac2-26, provoked detachment of adherent leukocytes in naive as well as in FPR-deficient mice, whereas the CXC chemokine KC or fMLP were inactive. The present findings demonstrate that endogenous regulatory autocoids such as lipoxin A4 and annexin 1–derived peptides function to disengage adherent cells during cell-cell interactions.
Mature parasite-infected erythrocyte surface antigen (MESA) of Plasmodium falciparum binds to the 30-kDa domain of protein 4.1 in malaria-infected red blood cells
Authors: Waller Karena L. , Nunomura Wataru , An Xiuli , Cooke Brian M. , Mohandas Narla , Coppel Ross L. 
Published: May 2003

Abstract
The Plasmodium falciparum mature parasite-infected erythrocyte surface antigen (MESA) is exported from the parasite to the infected red blood cell (IRBC) membrane skeleton, where it binds to protein 4.1 (4.1R) via a 19-residue MESA sequence. Using purified RBC 4.1R and recombinant 4.1R fragments, we show MESA binds the 30-kDa region of RBC 4.1R, specifically to a 51-residue region encoded by exon 10 of the 4.1R gene. The 3D structure of this region reveals that the MESA binding site overlaps the region of 4.1R involved in the p55, glycophorin C, and 4.1R ternary complex. Further binding studies using p55, 4.1R, and MESA showed competition between p55 and MESA for 4.1R, implying that MESA bound at the IRBC membrane skeleton may modulate normal 4.1R and p55 interactions in vivo. Definition of minimal binding domains involved in critical protein interactions in IRBCs may aid the development of novel therapies for falciparum malaria.
Molecular sequelae of histone deacetylase inhibition in human malignant B cells
Authors: Mitsiades Nicholas , Mitsiades Constantine S. , Richardson Paul G. , McMullan Ciaran , Poulaki Vassiliki , Fanourakis Galinos , Schlossman Robert , Chauhan Dharminder , Munshi Nikhil C. , Hideshima Teru , Richon Victoria M. , Marks Paul A. , Anderson Kenneth C. 
Published: May 2003

AbstractHistone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid–based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor–mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion–mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.