bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulated Expression of the Eph-Related Receptor Tyrosine Kinase Hek11 in Early Human B Lymphopoiesis
Authors: Aasheim Hans-Christian , Terstappen Leon W.M.M. , Logtenberg Ton 
Published: October 2019

AbstractMembers of the large Eph family of receptor tyrosine kinases (RTKs) display temporally and spatially restricted expression patterns during embryogenesis, suggesting a role in various developmental processes. We have begun to investigate the expression of members of this receptor family during human hematopoiesis, in particular B lymphopoiesis. Expression of Eph RTKs in cells of the B-lymphoid lineage was assessed by using degenerate oligonucleotide primers based on stretches of conserved nucleic acid sequences in members of the Eph family. First, the content of Eph-family RTKs was assessed in freshly sorted fetal bone marrow pro–B cells. This population was found to harbor transcripts of the Hek8 and Hek11 members of this gene family. Subsequent analysis of expression of these genes in B cells representing various differentiation and ontogenic stages showed that the Hek8 transcript is constitutively present in all fetal and adult B-lineage cells, with high levels of expression in peripheral blood B cells. In contrast, the Hek11 transcript was exclusively found in fetal bone marrow pro–B cells and pre–B cells, but not in more mature fetal B-lineage cells. All adult B-lineage cells, from early pro–B cells to end-stage plasma cells, lacked Hek11 transcripts. The developmentally regulated expression of Hek11 during fetal B lymphopoiesis suggests a role for this gene in pre/pro–B cell expansion and/or differentiation and defines a difference in progenitor B cell populations isolated from fetal versus adult human bone marrow.
Protease Activation Is Required for Glucocorticoid-Induced Apoptosis in Chronic Lymphocytic Leukemic Lymphocytes
Authors: Chandra Joya , Gilbreath Joyce , Freireich Emil J , Kliche Kay-Oliver , Andreeff Michael , Keating Michael , McConkey David J. 
Published: October 2019

AbstractRecent work has demonstrated that glucocorticoids, nucleoside analogues, and other cancer chemotherapeutics induce apoptosis in chronic lymphocytic leukemia (CLL) cells. In this study, we investigated the involvement of protease activation in these responses using selective peptide inhibitors of the interleukin-1β converting enzyme (ICE)/caspase family and a Ca2+-activated protease we recently implicated in thymocyte apoptosis. Apoptosis was associated with proteolytic cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) and increased caspase protease activity, and cell-permeant caspase antagonists [zVAD(OMe)fmk and Boc-D(OBzl)cmk] blocked apoptosis in response to the glucocorticoid methylprednisolone or the nucleoside analogue fludarabine, indicating that caspase activation was required for these responses. However, a peptide-based inhibitor of the Ca2+-dependent lamin protease (zAPFcmk) also completely suppressed DNA fragmentation and the cleavage of lamin B1 . Strikingly, treatment of cells with zAPFcmk alone led to characteristic PARP cleavage, depletion of the precursor forms of two ICE family proteases (CPP32 and ICH-1), and phosphatidylserine exposure, suggesting that blockade of the lamin protease led to activation of the ICE family. Our results implicate the lamin protease as a target for Ca2+ during chemotherapy-induced apoptosis in CLL lymphocytes, and they identify a novel functional interaction between the protease and members of the ICE family.
Morbidity and Mortality Due to Liver Disease in Children Undergoing Allogeneic Bone Marrow Transplantation: A 10-Year Prospective Study
Authors: Locasciulli Anna , Testa Marina , Valsecchi Maria Grazia , Vecchi Laura , Longoni Daniela , Sparano Paola , Rovelli Attilio , Uderzo Cornelio , Masera Giuseppe , Alberti Alfredo 
Published: October 2019

