bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia
Authors: Coustan-Smith Elaine , Sancho Jose , Behm Frederick G. , Hancock Michael L. , Razzouk Bassem I. , Ribeiro Raul C. , Rivera Gaston K. , Rubnitz Jeffrey E. , Sandlund John T. , Pui Ching-Hon , Campana Dario 
Published: October 2002

Abstract
Early clearance of leukemic cells is a favorable prognostic indicator in childhood acute lymphoblastic leukemia (ALL). However, identification of residual leukemic cells by their morphologic features is subjective and lacks sensitivity. To improve estimates of leukemia clearance, we applied flow cytometric techniques capable of detecting 1 leukemic cell in 10 000 or more normal cells and prospectively measured residual leukemia in bone marrow samples collected on day 19 of remission-induction chemotherapy from 248 children with newly diagnosed ALL. In 134 samples (54.0%), we identified at least 0.01% leukemic cells (0.01%-&lt; 0.1% in 51 samples [20.6%], 0.1%-&lt; 1% in 36 [14.5%], and ≥ 1% in 47 [19.0%]). Among 110 children treated within a single chemotherapy program, the 5-year mean ± SE cumulative incidence of relapse or failure to achieve remission was 32.2% ± 6.5% for the 59 patients with 0.01% residual leukemic cells or greater on day 19 and 6.0% ± 3.4% for the 51 patients with less than 0.01% leukemic cells (P &lt; .001). The prognostic value of day-19 bone marrow status defined by flow cytometry was superior to that defined by morphologic studies and remained significant after adjustment for other clinical and biologic variables. Lack of detectable leukemic cells on day 19 was more closely associated with relapse-free survival than was lack of detectable residual disease at the end of remission induction (day 46). Thus, approximately half of the children with ALL achieve profound clearance of leukemic cells after 2 to 3 weeks of remission-induction chemotherapy, and these patients have an excellent treatment outcome.
Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses
Authors: Juul Klaus , Tybjærg-Hansen Anne , Steffensen Rolf , Kofoed Steen , Jensen Gorm , Nordestgaard Børge Grønne 
Published: October 2002

AbstractFactor V Leiden (FVL) is associated with venous thrombosis; however, an association between FVL and arterial thrombosis remains controversial. We investigated FVL as a risk factor for myocardial infarction (MI), ischemic stroke (IS), or non-MI ischemic heart disease (non-MI–IHD). The design was 3 case-control studies and 3 prospective studies with 21 years' follow-up. The setting was the general population in Copenhagen, Denmark. The participants for The Copenhagen City Heart Study were 20- to 95-year-old participants without cardiovascular disease (control population, n = 7907) or participants diagnosed with MI (n = 469), IS (n = 231), or non-MI–IHD (n = 365). In addition, 3 independent patient populations from Copenhagen University Hospital with MI (n = 493), IS (n = 231), or non-MI–IHD (n = 448) were included. We measured FVL genotype; major cardiovascular risk factors; and MI, IS, and non-MI–IHD incidence and prevalence. Prevalences of FVL heterozygotes and homozygotes in control subjects from the general population were 7.7% and 0.2%. Odds ratios and relative risks of MI in FVL carriers (heterozygotes + homozygotes) versus noncarriers were 1.24 (95% confidence interval [CI], 0.91-1.69) and 0.83 (0.58-1.20) in case-control and prospective studies, respectively. Corresponding risks for IS were 0.92 (95% CI, 0.56-1.53) and 0.68 (0.45-1.04), and for non-MI–IHD 1.01 (95% CI, 0.71-1.44) and 0.97 (0.66-1.42). Findings from The Copenhagen City Heart Study suggest that FVL is not associated with MI, IS, or non-MI–IHD.
Epstein-Barr virus–specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential
Authors: Dunne Padraic J. , Faint Jeffery M. , Gudgeon Nancy H. , Fletcher Jean M. , Plunkett Fiona J. , Soares Maria Vieira D. , Hislop Andrew D. , Annels Nicola E. , Rickinson Alan B. , Salmon Mike , Akbar Arne N. 
Published: October 2002

