bluuebunny/crossref_metadata_2025_split huggingface dataset:
The CXC-Chemokine Neutrophil-Activating Peptide-2 Induces Two Distinct Optima of Neutrophil Chemotaxis by Differential Interaction With Interleukin-8 Receptors CXCR-1 and CXCR-2
Authors: Ludwig Andreas , Petersen Frank , Zahn Stefan , Götze Otto , Schröder Jens-Michael , Flad Hans-Dieter , Brandt Ernst 
Published: October 2019

AbstractThe CXC-chemokines interleukin-8 (IL-8), neutrophil-activating peptide-2 (NAP-2), and melanoma growth-stimulatory activity (MGSA) are chemoattractants with high selectivity for neutrophils. Although IL-8 has been shown to act as an extremely potent mediator, reports on NAP-2 and MGSA are still contradictory. Here we show for the first time that NAP-2 and MGSA induce two distinct optima of neutrophil chemotaxis. A first optimum is elicited within a concentration range as low as it is characteristic for IL-8. However, a second optimum appears at more than 200-fold higher stimulus concentrations, at which IL-8 is inactive. Investigating the involvement of the two chemokine receptors CXCR-1 and CXCR-2 in NAP-2–mediated chemotaxis, we observe that the cells become desensitized to the first optimum of the chemokine after selective downregulation of CXCR-2, while both optima disappear upon simultaneous downregulation of both receptors. Blocking monoclonal antibodies (MoAbs) specific for CXCR-2 or CXCR-1 either suppress the first optimum of NAP-2–induced chemotaxis or drastically reduce the second one, respectively. These results provide evidence that both receptors are involved in NAP-2–induced neutrophil chemotaxis, with CXCR-2 rendering the cells responsive to low dosages of the chemokine, and with CXCR-1 extending their responsiveness to NAP-2 dosages higher by several orders of magnitude.
Gene Therapy for Chronic Myelogenous Leukemia (CML): A Retroviral Vector That Renders Hematopoietic Progenitors Methotrexate-Resistant and CML Progenitors Functionally Normal and Nontumorigenic In Vivo
Authors: Zhao Robert C.H. , McIvor R. Scott , Griffin James D. , Verfaillie Catherine M. 
Published: October 2019

AbstractChronic myelogenous leukemia (CML) is a malignant disease of the human hematopoietic stem cell caused by the BCR/ABL gene rearrangement. The only curative therapy is allogeneic transplantation. Although autologous transplants may prolong survival, most patients relapse because of disease persisting in the host and in the graft. Continued administration of chemotherapy after transplant could reduce the incidence of relapse provided that the autograft can be protected by transfer of a drug-resistance gene. However, CML autografts will almost certainly contain malignant stem cells that will also be rendered drug-resistant. The presence of the BCR/ABL oncoprotein is necessary and sufficient for malignant transformation seen in CML. We thus hypothesized that transfer of a vector that combines a drug-resistance gene with anti-BCR/ABL antisense (AS) sequences may allow for posttransplant chemotherapy to decrease persistent disease while rendering inadvertently transduced CML stem and progenitor cells functionally normal. We constructed a retroviral vector, LasBD, that combines the methotrexate (MTX)-resistant tyrosine-22 dihydrofolate-reductase (tyr22-DHFR) gene and AS sequences directed at the b3a2 BCR/ABL breakpoint. b3a2 BCR/ABL containing 32D and MO7e cells were transduced with LasBD and selected in MTX for 14 days. Expression of the AS sequences reduced BCR/ABL mRNA and p210BCR/ABL protein levels by 6- to 10-fold in most cells. This subsequently led to the restoration of normal function of BCR/ABL cDNA+ cells: they grew significantly slower in the presence of interleukin-3 (IL-3); they underwent apoptotic cell death when cultured without IL-3; and they had restored expression and function of adhesion receptors. These effects were specific, because LasBD-containing AS sequences directed at the b3a2 BCR/ABL breakpoint did not affect p190BCR/ABL-containing cells. LasBD also rendered 20% to 30% of primary Ph− and Ph+ CD34+ cells MTX-resistant and decreased BCR/ABL mRNA levels in MTX resistant Ph+ CD34+ cells by 10-fold. Expression of the MTX-resistant DHFR gene and the AS sequences has been stable for at least 1 year in vitro and for more than 70 days in vivo. Finally, LasBD decreased tumorigenicity of 32DBCR/ABL cells in vivo by 3 to 4 logs. In conclusion, the tyr22-DHFR gene in the LasBD vector can protect normal hematopoietic cells from MTX-mediated toxicity, whereas the AS sequences in LasBD can suppress expression of the BCR/ABL gene and restore normal function of BCR/ABL cDNA-containing cells. The LasBD vector may therefore prove to be an extremely useful adjunct in autologous transplantation for CML.
Implications of Potential Cure in Acute Myelogenous Leukemia: Development of Subsequent Cancer and Return to Work
Authors: de Lima Marcos , Strom Sara S. , Keating Michael , Kantarjian Hagop , Pierce Sherry , O'Brien Susan , Freireich Emil , Estey Elihu 
Published: October 2019