Abstract
We have conducted a long-term prospective study of children undergoing bone marrow transplantation (BMT) to assess morbidity and mortality for liver disease. One hundred eleven consecutive children were enrolled between June 1985 and June 1995 and were followed-up for a median of 5.5 years after BMT. Before transplant 48/111 children (43%) had abnormal alanine aminotransferase (ALT), none were HBsAg+ and 4/111 were anti-HCV+. After BMT 4/111 patients (3.6%) died of liver failure. No relationship was found between pretransplant hepatitis B (HBV) or C (HCV) infection or elevated transaminases and development of severe liver damage. Eighty-two out of one hundred and eleven patients (74%) had abnormalities of ALT after BMT, transient (n = 54) or persistent (n = 28). None developed clinical signs or symptoms of end stage liver disease or of cirrhosis during follow-up. No significant difference in prevalence of liver disease, was found between children with normal or abnormal ALT at BMT (relative risk [RR] = 1.04). HCV infection could be implicated in the etiology of chronic liver disease in 14/28 patients; 2 other patients were found infected by HBV alone (1 case) or combined with HCV (1 case). In the remaining 12 the etiology of chronic liver disease could not be defined. Posttransplant hepatitis B occurred in 4/111 children (3.6%), including a recipient from a donor who had been previously vaccinated against HBV, while no patient who had been vaccinated developed hepatitis B. The rate of posttransplant seroconversion to anti-HCV was 15%.
The Cytoplasmic Domain of Stem Cell Antigen CD34 Is Essential for Cytoadhesion Signaling But Not Sufficient for Proliferation Signaling
Authors: Hu Mickey C.-T. , Chien Shu L. 
Published: October 2019

AbstractCD34 is widely used as a marker in the identification and purification of human hematopoietic stem and progenitor cells; however, its function within hematopoiesis is largely unknown. We have investigated the contribution of cytoplasmic domain of CD34 in cytoadhesion signaling and proliferation signaling in hematopoietic cells. Engagement of particular determinants of CD34 by monoclonal antibodies leads to homotypic adhesiveness of the full-length CD34-transfected BaF3 cells. However, this homotypic adhesiveness is abrogated in BaF3 cells transfected with the truncated CD34 lacking the cytoplasmic domain. Cytoadhesion signaling through the cytoplasmic domain of CD34 cannot be restored through that of erythropoietin receptor (EPOR) or granulocyte colony-stimulating factor receptor (G-CSFR), suggesting that the cytoplasmic domain of CD34 is required for its signal transduction of cellular adhesion. In constrast, we show that replacing the cytoplasmic domain of EPOR or G-CSFR with that of CD34 abolished growth signal transduction in response to EPO or G-CSF in the chimeric receptor-transfected BaF3, 32D, and FDCP1 cells, whereas the wild-type EPOR- or G-CSFR-transfected cells responded to EPO or G-CSF growth signaling well. These results suggest that the cytoplasmic portion of CD34 may not contain the elements necessary to transduce a proliferative signal in hematopoietic cells. Thus, the function of CD34 in hematopoiesis is primarily on hematopoietic cell adhesion.
Risk Factors, Treatment, and Outcome of Central Nervous System Recurrence in Adults With Intermediate-Grade and Immunoblastic Lymphoma
Authors: van Besien Koen , Ha Chul S. , Murphy Sandy , McLaughlin Peter , Rodriguez Alma , Amin Kamal , Forman Arthur , Romaguera Jorge , Hagemeister Fredrick , Younes Anas , Bachier Carlos , Sarris Andreas , Sobocinski Kathleen S. , Cox James D. , Cabanillas Fernando 
Published: October 2019

Abstract
To evaluate the incidence, risk factors, and outcome of central nervous system (CNS) recurrence in adult patients with non-Hodgkin's lymphoma, we evaluated 605 newly diagnosed patients with large-cell and immunoblastic lymphoma who participated in prospective chemotherapy studies. The Kaplan-Meier estimate of probability of CNS recurrence at 1 year after diagnosis was 4.5% (95% confidence interval [CI], 4.4 to 4.6). Twenty-four patients developed CNS recurrence after a median of 6 months from diagnosis (range, 0 to 44 months). In univariate analysis, an increased risk for CNS recurrence was associated with an advanced disease stage (P = .0014), an increased LDH (P = .0000), the presence of B-symptoms (P = .0037), involvement of more than one extranodal site (P = .0000), poor performance status (P = .0005), and B-cell phenotype (P = .008). Bone marrow involvement (P = .005), involvement of parenchymal organs (P = .03), and involvement of skin, subcutaneous tissue, and muscle (P = .002) were also associated with an increased risk for CNS disease. Multivariate logistic regression analysis identified only involvement of more than one extranodal site (P = .0005) and an increased LDH (P = .0008) as independent predictors of CNS recurrence. Established CNS recurrence had a poor prognosis. Only 1 of 24 patients remains alive and the Kaplan-Meier estimate of probability of survival at 1 year after the diagnosis of CNS recurrence is only 25.3% (95% CI, 6.9 to 43.7). Intrathecal treatment provided symptomatic benefit in only 1 of 6 patients. Radiation treatment provided symptomatic improvement in 6 of 9 patients treated. However, remissions were short and followed by systemic or CNS recurrence. Serum LDH and involvement of more than one extranodal site are independent risk factors for CNS recurrence in patients with large-cell lymphoma. The presence of both risk factors identifies a patient group at high risk for CNS recurrence. Established CNS recurrence can be rapidly fatal. Transient responses occur after radiation treatment.
Thrombopoietin, kit Ligand, and flk2/flt3 Ligand Together Induce Increased Numbers of Primitive Hematopoietic Progenitors From Human CD34+Thy-1+Lin− Cells With Preserved Ability to Engraft SCID-hu Bone
Authors: Luens Karin M. , Travis Marilyn A. , Chen Ben P. , Hill Beth L. , Scollay Roland , Murray Lesley J. 
Published: October 2019

