bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concentric zoning patterns in crystallizing (Cd,Ca)CO3solid solutions from aqueous solutions
Authors: Fernández-González Á. , Prieto M. , Putnis A. , López-Andrés S. 
Published: July 2002

AbstractOtavite-calcite solid solutions have been synthesized to investigate the factors which control the patterns of compositional zoning. The equilibrium partitioning of otavite between the aqueous and the solid phase can be described by means of a functionXCdCO3(XCd,aq)eq, which relates the solid mole fraction and the aqueous activity fraction of Cd. According to this function, there is a strong preferential partitioning of Cd towards the solid. A set of experiments starting with parent solutions with different Cd2+/Ca2+ratios was carried out. In these experiments nucleation takes place at high supersaturations and the Cd2+and Ca2+ions tend to be laid down in a ratio which deviates from the equilibrium distribution. Experimental nucleation data can be fitted to a curveXCdCO3(XCd,aq)efof the same functionality as that for equilibrium.After nucleation, supersaturation decreases as the crystals grow. During this process, substituting ions are not incorporated into the solid in the same stoichiometric proportion as in the aqueous solution. Therefore, crystal and fluid compositions tend to vary as growth proceeds and this evolution is registered as a compositional zoning. The curvesXCdCO3(XCd,aq)eqandXCdCO3(XCd,aq)efconfine the reaction path corresponding to the growth process. Here, these curves are used to account for the observed zoning patterns.
Molecular mechanism for ganciclovir resistance in human T lymphocytes transduced with retroviral vectors carrying the herpes simplex virus thymidine kinase gene
Authors: Garin Marina I. , Garrett Elaine , Tiberghien Pierre , Apperley Jane F. , Chalmers David , Melo Junia V. , Ferrand Christophe 
Published: July 2002

AbstractThe herpes simplex virus thymidine kinase gene type 1 (HSV-Tk) ganciclovir (GCV) system is a novel therapeutic strategy for the modulation of graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation (allo-SCT). Retroviral-mediated gene transfer of the HSV-Tk gene into donor T lymphocytes before allo-SCT may allow their in vivo selective depletion after treatment with GCV. The expression of theHSV-Tk gene was analyzed in vitro in CEM cells, a human lymphoblastoid cell line, transduced with 2 different vectors, each containing the HSV-Tk gene and a selectable marker gene. GCV-resistant clones were identified within the clones expressing the marker gene. Characterization of the molecular events leading to this resistance revealed a 227-bp deletion in the HSV-Tk gene due to the presence of cryptic splice donor and acceptor sites within the HSV-Tk gene sequence. Furthermore, it was confirmed that this deletion was present in human primary T cells transduced with either vector and in 12 patients who received transduced donor T cells, together with a T-cell–depleted allo-SCT. In vivo circulating transduced T cells containing the truncated HSV-Tk gene were identified in all patients immediately after infusion and up to 800 days after transplantation. In patients who received GCV as treatment for GVHD, a progressive increase in the proportion of transduced donor T cells carrying the deleted HSV-Tkgene was observed. These results suggest that the limitations within the HSV-Tk/GCV system can be improved by developing optimized retroviral vectors to ensure maximal killing ofHSV-Tk–transduced cells.
Recombinant human granulocyte colony-stimulating factor therapy for patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease type 1b
Authors: Calderwood Stanley , Kilpatrick Laurie , Douglas Steven D. , Freedman Melvin , Smith-Whitley Kim , Rolland Martha , Kurtzberg Joanne 
Published: July 2002