AbstractDuring acute infection, latent and lytic Epstein-Barr virus (EBV) epitope-specific CD8+ T cells have a CD45RO+CD45RA− phenotype. However, after resolution of the infection, a large proportion of these cells, particularly those specific for lytic viral epitopes, re-express the CD45RA molecule. The role of CD8+ CD45RA+ T cells in ongoing immunity to EBV and other viruses is unknown. We now demonstrate that, relative to their CD45RO+ counterparts, the EBV-specific CD8+ T cells that revert to CD45RA expression after acute infectious mononucleosis are not in cell cycle, have longer telomeres, and are more resistant to apoptosis partly because of increased Bcl-2 expression. However, the EBV-specific CD8+CD45RA+ T cells have shorter telomeres than the total CD8+ CD45RA+ T-cell pool and predominantly express low levels of the CCR7 chemokine receptor, indicating that they are not naive cells. In addition, EBV-specific CD8+CD45RA+ T cells can be induced to proliferate and exhibit potent cytotoxic activity against target cells loaded with specific peptide. Our results strongly suggest, therefore, that EBV-specific CD8+ CD45RA+ T cells represent a stabilized virus-specific memory pool and not terminally differentiated effector cells. The identification of mechanisms that enable stable virus-specific CD8+ T cells to persist after acute infection may lead to the enhancement of antiviral immunity in immunocompromised and elderly persons.
Sperm protein 17 (Sp17) is a suitable target for immunotherapy of multiple myeloma
Authors: Chiriva-Internati Maurizio , Wang Zhiqing , Salati Emanuela , Bumm Klaus , Barlogie Bart , Lim Seah H. 
Published: October 2002

Abstract
Sperm protein 17 (Sp17) is a protein recently identified as a novel cancer-testis (CT) antigen in multiple myeloma (MM). Because this tumor antigen demonstrates a very restricted normal tissue expression, Sp17 may be an excellent target for tumor vaccine of MM. In this study, we determined the ability to generate Sp17-specific HLA class I–restricted cytotoxic T lymphocytes (CTLs) from the peripheral blood of 4 patients with MM, 3 consecutive Sp17+patients, and 1 Sp17− patient. Dendritic cells were generated from monocytes of 4 patients with MM and used to present a recombinant Sp17 protein to autologous T cells. Following 4 rounds of antigen stimulation, the CTLs were tested for their ability to kill autologous targets in an Sp17-dependent and HLA-class I– restricted manner in standard cytotoxicity assays. Despite previous chemotherapy and the immunosuppression so often associated with MM, CTL generation was successful in all 4 patients, irrespective of the Sp17 status of their tumors. Most importantly, the CTLs were able to lyse autologous tumor cells that expressed Sp17. Tumor cell lysis in all cases appeared to be mainly mediated by perforin and could be blocked by concanamycin A. We conclude that Sp17 is a suitable target for immunotherapy of MM. Our findings provide the basis for a clinical study aimed at inducing a cellular immune response directed at Sp17+ MM.
Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy
Authors: Wilson Wyndham H. , Grossbard Michael L. , Pittaluga Stefania , Cole Diane , Pearson Deborah , Drbohlav Nicole , Steinberg Seth M. , Little Richard F. , Janik John , Gutierrez Martin , Raffeld Mark , Staudt Louis , Cheson Bruce D. , Longo Dan L. , Harris Nancy , Jaffe Elaine S. , Chabner Bruce A. , Wittes Robert , Balis Frank 
Published: October 2002

AbstractWe hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 × 109/L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r = −0.54 andP2 = .08 and r = −0.45 andP2 = .034, respectively). Free-etoposide clearance increased significantly during successive cycles (P2 = .015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P2 = .04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EPOCH may produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance over time.
Autoimmunity in human primary immunodeficiency diseases
Authors: Arkwright Peter D. , Abinun Mario , Cant Andrew J. 
Published: October 2002

