bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of exogenous interleukin-7 on human thymus function
Authors: Okamoto Yukari , Douek Daniel C. , McFarland Richard D. , Koup Richard A. 
Published: October 2002

AbstractImmune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a+CD3−CD4+CD8+stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3− cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-αβ rearrangement and indicate the potential use of IL-7 for enhancing de novo naı̈ve T-cell generation in immunocompromised patients.
Activated eosinophils in upper gastrointestinal tract of patients with graft-versus-host disease
Authors: Daneshpouy Marjan , Socie Gerard , Lemann Marc , Rivet Jacqueline , Gluckman Eliane , Janin Anne 
Published: October 2002

AbstractDigestive tract damage during graft-versus-host reaction (GVHR) causes high morbidity and mortality. Diagnosis is often late because biopsies are performed when clinical signs are severe and pathologic markers of early inflammatory lesions are lacking. Eosinophils are inflammatory cells, cytotoxic in vitro to digestive epithelium; they are found in biopsy specimens taken during acute flare-ups of inflammatory bowel disease. We performed systematic duodenal biopsies immediately after digestive symptoms occurred and found a digestive GVHR incidence of 73.1% (n = 93), higher than that found when digestive biopsies were performed immediately after severe clinical signs. Eosinophils were only present when there were histologic signs of GVHR; eosinophil presence correlated with GVHR severity. Electron microscopy with immunogold staining showed pathologic signs of in situ eosinophil activation, such as cytoplasmic granule alterations, and eosinophil peroxidase release in all patients. Interleukin-5 presence in activated eosinophils suggests eosinophil recruitment in digestive GVHR is an autocrine mechanism. Eosinophil density also correlated with GVHR severity, whether in acute or chronic clinical phases. Tissue eosinophils could thus be a marker of acute inflammatory flare-ups in GVHR. Systematic duodenal biopsy performed at the onset of digestive symptoms should allow early GVHR detection, and pathologic signs of GVHR, together with eosinophil density, might help modulate immunosuppressive therapy.
Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration
Authors: Ticchioni Michel , Charvet Céline , Noraz Nelly , Lamy Laurence , Steinberg Marcos , Bernard Alain , Deckert Marcel 
Published: October 2002

AbstractTransendothelial migration of activated lymphocytes from the blood into the tissues is an essential step for immune functions. The housekeeping chemokine CXCL12 (or stroma cell–derived factor-1α), a highly efficient chemoattractant for T lymphocytes, drives lymphocytes to sites where they are highly likely to encounter antigens. This suggests that cross-talk between the T-cell receptor (TCR) and CXCR4 (the CXCL12 receptor) might occur within these sites. Here we show that the zeta-associated protein 70 (ZAP-70), a key element in TCR signaling, is required for CXCR4 signal transduction. The pharmacologic inhibition of ZAP-70, or the absence of ZAP-70 in Jurkat T cells and in primary CD4+ T cells obtained from a patient with ZAP deficiency, resulted in an impairment of transendothelial migration that was rescued by the transfection of ZAP-70. Moreover, the overexpression of mutated forms of ZAP-70, whose kinase domain was inactivated, also abrogated the migratory response of Jurkat T cells to CXCL12. In contrast, no involvement of ZAP-70 in T-cell arrest on inflammatory endothelium under flow conditions or in CXCL12-induced actin polymerization was observed. Furthermore, CXCL12 induced time-dependent phosphorylation of ZAP-70, Vav1, and extracellular signal-regulated kinases (ERKs); the latter were reduced in the absence of functional ZAP-70. However, though a dominant-negative Vav1 mutant (Vav1 L213A) blocked CXCL12-induced T-cell migration, pharmacologic inhibition of the ERK pathway did not affect migration, suggesting that ERK activation is dispensable for T-cell chemotaxis. We conclude that cross-talk between the ZAP-70 signaling pathway and the chemokine receptor CXCR4 is required for T-cell migration.
Modulation of p210BCR-ABL activity in transduced primary human hematopoietic cells controls lineage programming
Authors: Chalandon Yves , Jiang Xiaoyan , Hazlewood Glen , Loutet Slade , Conneally Eibhlin , Eaves Allen , Eaves Connie 
Published: October 2002