AbstractThe purpose of this study was to evaluate the efficacy and toxicity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy in patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease (GSD) type 1b. Thirteen patients with neutropenia and/or neutrophil dysfunction secondary to GSD type 1b were treated with rhG-CSF. The effects of therapy on neutrophil numbers and in vitro neutrophil function and on bone marrow cellularity and morphology were studied. The clinical status of the patients and the occurrence of adverse events associated with rhG-CSF use were monitored. Use of rhG-CSF therapy was associated with a significant increase in circulating neutrophil numbers (P &lt; .01) and an improvement in neutrophil function as assessed in vitro. In addition, rhG-CSF therapy produced a significant increase in marrow cellularity and an increase in myeloid:erythroid (M:E) ratio, indicating stimulation of granulopoeisis. No adverse effects on marrow function were noted; in particular, no myelodysplasia or marrow exhaustion was seen. Use of rhG-CSF therapy was associated with objective and subjective improvements in infection-related morbidity. The therapy was well tolerated, although all patients developed splenomegaly, and 5 patients developed mild hypersplenism that did not require any specific treatment. rhG-CSF therapy is efficacious in the management of neutropenia and neutrophil dysfunction associated with GSD type 1b. Patients on this therapy need to be monitored for hypersplenism. Continued follow-up will be necessary to confirm long-term safety; however, no significant short-term toxicity was noted.
Potent and specific antitumor effects of an anti-CD22–targeted cytotoxic ribonuclease: potential for the treatment of non-Hodgkin lymphoma
Authors: Newton Dianne L. , Hansen Hans J. , Mikulski Stanislaw M. , Goldenberg David M. , Rybak Susanna M. 
Published: July 2002

AbstractLL2, an anti-CD22 monoclonal antibody against B-cell lymphoma, was covalently linked to the amphibian ribonuclease, onconase, a member of the pancreatic RNase A superfamily. LL2 increased in vitro potency (10 000-fold) and specificity against human Daudi Burkitt lymphoma cells while decreasing systemic toxicity of onconase. Monensin further increased potency of LL2-onconase on Daudi cells (IC50, 20 and 1.5 pM, absence and presence of monensin, respectively). A 1-hour exposure to LL2-onconase was sufficient to kill Daudi cells in culture. These favorable in vitro properties translated to significant antitumor activity against disseminated Daudi lymphoma in mice with severe combined immunodeficiency disease. In mice inoculated with tumor cells intraperitoneally (ip), LL2-onconase (100 μg 5 times ip every day) increased the life span of animals with minimal disease 200%. The life span of mice with advanced disseminated Daudi lymphoma (tumor cells inoculated intravenously) was increased 135%. Mice injected with LL2-onconase tolerated a dose as high as 300 mg/kg. Because both onconase and LL2 are in clinical trials as cancer therapeutics, the covalently linked agents should be considered for treatment of non-Hodgkin lymphoma.
Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603
Authors: Lu Yue , Sakamaki Sumio , Kuroda Hiroyuki , Kusakabe Toshiro , Konuma Yuichi , Akiyama Takehide , Fujimi Akihito , Takemoto Naofumi , Nishiie Kyokusen , Matsunaga Takuya , Hirayama Yasuo , Kato Junji , Kon Shinichiro , Kogawa Katsuhisa , Niitsu Yoshiro 
Published: July 2002

AbstractAcute graft-versus-host diseases (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). T helper 1 (Th1)-type cytokines such as interferon-γ or tumor necrosis factor-α have been implicated in the pathogenesis of acute GVHD. TAK-603 is a new quinoline derivative, which is now in clinical trials for use as a disease-modifying antirheumatic drug. In preclinical studies, it inhibited delayed-type hypersensitivity, but not Arthus-type reaction, in mice, and selectively suppressed Th1 cytokine production. Thus, the present study was designed to investigate whether the Th1 inhibitor (TAK-603) ameliorates lethal acute GVHD in a mouse model. Administration of TAK-603 into BALB/c mice given 10 Gy total body irradiation followed by transplantation of bone marrow and spleen cells from C57BL/6 mice markedly reduced the mortality in association with minimal signs of GVHD pathology in the liver, intestine, and skin. TAK-603 reduced not only the production of Th1-type cytokines, but also the proportion of Th1 cells in CD4+ helper T cells in this GVHD mouse model. These results suggest that TAK-603 could be a potent therapeutic agent for acute lethal GVHD.
An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs
Authors: Gottschalk Stephen , Ng Catherine Y. C. , Perez Margot , Smith Colton A. , Sample Clare , Brenner Malcolm K. , Heslop Helen E. , Rooney Cliona M. 
Published: July 2002