AbstractHuman primary immunodeficiency diseases are experiments of nature characterized by an increased susceptibility to infection. In many cases, they are also associated with troublesome and sometimes life-threatening autoimmune complications. In the past few years, great strides have been made in understanding the molecular basis of primary immunodeficiencies, and this had led to more focused and successful treatment. This review has 3 aims: (1) to highlight the variety of autoimmune phenomena associated with human primary immunodeficiency diseases; (2) to explore how primary immunodeficiencies predispose patients to autoimmune phenomena triggered by opportunistic infections; and (3) to consider the rationale for the current treatment strategies for autoimmune phenomena, specifically in relation to primary immunodeficiency diseases. Reviewing recent advances in our understanding of the small subgroup of patients with defined causes for their autoimmunity may lead to the development of more effective treatment strategies for idiopathic human autoimmune diseases.
Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells
Authors: Samper Enrique , Fernández Piedad , Eguı́a Raúl , Martı́n-Rivera Luis , Bernad Antonio , Blasco Marı́a A. , Aracil Miguel 
Published: October 2002

AbstractTelomere length must be tightly regulated in highly proliferative tissues, such as the lymphohematopoietic system. Under steady-state conditions, the levels and functionality of hematopoietic-committed or multipotent progenitors were not affected in late-generation telomerase-deficient mice (mTerc−/−) with critically short telomeres. Evaluation of self-renewal potential of mTerc−/− day-12 spleen colony-forming units demonstrated no alteration as compared with wildtype progenitors. However, the replating ability of mTerc−/− granulocyte-macrophage CFUs (CFU-GMs) was greatly reduced as compared with wildtype CFU-GMs, indicating a diminished capacity of late-generation mTerc−/− committed progenitors when forced to proliferate. Long-term bone marrow cultures of mTerc−/−bone marrow (BM) cells show a reduction in proliferative capacity; this defect can be mainly attributed to the hematopoietic, not to the stromal, mTerc−/− cells. In serial and competitive transplantations, mTerc−/− BM stem cells show reduced long-term repopulating capacity, concomitant with an increase in genetic instability compared with wildtype cells. Nevertheless, in competitive transplantations late-generation mTerc−/− precursors can occasionally overcome this proliferative impairment and reconstitute irradiated recipients. In summary, our results demonstrate that late-generation mTerc−/− BM cells with short telomeres, although exhibiting reduced proliferation ability and reduced long-term repopulating capacity, can still reconstitute myeloablated animals maintaining stem cell function.
B7-CTLA4 interaction promotes cognate destruction of tumor cells by cytotoxic T lymphocytes in vivo
Authors: Bai Xue-Feng , Liu Jinqing , May Kenneth F. , Guo Yong , Zheng Pan , Liu Yang 
Published: October 2002

AbstractCostimulatory molecules B7-1 and B7-2 (hereby collectively called B7) interact with CD28 and CTLA4 on T cells and promote antitumor immunity. The function of B7-CTLA4 interaction in antitumor CTL response remains controversial. Here we used CD28−/− and CD28+/− or CD28+/+ transgenic mice that express the T-cell receptor specific for an unmutated tumor antigen, P1A, and for tumor cells expressing a CTLA4-specific B7 mutant to evaluate the function of CD28-B7 and CTLA4-B7 interactions in induction and effector phases of antitumor immunity. We report that B7-CD28 and B7-CTLA4 interactions promote tumor rejection. However, this is achieved by distinct mechanisms. B7-CD28 interaction enhances T-cell clonal expansion, though a role for this interaction in the effector phase cannot be ruled out. In contrast, B7-CTLA4 interaction enhances the CTL-mediated destruction of tumors, but not T-cell clonal expansion.
CD95 engagement induces disseminated endothelial cell apoptosis in vivo: immunopathologic implications
Authors: Janin Anne , Deschaumes Christophe , Daneshpouy Marjan , Estaquier Jérôme , Micic-Polianski Juliette , Rajagopalan-Levasseur Premavathy , Akarid Khadija , Mounier Nicolas , Gluckman Eliane , Socié Gérard , Ameisen Jean Claude 
Published: October 2002