AbstractCD34+Thy-1+Lin− cells are enriched for primitive hematopoietic progenitor cells (PHP), as defined by the cobblestone area-forming cell (CAFC) assay, and for bone marrow (BM) repopulating hematopoietic stem cells (HSC), as defined by the in vivo SCID-hu bone assay. We evaluated the effects of different cytokine combinations on BM-derived PKH26-labeled CD34+Thy-1+Lin− cells in 6-day stroma-free cultures. Nearly all (>95%) of the CD34+Thy-1+Lin− cells divided by day 6 when cultured in thrombopoietin (TPO), c-kit ligand (KL), and flk2/flt3 ligand (FL). The resulting CD34hiPKHlo (postdivision) cell population retained a high CAFC frequency, a mean 3.2-fold increase of CAFC numbers, as well as a capacity for in vivo marrow repopulation similar to freshly isolated CD34+Thy-1+Lin− cells. Initial cell division of the majority of cells occurred between day 2 and day 4, with minimal loss of CD34 and Thy-1 expression. In contrast, cultures containing interleukin-3 (IL-3), IL-6, and leukemia inhibitory factor contained a mean of 75% of undivided cells at day 6. These CD34hi PKHhi cells retained a high frequency of CAFC, whereas the small population of CD34hiPKHlo postdivision cells contained a decreased frequency of CAFC. These data suggest that use of a combination of TPO, KL, and FL for short-term culture of CD34+Thy-1+Lin− cells increases the number of postdivision PHP, measured as CAFC, while preserving the capacity for in vivo engraftment.
Integrin β2 (CD18)-Mediated Cell Proliferation of HEL Cells on a Hematopoietic-Supportive Bone Marrow Stromal Cell Line, HESS-5 Cells
Authors: Tsuji Takashi , Waga Iwao , Tezuka Katsunari , Kamada Masafumi , Yatsunami Kimio , Kodama Hisashi 
Published: October 2019

AbstractCellular interactions between hematopoietic cells and stromal cells play important roles in the proliferation and differentiation of hematopoietic cells. The proliferation of a human erythroleukemia cell line, HEL cells, which can differentiate into macrophage- and megakaryocyte-like cells, and erythroid precursors was dramatically induced on coculture with a hematopoietic-supportive stromal cell line, HESS-5 cells, which can support long-term hematopoiesis in vitro without fetal bovine serum. HEL cells proliferated when they were cocultured with but not without direct cell contact. Because the coculture supernatants with direct cell contact and cytokines such as interleukins and growth factors did not exhibit growth-stimulating activity toward HEL cells, it was suggested that some molecule that has growth-stimulating activity exists on the surface of the cells. Extracellular matrix components such as fibronectin, laminin, vitronectin, and collagen did not affect the proliferation of HEL cells. An anti-CD18 monoclonal antibody, which recognizes the common β chain of the β2 integrin subfamily, induced dramatic proliferation of HEL cells. Moreover, the proliferation of HEL cells was inhibited by an antisense oligonucleotide of CD18 mRNA. As judged from these observations, the proliferation of HEL cells was mediated by CD18 molecules expressed on HEL cells. On the contrary, the common counter-receptor of the β2 integrin subfamily, intercellular adhesion molecule-1, which is expressed on CHO-K1 cells, did not stimulate the growth of HEL cells. It is known that other counter molecules of the β2 integrin subfamily, such as complement C3bi and fibrinogen, are not produced by stromal cells. These findings suggest that the proliferation of HEL cells may be induced through an interaction between a novel molecule of the β2 integrin subfamily on HEL cells and the counter-receptor on HESS-5 cells. The β2 integrin subfamily may regulate the growth of hematopoietic cells in hematopoiesis in vivo and/or cause the abnormal growth of leukemia cells.
Epstein-Barr Virus (EBV) in Endemic Burkitt's Lymphoma: Molecular Analysis of Primary Tumor Tissue
Authors: Tao Qian , Robertson Keith D. , Manns Angela , Hildesheim Allan , Ambinder Richard F. 
Published: October 2019