AbstractThere is a growing interest in using antigen-specific T cells for the treatment of human malignancy. For example, adoptive transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) has been effective prophylaxis and treatment of EBV-associated lymphoproliferative disease in immunocompromised patients. For all immunotherapies, however, there has been a hypothetical concern that mutations in tumor-specific antigens may lead to tumor escape. We now demonstrate that such events may indeed occur, with lethal outcome. A patient who developed lymphoma after marrow transplantation received donor-derived, EBV-specific CTLs but died with progressive disease. The tumor cells proved substantially less sensitive to cytolysis than the EBV-transformed B-cell line used for CTL generation. The major cytolytic activity of the donor CTL was directed against 2 HLA-A11–restricted epitopes in the viral EBNA-3B antigen. Sequence analysis of this gene in the tumor virus revealed a 245–base pair deletion, which removed these 2 CTL epitopes. Hence, the viral antigen in the tumor had mutated in a way that allowed escape from CTLs. Analysis of EBV polymorphisms demonstrated that before CTL infusion, more than one virus was present, including a virus with wild-type EBNA-3B. After CTL infusion, only the virus with the EBNA-3B deletion could be detected, suggesting that the infused CTLs had selected a resistant strain in vivo. Such an occurrence, even when polyclonal CTL lines are used against genetically stable virus antigens, suggests that escape mutants may be a serious problem when CTL therapy is directed against more unstable tumor cell–derived targets.
Different expression of CD41 on human lymphoid and myeloid progenitors from adults and neonates
Authors: Debili Najet , Robin Catherine , Schiavon Valérie , Letestu Rémi , Pflumio Françoise , Mitjavila-Garcia Maria-Teresa , Coulombel Laure , Vainchenker William 
Published: July 2002

Abstract
The glycoprotein (Gp) IIb/IIIa integrin, also called CD41, is the platelet receptor for fibrinogen and several other extracellular matrix molecules. Recent evidence suggests that its expression is much wider in the hematopoietic system than was previously thought. To investigate the precise expression of the CD41 antigen during megakaryocyte (MK) differentiation, CD34+ cells from cord blood and mobilized blood cells from adults were grown for 6 days in the presence of stem cell factor and thrombopoietin. Two different pathways of differentiation were observed: one in the adult and one in the neonate cells. In the neonate samples, early MK differentiation proceeded from CD34+CD41− through a CD34−CD41+CD42− stage of differentiation to more mature cells. In contrast, in the adult samples, CD41 and CD42 were co-expressed on a CD34+ cell. The rare CD34+CD41+CD42− cell subset in neonates was not committed to MK differentiation but contained cells with all myeloid and lymphoid potentialities along with long-term culture initiating cells (LTC-ICs) and nonobese diabetic/severe combined immune-deficient repopulating cells. In the adult samples, the CD34+CD41+CD42−subset was enriched in MK progenitors, but also contained erythroid progenitors, rare myeloid progenitors, and some LTC-ICs. All together, these results demonstrate that the CD41 antigen is expressed at a low level on primitive hematopoietic cells with a myeloid and lymphoid potential and that its expression is ontogenically regulated, leading to marked differences in the surface antigenic properties of differentiating megakaryocytic cells from neonates and adults.
Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination
Authors: Stucki Anne , Rivier Anne-Sophie , Gikic Milica , Monai Natacha , Schapira Marc , Spertini Olivier 
Published: July 2002

AbstractLeukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested the hypothesis that adhesion receptors and cytokines secreted by blast cells play central roles in these reactions. Immunophenotypic studies showed that acute myeloid leukemia (AML) cells (n = 78) of the M0 to M5 subtypes of the French-American-British Cooperative Group expressed various amounts of adhesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15, and L-selectin. The presence of functional adhesion receptors was evaluated using a nonstatic adhesion assay. The number of blast cells attached to unactivated endothelium increased by 7 to 31 times after a 6-hour exposure of endothelium to tumor necrosis factor (TNF)-α. Inhibition studies showed that multiple adhesion receptors—including L-selectin, E-selectin, VCAM-1, and CD11/CD18—were involved in blast cell adhesion to TNF-α–activated endothelium. Leukemic cells were then cocultured at 37°C on unactivated endothelial cell monolayers for time periods up to 24 hours. A time-dependent increase in the number of blasts attached to the endothelium and a concomitant induction of ICAM-1, VCAM-1, and E-selectin were observed. Additional experiments revealed that endothelial cell activation by leukemic myeloblasts was caused by cytokine secretion by blast cells, in particular TNF-α and IL-1β, and direct contacts between adhesion receptors expressed by blast cells and endothelial cells. Thus, leukemic cells have the ability to generate conditions that promote their own adhesion to vascular endothelium, a property that may have important implications for the pathophysiology of leukostasis and tissue infiltration by leukemic blast cells.
Detection of viral interleukin-6 in Kaposi sarcoma–associated herpesvirus–linked disorders
Authors: Aoki Yoshiyasu , Yarchoan Robert , Wyvill Kathleen , Okamoto Shin-ichiro , Little Richard F. , Tosato Giovanna 
Published: July 2002