Abstract
Chemotherapy produces extended remissions, and potential cures, in a small minority of patients with acute myeloid leukemia (AML). We explored whether potentially cured patients were at increased risk of subsequent invasive cancer and were able to return to work. Potentially cured patients were defined as those in first or second complete remission (CR) for at least 3 years based on hazard rates for recurrence or death in CR, which declined sharply after this time. Patients who received allogeneic marrow transplant were excluded. We used questionnaires, phone contact, and chart review to obtain information about subsequent cancer and work status. The number of patients who developed invasive cancer was compared with the number expected based on age, gender, and years of follow-up using the Connecticut Tumor Registry. A total of 215 patients met our criteria for potential cure: 203 in first CR and 12 in second CR (of 1,663 treated between 1965 and December, 1992). At a median of 9.2 years from first or second CR, 163 (76%) remain alive in CR. Fifteen patients developed 18 invasive cancers (expected number of patients, 8.8; observed/expected, 1.70; 95% CI, 0.96 to 2.84; P = .06). Patients initially treated between 1973 to 1979, patients above the potentially cured cohort's median age of 40 years, and those who presented with abnormalities of chromosomes 5 and/or 7 were more likely to develop subsequent cancer, whereas the observed/expected ratio for younger patients was 1.05 (95% CI, 0.13 to 3.80; P = .56). Seventy-four percent of the patients who were working full-time and who were under age 50 at time of treatment for AML have been working full-time in the last 6 months. Only 17 of 56 patients who are currently not working cited physical limitation as the reason. Patients with potentially cured AML are likely to be able to return to work, and at least if younger do not, on average, have an increased risk of invasive cancer.
Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors
Authors: Jabado Nada , de Graeff-Meeder Elizabeth R. , Cavazzana-Calvo Marina , Haddad Elie , Le Deist Françoise , Benkerrou Malika , Dufourcq Rémi , Caillat Sophie , Blanche Stephane , Fischer Alain 
Published: October 2019

AbstractFamilial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.
Secretion of Ferritin by Rat Hepatoma Cells and Its Regulation by Inflammatory Cytokines and Iron
Authors: Tran Tue N. , Eubanks Sharon K. , Schaffer Kenneth J. , Zhou Cecilia Y.J. , Linder Maria C. 
Published: October 2019

AbstractThe possibility that serum ferritin is a secreted protein and an acute phase reactant regulated by inflammatory hormones and iron was examined in a hepatic cell line that secretes plasma proteins. Differentiated rat hepatoma cells released albumin and ferritin into the medium, as determined by rocket immunoelectrophoresis and isolation of ferritin by standard procedures plus immunoaffinity chromatography, following labeling with radioactive amino acid. Administration of interleukin-1–β (IL-1) or tumor necrosis factor-α (TNF) doubled the amounts of ferritin released into the medium over 24 and 48 hours. Together, the cytokines had more than an additive effect. Albumin secretion was diminished by IL-1, but not TNF. Iron, administered as an iron dextran complex or as a 1:1 chelate with nitrilotriacetate (Fe-NTA), also enhanced ferritin release, but had no effect on albumin. Intracellular ferritin concentrations did not change significantly with cytokine treatment, but increased in response to iron. With or without treatments, release of ferritin and albumin from cells into the medium was inhibited by brefeldin A, an inhibitor of Golgi function. The effect of each of the cytokines and of iron on ferritin and albumin was also blocked by dichlorofuranosylbenzimidazole (DRB), an inhibitor of transcription. The stimulatory effect of Fe-NTA on ferritin secretion was diminished by TNF, and this was partially counteracted by IL-1, indicating additional regulatory complexity. These results show for the first time that hepatic cells secrete ferritin, that this ferritin secretion is regulated by iron and inflammatory cytokines, and that the mechanisms of regulation differ from those for intracellular ferritin. The results would explain why serum ferritin increases in inflammation or when iron flux is enhanced.
A Novel Five-Transmembrane Hematopoietic Stem Cell Antigen: Isolation, Characterization, and Molecular Cloning
Authors: Miraglia Sheri , Godfrey Wayne , Yin Amy H. , Atkins Kristin , Warnke Roger , Holden Jeannine T. , Bray Robert A. , Waller Edmund K. , Buck David W. 
Published: October 2019