AbstractMany aspects of Epstein-Barr virus (EBV) and tumor biology have been studied in Burkitt's lymphoma (BL)-derived cell lines. However, in tissue culture, patterns of gene expression and C promoter-G (CpG) methylation often change and viral strain selection may occur. In this report, 10 cases of snap-frozen endemic BL tumors are characterized in terms of viral gene expression, promoter usage, methylation, and viral strain. EBNA1 and BamHI-A rightward transcripts (BART) were detected in 7 of 7 and LMP2A transcripts in 5 of 7 tumors with well-preserved RNA. Transcripts for the other EBNAs and for LMP1 were not detected in any tumor. These tumors differ from BL cell lines in that they lack a variety of lytic cycle transcripts. This pattern of viral gene expression in endemic BL is similar to that reported in peripheral blood mononuclear cells (PBMCs) from healthy EBV–seropositive individuals. EBNA1 transcripts originated from the Q promoter (Qp) but not C, W, or F promoters that drive transcription of EBNA1 in other circumstances. Whereas Cp has been previously shown to be entirely CpG methylated in BL, bisulfite genomic sequencing showed virtually no methylation in Qp. Type-A EBV was detected in 6 of 10 and type B in 4 of 10 cases. A previously reported 30bp deletion variant in the carboxyl terminal of LMP1 gene was detected in 5 of 10 cases. The association with both A and B strains contrasts with EBV–associated Hodgkin's disease, nasopharyngeal carcinoma, and post-transplant lymphoproliferative disease, which are much more consistently associated with A strain virus.
Fluorescence In Situ Hybridization Characterization of New Translocations Involving TEL (ETV6) in a Wide Spectrum of Hematologic Malignancies
Authors: Wlodarska Iwona , La Starza Roberta , Baens Mathijs , Dierlamm Judith , Uyttebroeck Ann , Selleslag Dominik , Francine Adrien , Mecucci Cristina , Hagemeijer Anne , Van den Berghe Herman , Marynen Peter 
Published: October 2019

Abstract
The ETV6 (also known as TEL) gene on chromosome 12p13 is the target of a number of translocations associated with various hematologic malignancies. The contribution of ETV6 to leukemogenesis occurs through different mechanisms that involve either its helix-loop-helix dimerization domain or its E26 transformation-specific (ETS) DNA-binding domain. Using fluorescence in situ hybridization we characterized seven newETV6 rearrangements in chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and non-Hodgkin's lymphoma. These aberrations, not always discernible at the cytogenetic level, include a t(5;12)(q31;p13), t(6;12;17)(p21;p13;q25), t(7;12)(p15;p13), t(7;12)(p12;p13), t(7;12)(q36;p13), t(12;13)(p13;q12), and a not completely defined t(12;?)(p13;?). Loss or disruption of the secondETV6 allele by a del(12)(p12p13) or by an intragenicETV6 deletion was detected in two cases. In six cases the 12p13 breakpoint occurred in the 5′ end of ETV6, upstream to exons encoding the HLH domain, whereas the remaining case had a breakpoint between the exons coding for the HLH domain and the exons coding for the ETS domain of ETV6. These observations provide further evidence for the multiple contributions of ETV6 in the pathogenesis of a wide range of hematologic malignancies.
Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases
Authors: Kampen Gita T. , Stafford Susan , Adachi Tetsuya , Jinquan Tan , Quan Sha , Grant J. Andrew , Skov Per S. , Poulsen Lars K. , Alam Rafeul 
Published: October 2019