Abstract
Expression of a viral interleukin-6 (vIL-6) has been detected in certain Kaposi sarcoma (KS)–associated herpesvirus positive (KSHV+) lesions. The release of vIL-6 systemically and its contribution to the pathogenesis of HIV-related malignancies was studied. Serum vIL-6 was detected in 13 (38.2%) of 34 HIV+ patients with KS, in 6 (85.7%) of 7 HIV+patients with primary effusion lymphoma (PEL) and/or multicentric Castleman disease (MCD), and in 18 (60.0%) of 30 HIV+, mostly homosexual, individuals without KS, MCD, or PEL. By contrast, serum vIL-6 was detected in only 3 (23.1%) of 13 patients with classic KS, 1 (2.5%) of 40 blood donors from the United States, and 4 (19.0%) of 21 blood donors from Italy. Circulating vIL-6 levels were associated with HIV+ status (P &lt; .0001). However, within the HIV+ cohort, serum vIL-6 levels were not associated with the occurrence of KSHV-associated malignancies (P = .43).
Deoxygenation of sickle cells stimulates Syk tyrosine kinase and inhibits a membrane tyrosine phosphatase
Authors: Merciris Patrick , Hardy-Dessources Marie-Dominique , Giraud Françoise 
Published: July 2002

AbstractPolymerization of hemoglobin S in sickle red cells, in deoxygenated conditions, is associated with K+ loss and cellular dehydration. It was previously reported that deoxygenation of sickle cells increases protein tyrosine kinase (PTK) activity and band 3 tyrosine phosphorylation and that PTK inhibitors reduce cell dehydration. Here, the study investigates which PTKs are involved and the mechanism of their activation. Deoxygenation of sickle cells induced a 2-fold increase in Syk activity, measured by autophosphorylation in immune complex assays, but had no effect on Lyn. Syk was not stimulated by deoxygenation of normal red cells, and stimulation was partly reversible on reoxygenation of sickle cells. Syk activation was independent of the increase in intracellular Ca++ and Mg2+ associated with deoxygenation. Lectins that promote glycophorin or band 3 aggregation did not activate Syk. In parallel to Syk stimulation, deoxygenation of sickle cells, but not of normal red cells, decreased the activity of both membrane-associated protein tyrosine phosphatase (PTPs) and membrane protein thiol content. In vitro pretreatment of Syk immune complexes with membrane PTP inhibited Syk autophosphorylation. It is suggested that Syk activation in vivo could be mediated by PTP inhibition, itself resulting from thiol oxidation, as PTPs are known to be inhibited by oxidants. Altogether these data indicate that Syk could be involved in the mechanisms leading to sickle cell dehydration.
Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes
Authors: O'Connor Fiona F. , Shields Denis C. , Fitzgerald Anthony , Cannon Christopher P. , Braunwald Eugene , Fitzgerald Desmond J. 
Published: July 2002