AbstractPhenotypic analysis of hematopoietic stem and progenitor cells (HSCs) has been an invaluable tool in defining the biology of stem cell populations. We have recently described the production of AC133, a monoclonal antibody (MoAb) that binds to a novel cell surface antigen present on a CD34bright subset of human HSCs. This antigen is a glycosylated protein with a molecular weight of 120 kD. Here, we report the molecular cloning of a cDNA encoding this antigen and show that it does not share homology with any previously described hematopoietic or other cell surface antigen(s). The AC133 polypeptide has a predicted size of 97 kD and contains five-transmembrane (5-TM) domains with an extracellular N-terminus and a cytoplasmic C-terminus. Whereas the expression of tetraspan (4-TM) and 7-TM molecules is well documented on mature and immature hematopoietic cells and leukocytes, this 5-TM type of structure containing two large (255–amino acid [aa] and 290-aa) extracellular loops is unique and does not share sequence homology with any known multi-TM family members. Expression of this protein appears limited to bone marrow in normal tissue by immunohistochemical staining; however, Northern analysis suggests that the mRNA transcript is present in a variety of tissues such as the kidney, pancreas, placenta, and fetal liver. The AC133 antigen is also expressed on subsets of CD34+ leukemias, suggesting that it may be an important early marker for HSCs, as well as the first described member of a new class of TM receptors.
A Metalloproteinase Inhibitor Prevents Lethal Acute Graft-Versus-Host Disease in Mice
Authors: Hattori Koichi , Hirano Takao , Ushiyama Chifuyu , Miyajima Hiroaki , Yamakawa Norifumi , Ebata Tomohiko , Wada Yukihisa , Ikeda Shoji , Yoshino Kohichiro , Tateno Masatoshi , Oshimi Kazuo , Kayagaki Nobuhiko , Yagita Hideo , Okumura Ko 
Published: October 2019

AbstractTumor necrosis factor (TNF ) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD), which is a major complication after allogeneic bone marrow transplantation. We examined here the ameliorating effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-α and FasL release in a lethal acute GVHD model in mice. Administration of KB-R7785 into (BALB/c × C57BL/6) F1 that received C57BL/6 spleen cells markedly reduced the mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. The ameliorating effect of KB-R7785 was superior to that of anti–TNF-α antibody. Our results suggest that KB-R7785 could be a potent therapeutic agent for GVHD.
Incidence and Clinical Relevance of TEL/AML1 Fusion Genes in Children With Acute Lymphoblastic Leukemia Enrolled in the German and Italian Multicenter Therapy Trials
Authors: Borkhardt Arndt , Cazzaniga Giovanni , Viehmann Susanne , Valsecchi Maria Grazia , Ludwig Wolf Dieter , Burci Linda , Mangioni Silvia , Schrappe Martin , Riehm Hansjörg , Lampert Fritz , Basso Giuseppe , Masera Giuseppe , Harbott Jochen , Biondi Andrea 
Published: October 2019

AbstractThe molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9; 22) and t(4; 11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12; 21)(p13; q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12; 21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12; 21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre–B immunophenotype. Among the B-lineage subgroup, the t(12; 21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (≥1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index ≥1.16 &lt;1.6). Our findings reinforce the need to include the molecular screening of the t(12; 21) translocation within ongoing prospective ALL trials to prove definitively its prognostic impact.
Regulation of Tie Receptor Expression on Human Endothelial Cells by Protein Kinase C-Mediated Release of Soluble Tie
Authors: Yabkowitz Rachel , Meyer Susanne , Yanagihara Donna , Brankow David , Staley Tabitha , Elliott Gary , Hu Sylvia , Ratzkin Barry 
Published: October 2019