AbstractRetroviral transduction of primary hematopoietic cells with human oncogenes provides a powerful approach to investigating the molecular mechanisms controlling the normal proliferation and differentiation of these cells. Here we show that primitive human CD34+ cord blood cells, including multipotent as well as granulopoietic- and erythroid-restricted progenitors, can be efficiently transduced with a MSCV-BCR-ABL-IRES-GFP retrovirus, resulting in the sustained expression by their progeny of very high levels of tyrosine phosphorylated p210BCR-ABL. Interestingly, even in the presence of growth factors that supported the exclusive production of granulopoietic cells from green fluorescent protein (GFP)–transduced control cells, BCR-ABL–transduced progenitor subpopulations generated large numbers of erythropoietin-independent terminally differentiating erythroid cells and reduced numbers of granulopoietic cells. Analyses of individual clones generated by single transduced cells in both semisolid and liquid cultures showed this BCR-ABL–induced erythroid differentiation response to be elicited at a high frequency from all types of transduced CD34+ cells independent of their apparent prior lineage commitment status. Additional experiments showed that this erythroid differentiation response was largely prevented when the cells were transduced and maintained in the presence of the BCR-ABL–specific tyrosine kinase inhibitor, STI-571. These findings indicate that overexpression of BCR-ABL in primary human hematopoietic cells can activate an erythroid differentiation program in apparently granulopoietic-restricted cells through a BCR-ABL kinase-dependent mechanism, thus providing a new molecular tool for elucidating mechanisms underlying lineage fate determination in human hematopoietic cells and infidelity in human leukemia.
Accumulation of c-Cbl and rapid termination of colony-stimulating factor 1 receptor signaling in interferon consensus sequence binding protein–deficient bone marrow–derived macrophages
Authors: Kallies Axel , Rosenbauer Frank , Scheller Marina , Knobeloch Klaus-Peter , Horak Ivan 
Published: October 2002

AbstractMice deficient for the transcription factor interferon consensus sequence binding protein (ICSBP) are immunodeficient and develop granulocytic leukemia. Further analyses indicated that ICSBP is a molecular switch factor directing the differentiation of bipotential myeloid precursors to the monocytic lineage. To reveal the molecular mechanisms responsible for the deregulation of myelopoiesis, we examined the signaling of the colony-stimulating factor 1 receptor (CSF-1R) in bone marrow–derived macrophages (BMMs) from ICSBP−/− mice. We found that in the absence of ICSBP, CSF-1R signaling is attenuated as seen from an accelerated termination of Erk phosphorylation and reduced cell growth. This finding coincides with an increased CSF-1R ubiquitination and an enhanced accumulation of c-Cbl. c-Cbl is an ubiquitin-ligase known to down-regulate activated CSF-1R by targeting it to the endocytic pathway. Our results indicate that upon CSF-1R activation, c-Cbl itself is partly proteolytically degraded in ICSBP+/+ but not in ICSBP−/−BMMs. Congruently, the expression of a major endosomal/lysosomal protease, cathepsin B, is strongly reduced in ICSBP−/− BMMs.
Interleukin-7–treated naive T cells can be productively infected by T-cell–adapted and primary isolates of human immunodeficiency virus 1
Authors: Steffens Carolyn M. , Managlia Elizabeth Z. , Landay Alan , Al-Harthi Lena 
Published: October 2002