AbstractThis study examined the influence of the PlApolymorphism of glycoprotein IIIa (GPIIIa) in determining the response to an oral GPIIb/IIIa antagonist, orbofiban, in patients with unstable coronary syndromes. Genotyping for the PlA polymorphism was performed in 1014 patients recruited into the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction 16) trial, in which patients were randomized to low- or high-dose orbofiban or placebo for 1 year. The primary end point (n = 165) was a composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke. Overall, orbofiban failed to reduce ischemic events when compared with placebo, but increased the rate of bleeding. In the whole population, PlA2 carriers had a significant increase in MI (n = 33) during follow up, with a relative risk (RR) of 2.71 (95% CI, 1.37 to 5.38; P = .004). There was a significant interaction between treatment (placebo and orbofiban) and the PlA polymorphism for bleeding (n = 187; P = .05). Thus, while orbofiban increased bleeding in noncarriers (RR = 1.87, 1.29 to 2.71;P &lt; .001) in a dose-dependent fashion, it did not increase bleeding events in PlA2 carriers (RR = 0.87, 0.46 to 1.64). There was no interaction between treatment (placebo and orbofiban) and the PlA polymorphism for the primary end point (P = .10). However, in the patients receiving orbifiban there was a higher risk of a primary event (RR = 1.55, 1.03 to 2.34; P = .04) and MI (RR 4.27, 1.82 to 10.03;P &lt; .001) in PlA2 carriers compared with noncarriers. In contrast, there was no evidence that PlA2influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the PlA polymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist.
High production of interferon γ but not interleukin-2 by human T-lymphotropic virus type I–infected peripheral blood mononuclear cells
Authors: Hanon Emmanuel , Goon Peter , Taylor Graham P. , Hasegawa Hitoshi , Tanaka Yuetsu , Weber Jonathan N. , Bangham Charles R. M. 
Published: July 2002

AbstractThe transactivator protein of human T-lymphotropic virus I (HTLV-I), Tax, has been associated with the up-regulation of several host cell genes, including interleukin 2 (IL-2), the IL-2 receptor-α(IL-2Rα) chain (CD25), interferon γ(IFN-γ), and tumor necrosis factor (TNF). It has been proposed that an IL-2/CD25 autocrine loop plays a part in maintaining the very high proviral loads often found in HTLV-I infection. Furthermore, abnormal production of inflammatory cytokines might contribute to the pathogenesis of the inflammatory diseases associated with HTLV-I infection. However, there has been no study of the expression of these genes in freshly isolated peripheral blood mononuclear cells (PBMCs) naturally infected with HTLV-I. In the present study, flow cytometry was used to determine which cytokines are produced by freshly isolated PBMCs that spontaneously express the HTLV-I Tax protein. Surprisingly, the results show that intracellular Tax expression is associated with rapid up-regulation of IFN-γ but not TNF or IL-2. A proportion of HTLV-I–infected cells express both IFN-γ and the surface markers of effector memory cells. Such cells are capable of migration through peripheral tissues and could therefore contribute to the inflammation seen in diseases such as HTLV-I–associated myelopathy/tropical spastic paraparesis.
The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression
Authors: Gao Jin , Richardson Des R. 
Published: July 2002

AbstractSome chelators of the pyridoxal isonicotinoyl hydrazone class have antiproliferative activity that is far greater than desferrioxamine (DFO). In this study, DFO was compared with one of the most active chelators (311) on the expression of molecules that play key roles in cell-cycle control. This was vital for understanding the role of iron (Fe) in cell-cycle progression and for designing chelators to treat cancer. Incubating cells with DFO, and especially 311, resulted in a decrease in the hyperphosphorylated form of the retinoblastoma susceptibility gene product (pRb). Chelators also decreased cyclins D1, D2, and D3, which bind with cyclin-dependent kinase 4 (cdk4) to phosphorylate pRb. The levels of cdk2 also decreased after incubation with DFO, and especially 311, which may be important for explaining the decrease in hyperphosphorylated pRb. Cyclins A and B1 were also decreased after incubation with 311 and, to a lesser extent, DFO. In contrast, cyclin E levels increased. These effects were prevented by presaturating the chelators with Fe. In contrast to DFO and 311, the ribonucleotide reductase inhibitor hydroxyurea increased the expression of all cyclins. Hence, the effect of chelators on cyclin expression was not due to their ability to inhibit ribonucleotide reductase. Although chelators induced a marked increase in WAF1 and GADD45 mRNA transcripts, there was no appreciable increase in their protein levels. Failure to translate these cell-cycle inhibitors may contribute to dysregulation of the cell cycle after exposure to chelators.