AbstractThe expression and activity of receptor tyrosine kinases (RTK) at the cell surface can be modulated by several different pathways including the proteolytic release of the extracellular domain as a soluble receptor. We investigated the regulation of tie receptor expression, an orphan RTK restricted to cells of hematopoietic and endothelial lineages, on primary human endothelial cells and a stably transfected Chinese hamster ovary (CHO) cell line. Tie was expressed in cells as a doublet of 135 and 125 kD; the 135-kD band represented mature cell surface receptor containing sialic acid and N-linked oligosaccharide residues, whereas the 125-kD band represented an intracellular pool of immature receptor. Phorbol 12-myristate 13-acetate (PMA) had dramatic effects on tie expression at the cell surface. Within 15 minutes of PMA treatment, the 135-kD band disappeared from the cell surface and was accompanied by the appearance of a 100-kD band in cell supernatants. The 100-kD band continued to accumulate in the media throughout the duration of PMA treatment during which mature tie receptor was undetectable on the cell surface by fluorescence-activated cell sorting (FACS) or in cell lysates by immunoblot analysis. Using specific antibodies, this 100-kD species was shown to be a soluble form of the tie receptor containing the extracellular domain. PMA-dependent release of soluble tie was mediated through the activation of protein kinase C (PKC); soluble tie was not released in the presence of PKC inhibitors, an inactive PMA analog, or following the downregulation of PKC through chronic PMA treatment. These results indicate that tie receptor expression on endothelial cells is regulated by the release of a soluble extracellular fragment following activation of PKC. Parallel pathways regulating c-kit, tumor necrosis factor (TNF), and colony-stimulating factor (CSF) receptor expression suggest that the release of extracellular receptor fragments represents an alternative mechanism through which cells modulate responses to growth factors and cytokines.
Wide Variety of Point Mutations in the H Gene of Bombay and Para-Bombay Individuals That Inactivate H Enzyme
Authors: Kaneko Mika , Nishihara Shoko , Shinya Naoko , Kudo Takashi , Iwasaki Hiroko , Seno Taiko , Okubo Yasuto , Narimatsu Hisashi 
Published: October 2019

AbstractThe H genes, encoding an α1,2fucosyltransferase, which defines blood groups with the H structure, of four Bombay and 13 para-Bombay Japanese individuals were analyzed for mutations. Four Bombay individuals were homologous for the same null H allele, which is inactivated by a single nonsense mutation at position 695 from G to A (G695A), resulting in termination of H gene translation. The allele inactivated by the G695A was designated h1. The other 13 para-Bombay individuals possessed a trace amount of H antigens on erythrocytes regardless of their secretor status. Sequence analysis of their H genes showed four additional inactivated H gene alleles, h2, h3, h4, and h5. The h2 allele possesed a single base deletion at position 990 G (990-del). The h3 and h4 alleles possessed a single missense mutation, T721C, which changes Tyr 241 to His, and G442T, which changes Asp148 to Tyr, respectively. The h5 allele possessed two missense mutations, T460C (Tyr154 to His) and G1042A (Glu348 to Lys). The h2, h3, h4, and h5 enzymes directed by these alleles were not fully inactivated by the deletion and the missense mutations expressing some residual enzyme activity resulting in synthesis of H antigen on erythrocytes. Thirteen para-Bombay individuals whose erythrocytes retained a trace amount of H antigen were determined to be heterozygous or homozygous for at least one of h2, h3, h4, or h5 alleles. This clarified that the levels (null to trace amount) of H antigen expression on erythrocytes of Bombay and para-Bombay individuals are determined solely by H enzyme activity. These mutations found in the Japanese H alleles differ from a nonsense mutation found in the Indonesian population. To determine the roles of the H, Se, and Le genes in the expression of H antigen in secretions and Lewis blood group antigen on erythrocytes, the Lewis and secretor genes were also examined in these Bombay and para-Bombay individuals. The Lewis blood group phenotype, Le(α- b+), was determined by the combinatorial activity of two fucosyltransferases, the Lewis enzyme and the secretor enzyme, and the secretor status was solely determined by the secretor enzyme activity, not by H enzyme activity. Bombay individuals were confirmed to be homozygous for the inactivated H and Se genes. As expected from the very low frequency of Bombay and para-Bombay individuals in the population, ie, approximately one in two or 300,000, the H gene mutations were found to be very variable, unlike the cases of the point mutations in the other glycosyltransferase genes; the ABO genes, the Lewis gene, and the secretor gene.