AbstractAlthough human immunodeficiency virus (HIV)gag/pol DNA can be detected in naive T cells, whether naive T cells can be productively infected by HIV is still questionable. Given that interleukin-7 (IL-7) is a prospective therapeutic immunomodulator for the treatment of HIV, we evaluated the effect of IL-7 on promoting naive T-cell infection of laboratory-adapted (IIIB), M-tropic, and primary isolates of HIV. Initially, we determined that the 3 cell surface markers widely used to identify naive T cells (CD45RA+CD45RO−, CD45RA+CD62L+, and CD45RO−CD27+CD95low) are all equivalent in T-cell receptor excision circle content, a marker for the replicative history of a cell as well as for de novo T cells. We therefore used CD45RA+CD45RO− expression to define naive T cells in this study. We demonstrate that although untreated or IL-2–treated naive T cells are not productively infected by HIV, IL-7 pretreatment mediated the productive infection of laboratory-adapted, M-tropic, and primary isolates of HIV as determined by p24 core antigen production. This up-regulation was between 8- and 58-fold, depending on the HIV isolate used. IL-7 pretreatment of naive T cells also potently up-regulated surface expression of CXCR4 but not CCR5 and mediated the expansion of naive T cells without the acquisition of the primed CD45RO phenotype. Collectively, these data indicate that IL-7 augments naive T-cell susceptibility to HIV and that under the appropriate environmental milieu, naive T cells may be a source of HIV productive infection. This information needs to be considered in evaluating IL-7 as an immunomodulator for HIV-infected patients.
Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor–induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration
Authors: Ueda Shuji , Mizuki Masao , Ikeda Hirokazu , Tsujimura Tohru , Matsumura Itaru , Nakano Kazushi , Daino Hanako , Honda Zen-ichiro , Sonoyama Junko , Shibayama Hirohiko , Sugahara Hiroyuki , Machii Takashi , Kanakura Yuzuru 
Published: October 2002

AbstractStem cell factor (SCF) has crucial roles in proliferation, survival, and differentiation of hematopoietic stem cells and mast cells through binding to c-Kit receptor (KIT). Chemotaxis is another unique function of SCF. However, little is known about the intracellular signaling pathway of SCF/KIT-mediated cell migration. To investigate the signaling cascade, we made a series of 22 KIT mutants, in which tyrosine (Y) residue was substituted for phenylalanine (F) in the cytoplasmic domain, and introduced into BAF3 cells or 293T cells. On stimulation with SCF, BAF3 expressing KITWT(WT) showed cell migration and Ca2+ mobilization. Among 22 YF mutants, Y567F, Y569F, and Y719F showed significantly reduced cell migration and Ca2+ mobilization compared to WT. In Y567F, Lyn activation on SCF stimulation decreased and C-terminal Src kinase (Csk) suppressed KIT-mediated Ca2+ influx and cell migration, suggesting that Y567-mediated Src family kinase (SFK) activation leads to Ca2+ influx and migration. Furthermore, we found that p38 mitogen-activated protein kinase (p38 MAPK) and Erk1/2 were also regulated by Y567/SFK and involved in cell migration, and that p38 MAPK induced Ca2+ influx, thereby leading to Erk1/2 activation. In Y719F, the binding of phosphatidylinositol 3′-kinase (PI3K) to KIT was lost and KIT-mediated cell migration and Ca2+ mobilization were suppressed by PI3K chemical inhibitors or dominant-negative PI3K, suggesting the involvement of Y719-mediated PI3K pathway in cell migration. Combination of Csk and the PI3K inhibitor synergistically reduced cell migration, suggesting the cooperation of SFK and PI3K. Taken together, these results indicate that 2 major KIT signaling pathways lead to cell migration, one is Y567-SFK-p38 MAPK-Ca2+ influx-Erk and the other is Y719-PI3K-Ca2+ influx.
Identification of an HLA  A*0201–restricted CD8+T-cell epitope for the glycoprotein B homolog of human herpesvirus 8
Authors: Wang Qiong J. , Huang Xiao-Li , Rappocciolo Giovanna , Jenkins Frank J. , Hildebrand William H. , Fan Zheng , Thomas Elaine K. , Rinaldo Charles R. 
Published: October 2002