AbstractFas (CD95) is a death receptor involved in apoptosis induction on engagement by Fas ligand (CD95L). Although CD95L-mediated apoptosis has been proposed as a pathogenic mechanism in a wide range of diseases, including graft-versus-host disease, systemic CD95 engagement in mice by agonistic CD95-specific antibodies or by soluble multimeric CD95L (smCD95L), though lethal, has been reported to cause apoptosis only in a limited range of cell types, that is, hepatocytes, hepatic sinusoidal endothelial cells, and lymphocytes. Another member of the tumor necrosis factor (TNF)/CD95L family, TNF-α, induces disseminated vascular endothelial cell apoptosis, which precedes apoptosis of other cell types and lethal multiorgan failure. Here we show that systemic CD95 engagement in vivo by agonistic CD95-specific antibody or smCD95L causes rapid, extensive, and disseminated endothelial cell apoptosis throughout the body, by a mechanism that does not depend on TNF-α. Disseminated endothelial cell apoptosis was also the first detectable lesion in a murine model of acute tissue damage induced by systemic transfer of allogeneic lymphocytes and did not occur when allogeneic lymphocytes were from CD95L-defective mice. Both vascular and additional tissue lesions induced by agonistic CD95-specific antibody, smCD95L, or allogeneic lymphocytes were prevented by treatment with an inhibitor of caspase-8, the upstream caspase coupled to CD95 death signaling. Vascular lesions are likely to play an important role in the pathogenesis of allogeneic immune responses and of other diseases involving circulating CD95L-expressing cells or smCD95L, and the prevention of CD95-mediated death signaling in endothelial cells may have therapeutic implications in these diseases.
HLA-B7 β-pleated sheet-derived synthetic peptides are immunodominant T-cell epitopes regulating alloresponses
Authors: Freese Anja , Zavazava Nicholas 
Published: October 2002

AbstractChronic rejection of transplanted allografts is the major cause of graft loss after clinical solid organ transplantation. Recent data link the indirect presentation of allopeptides to chronic graft loss; thus, identification of immunodominant epitopes on major histocompatibility complex (MHC) antigens could significantly contribute to establishing novel ways for monitoring and managing chronic rejection. Here, we show that synthetic allo-MHC–derived peptides covering the polymorphic region 56 to120 of HLA-B7 modulate alloresponses. In particular, the 2 β-pleated sheet-derived peptides covering residues 91 to 105 and 96 to 120, respectively, but not sequences from the α1 helix, were presented by autologous peripheral blood lymphocytes to induce T-cell proliferation. In addition, the 2 β-pleated sheet-derived peptides and the α1-derived peptide residues 60 to 75 abrogated lysis of HLA-B7 target cells by anti–HLA-B7 cytotoxic T lymphocytes (CTLs). Although most residues between 91 and 120 are normally not directly accessible to T cells, our results indicate that peptides derived from the lower surface of the peptide-binding groove of HLA-B7 are immunodominant in HLA-B7 alloresponses. To characterize the binding and stability of allopeptides to T cells, the 62-70 peptide—derived from the 60-75 allopeptide that blocked cytotoxicity of anti–HLA-B7 CTL—was synthesized and coupled with fluorescein isothiocyanate. The peptide specifically labeled anti-B7 CTL, but not anti–HLA-A2 CTL as measured by flow cytometry. Peptide binding to CTL was specific at 4°C and remained stable for 12 hours, whereas it remained stable for less than 2 hours at 37°C. These studies allow the identification of HLA-B7 T-cell epitopes and reveal for the first time a novel, previously unrecognized application of synthetic HLA-derived allopeptides to visualize alloreactive T cells.
Cytokine production and cytolytic mechanism of CD4+cytotoxic T lymphocytes in ex vivo expanded therapeutic Epstein-Barr virus–specific T-cell cultures
Authors: Sun Qi , Burton Robert L. , Lucas Kenneth G. 
Published: October 2002