AbstractHuman herpesvirus 8 (HHV-8; Kaposi sarcoma–associated herpesvirus)–specific cytotoxic T-lymphocyte (CTL) and interferon-γ (IFN-γ) responses to proteins produced during the lytic cycle of HHV-8 replication are mediated by HLA class I–restricted, CD8+ T cells. We have characterized the fine specificity of the CD8+ T-cell response to 25 peptides derived from 5 HHV-8 lytic cycle proteins based on a prediction model for HLA A*0201 binding motifs. One of the 25 HLA A*0201 peptides derived from the glycoprotein B (gB) homolog of Epstein-Barr virus (gB492-500; LMWYELSKI; single-letter amino acid codes) bound to HLA A*0201 and stimulated IFN-γ responses in CD8+ T cells from HHV-8+, HLA A*0201 persons, but not HHV-8–seronegative or non–HLA A*0201 persons. The peptide also induced IFN-γ and CTL reactivity to naturally processed gB protein. The peptide was a major immunogenic epitope of HHV-8 as indicated by induction of IFN-γ responses in peripheral blood mononuclear cells from 5 of 5 HHV-8 seropositive, HLA A*0201 persons when gB492-500 was presented by autologous dendritic cells. T-cell reactivity to gB492-500 was not related to detectable HHV-8 DNA in the blood. These data show that CD8+ T cells recognize an HLA A*0201–restricted epitope for HHV-8 lytic cycle protein gB, particularly when presented by dendritic cells. This epitope may be important in control of HHV-8 infection by CD8+ T cells.
Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation
Authors: O'Brien Stephen G. , Vieira Sara A. D. , Connors Samantha , Bown Nick , Chang James , Capdeville Renaud , Melo Junia V. 
Published: October 2002

Abstract
We report the transient response of a patient with theETV6-ABL fusion gene to imatinib mesylate (STI571). A 38-year-old man was referred with an erroneous diagnosis of Philadelphia-positive chronic myeloid leukemia in blastic transformation for treatment with the ABL tyrosine kinase inhibitor, STI571. Further investigation indicated that the patient in fact had acute myeloid leukemia; no evidence of the Philadelphia translocation or BCR-ABL was found using fluorescence in situ hybridization (FISH) or reverse transcription–polymerase chain reaction. Detailed FISH analysis identified a cryptic t(9;12) translocation, and molecular studies confirmed the presence of the ETV6-ABL fusion transcript. Because the patient was gravely ill at presentation, treatment was commenced immediately with STI571 monotherapy, resulting in considerable initial improvement. However within 10 days the patient's condition again deteriorated, and he required conventional chemotherapy. This case has implications for the design of future studies using STI571 in leukemias involving ABL-encoded fusion proteins other than BCR-ABL.
Three‐dimensional induction logging problems, Part I: An integral equation solution and model comparisons
Authors: Avdeev Dmitry B. , Kuvshinov Alexei V. , Pankratov Oleg V. , Newman Gregory A. 
Published: October 2002

A 3‐D frequency‐domain solution based on a volume integral equation approach has been implemented to simulate induction log responses. In our treatment of the problem, we assume that the electrical properties of the bedding as well as the borehole and invasion zones can exhibit transverse anisotropy. The solution process uses a Krylov subspace iteration to solve the scattering equation, which is based on the modified iterative dissipative method. Internal consistency checks and comparisons with mode matching and finite‐difference solutions for vertical borehole models demonstrate the accuracy of the solution.There are no known analytical solutions for induction log responses arising from deviated boreholes intersecting horizontal bed boundaries. To simulate such responses requires the numerical solution of Maxwell's equations in three dimensions along with independent tests to validate the solution approach and its accuracy. In this paper, we compare two independent 3‐D frequency‐domain solutions for the problem, based on finite differences and the integral equation technique. Specific examples in the quasi‐static limit are studied, including a 45° deviated borehole that intersects formation bed boundaries as well as cases where the bedding exhibits transverse anisotropy. All comparisons made in this paper show very good agreement and demonstrate, for the first time, verifiable induction log responses in the presence of deviated boreholes. We also show that responses arising from deviated boreholes can be significant and must be accounted for properly when interpreting induction logs.
Generation of T-Cell Immunity to the HER-2/neu Protein After Active Immunization With HER-2/neu Peptide–Based Vaccines
Authors: Disis Mary L. , Gooley Theodore A. , Rinn Kristine , Davis Donna , Piepkorn Michael , Cheever Martin A. , Knutson Keith L. , Schiffman Kathy 
Published: October 2002

PURPOSE: The HER-2/neu protein is a nonmutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. Many tumor antigens, such as MAGE and gp100, are self-proteins; therefore, effective vaccine strategies must circumvent tolerance. We hypothesized that immunizing patients with subdominant peptide epitopes derived from HER-2/neu, using an adjuvant known to recruit professional antigen-presenting cells, granulocyte-macrophage colony-stimulating factor, would result in the generation of T-cell immunity specific for the HER-2/neu protein.PATIENTS AND METHODS: Sixty-four patients with HER-2/neu–overexpressing breast, ovarian, or non–small-cell lung cancers were enrolled. Vaccines were composed of peptides derived from potential T-helper epitopes of the HER-2/neu protein admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally. Peripheral-blood mononuclear cells were evaluated at baseline, before vaccination, and after vaccination for antigen-specific T-cell immunity. Immunologic response data are presented on the 38 subjects who completed six vaccinations. Toxicity data are presented on all 64 patients enrolled.RESULTS: Ninety-two percent of patients developed T-cell immunity to HER-2/neu peptides (stimulation index, 2.1 to 59) and 68% to a HER-2/neu protein domain (stimulation index range, 2 to 31). Epitope spreading was observed in 84% of patients and significantly correlated with the generation of a HER-2/neu protein–specific T-cell immunity (P = .03). At 1-year follow-up, immunity to the HER-2/neu protein persisted in 38% of patients.CONCLUSION: The majority of patients with HER-2/neu–overexpressing cancers can develop immunity to both HER-2/neu peptides and protein. In addition, the generation of protein-specific immunity, after peptide immunization, was associated with epitope spreading, reflecting the initiation of an endogenous immune response. Finally, immunity can persist after active immunizations have ended.
Use of Adjuvant Chemotherapy and Radiation Therapy for Rectal Cancer Among the Elderly: A Population-Based Study
Authors: Neugut Alfred I. , Fleischauer Aaron T. , Sundararajan Vijaya , Mitra Nandita , Heitjan Daniel F. , Jacobson Judith S. , Grann Victor R. 
Published: October 2002

PURPOSE: Combined adjuvant fluorouracil (5-FU)–based chemotherapy with radiation is now the standard of care for locally advanced rectal cancer in the United States. We investigated the use of these treatments for stages II and III rectal cancer among the elderly and the effectiveness of these treatments on a population-based scale. PATIENTS AND METHODS: The linked Surveillance, Epidemiology, and End-Results–Medicare database was used to identify 1,807 Medicare beneficiaries ≥ 65 years of age with stage II or III rectal cancer who underwent surgical resection between 1992 and 1996. We excluded members of a health maintenance organization in the 12 months before or 4 months after their diagnosis and those who died within 4 months of diagnosis. We used multivariate analysis to identify factors associated with combined 5-FU and radiation therapy, and propensity score methodology to determine survival benefit for those treated. RESULTS: We found that 37% of patients received both adjuvant 5-FU and radiation therapy, 11% 5-FU alone, and 14% radiation alone. Decreasing age, increasing lymph node positivity, comorbid conditions, and nonblack race were associated with increased probability of treatment with 5-FU and radiation. Combined chemotherapy/radiation therapy was associated with improved survival for stage III (relative risk, 0.71; 95% confidence interval, 0.56 to 0.90), but not for stage II rectal cancer (relative risk, 0.89; 95% confidence interval, 0.70 to 1.14). CONCLUSION: The association of combined treatment with improved survival in node-positive disease was similar to that observed in other studies. In the absence of data from well-designed randomized controlled trials, our observational data support efforts on the part of clinicians to make appropriate referrals and provide combined treatment for elderly patients with stage III rectal cancer.