AbstractEx vivo expanded Epstein-Barr virus (EBV)–specific T cells have been successfully applied clinically for adoptive immunotherapy. However, the role of CD4+ T cells in the therapeutic T-cell culture has not been established for the reconstitution of EBV-specific immunity. We isolated and characterized CD4+ T-cell lines from the ex vivo T-cell cultures. Monoclonal line PD-F4 and oligoclonal lines ND-R4 and TD-B4 were CD3+CD4+CD8−. Cytolytic tests with targets of mismatched major histocompatibility complex (MHC) and anti-MHC antibodies confirmed that the cytotoxicity of these CD4+ cells was restricted by MHC class II. Single cells of ND-R4 expressed interferon-γ (IFN-γ, or interleukin 4 (IL-4), but rarely coexpressed these 2 cytokines. In contrast, PD-F4 coexpressed IFN-γ, IL-2, and IL-4. Kinetic studies with PD-F4 showed that expression of the 3 cytokines plateaued 5 hours upon stimulation and was then drastically reduced, with a pattern consistent with independent modulation and differential off-cycle signal requirements. The cytotoxicity of these CD4+ cells was largely resistant to brefeldin A, an inhibitor for cytolytic pathways by Fas-ligand family molecules. Although sensitive to concanamycin A and ethyleneglycotetraacetic acid, which inhibit cytotoxicity by granule exocytosis, the CD4+ cytotoxic T lymphocytes (CTLs) did not express perforin, suggesting a cytotoxic mechanism independent of perforin although involving exocytosis. Flow cytometric analysis showed that the CD4+ CTLs expressed granulysin, a recently identified cytolytic molecule associated with exocytotic cytolytic granules. These data suggested that CD4+ T cells in the therapeutic B-lymphoblastoid cell lines–primed T-cell culture are diverse in producing TH1 and TH2 cytokines, and may exert specific cytotoxicity via exocytosis of granulysin.
MDM2 induces NF-κB/p65 expression transcriptionally through Sp1-binding sites: a novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia
Authors: Gu Lubing , Findley Harry W. , Zhou Muxiang 
Published: October 2002

Abstract
MDM2 protein is thought to exhibit tumorigenic activity by binding to the p53 tumor-suppressor protein and inhibiting its function. Alternatively, MDM2 may have oncogenic roles other than those resulting from p53 interactions. Here we report that MDM2 can induce expression of the p65 subunit of NF-κB, which is an anti-apoptotic factor expressed in certain neoplastic cells in response to chemotherapy. Initially, we noted that the overexpression of MDM2 protein in leukemic bone marrow cells of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and an ALL cell line (EU-4) transfected with theMDM2 gene was associated with elevated expression of p65 and in vitro resistance to doxorubicin (Adriamycin). By cotransfection of the MDM2 gene and p65-promoter-reporter constructs into EU-4 cells, we found that transient and high-level MDM2 expression induced p65 promoter activity. In the presence of wild-type (wt) p53, MDM2 increased p65 promoter activity by reversing p53-mediated suppression of p65. In the absence of p53, MDM2 directly increased p65 promoter activity. Deletion and mutation analysis of the p65 promoter indicated that the region between nt −575 and −178, which contains the first and second Sp1-binding sites, was required for activation by MDM2. Further studies using chromatin immunoprecipitation (CHIP) and electrophoretic mobility shift assay (EMSA) showed that MDM2 was able to directly bind to the Sp1 site of the p65 promoter. Our findings suggest that by inducing p65 expression, MDM2 has a p53-independent role in tumorigenesis, which may further elucidate the association between MDM2 overexpression and resistant disease in childhood ALL.
Ex vivo treatment of proliferating human cord blood stem cells with stroma-derived factor–1 enhances their ability to engraft NOD/SCID mice
Authors: Glimm Hanno , Tang Patrick , Clark-Lewis Ian , von Kalle Christof , Eaves Connie 
Published: October 2002

Abstract
Ex vivo proliferation of hematopoietic stem cells (HSCs) is important for cellular and gene therapy but is limited by the observation that HSCs do not engraft as they transit S/G2/M. Recently identified candidate inhibitors of human HSC cycling are transforming growth factor-β1(TGF-β1) and stroma-derived factor–1 (SDF-1). To determine the ability of these factors to alter the transplantability of human HSCs proliferating in vitro, lin− cord blood cells were first cultured for 96 hours in serum-free medium containing Flt3 ligand, Steel factor, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor. These cells were then transferred to medium containing Steel factor and thrombopoietin with or without SDF-1 and/or TGF-β1 for 48 hours. Exposure to SDF-1 but not TGF-β1 significantly increased (&gt; 2-fold) the recovery of HSCs able to repopulate nonobese diabetic/severe combined immunodeficiency mice. These results suggest new strategies for improving the engraftment activity of HSCs stimulated to proliferate ex vivo.