AbstractEotaxin and other CC chemokines acting via CC chemokine receptor-3 (CCR3) are believed to play an integral role in the development of eosinophilic inflammation in asthma and allergic inflammatory diseases. However, little is known about the intracellular events following agonist binding to CCR3 and the relationship of these events to the functional response of the cell. The objectives of this study were to investigate CCR3-mediated activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase-2 (ERK2), p38, and c-jun N-terminal kinase (JNK) in eosinophils and to assess the requirement for MAP kinases in eotaxin-induced eosinophil cationic protein (ECP) release and chemotaxis. MAP kinase activation was studied in eotaxin-stimulated eosinophils (more than 97% purity) by Western blotting and immune-complex kinase assays. ECP release was measured by radioimmunoassay. Chemotaxis was assessed using Boyden microchambers. Eotaxin (10−11 to 10−7 mol/L) induced concentration-dependent phosphorylation of ERK2 and p38. Phosphorylation was detectable after 30 seconds, peaked at about 1 minute, and returned to baseline after 2 to 5 minutes. Phosphorylation of JNK above baseline could not be detected. The kinase activity of ERK2 and p38 paralleled phosphorylation. PD980 59, an inhibitor of the ERK2-activating enzyme MEK (MAP ERK kinase), blocked phosphorylation of ERK2 in a concentration-dependent manner. The functional relevance of ERK2 and p38 was studied using PD98 059 and the p38 inhibitor SB202 190. PD98 059 and SB202 190 both caused inhibition of eotaxin-induced ECP release and chemotaxis. We conclude that eotaxin induces a rapid concentration-dependent activation of ERK2 and p38 in eosinophils and that the activation of these MAP kinases is required for eotaxin-stimulated degranulation and directed locomotion.
Rifampicin-dependent antibodies bind a similar or identical epitope to glycoprotein IX–specific quinine-dependent antibodies
Authors: Burgess Janette K. , Lopez Jose A. , Gaudry Leonie E. , Chong Beng H. 
Published: October 2019

AbstractThe drug-dependent antibody of a patient with rifampicin-induced thrombocytopenia was characterized using the antigen-capture enzyme-linked immunosorbent assay (MAIPA assay), flow cytometry, and immunoprecipitation. The antibody was found to bind glycoprotein (GP) Ib-IX but not GPIIb-IIIa because (1) it immunoprecipitated drug-dependently the former but not the latter glycoprotein complex and (2) the MAIPA assay showed strong rifampicin-dependent antibody binding when anti-GPIb-IX monoclonal antibodies (mAbs) (AK2 and FMC25) but not anti-GPIIb-IIIa mAbs (AP2, SZ21, and SZ22) were used to capture the antigen. The antibody binding site was further localized to the GPIX subunit of the GPIb-IX complex because flow cytometric analysis revealed drug-dependent antibody binding to L cells transfected with human GPIbβ and GPIX complementary DNA (L βIX cells) but not with human GPIb and GPIbβ complementary DNA (L β cells). Finally, in the MAIPA assay, the rifampicin-dependent antibody almost completely cross-blocked the binding of the anti-GPIX mAb (SZ1) to platelets. Similar cross-blocking of SZ1binding to platelets by the quinine-dependent antibodies was also observed. This finding not only confirms that the epitope of the rifampicin-dependent antibody is on GPIX but it is also identical to or located in close proximity to that of the quinine-dependent antibody and SZ1. Further characterization of the epitopes of these antibodies may have important implications for a general understanding of the mechanism of drug-induced thrombocytopenia.
Inducible loss of NF-κB activity is associated with apoptosis and Bcl-2 down-regulation in Epstein-Barr virus-transformed B lymphocytes
Authors: Feuillard Jean , Schuhmacher Marino , Kohanna Sylvie , Asso–Bonnet Marianne , Ledeur Frédérique , Joubert–Caron Raymonde , Bissières Philippe , Polack Axel , Bornkamm Georg W. , Raphaël Martine 
Published: October 2019

AbstractThe Epstein–Barr virus (EBV)-encoded latent membrane protein-1 induces NF-κB activity by targeting IκBα. To understand the role of NF-κB activation in EBV-related oncogenesis, we have subcloned mutated IκBα32/36A cDNA into a pHEBo vector containing doxycycline regulatory sequences and stably transfected this construct into a lymphoblastoid cell line. Two tightly regulated clones were obtained in which IκBα32/36A was inducible in a doxycycline dose-dependent manner. Levels of inducible IκBα32/36A peaked at day 2. Inhibition of NF-κB activity was closely correlated with levels of inducible IκBα32/36A. Levels of 3 well-known NF-κB-dependent genes, CD54, p105, and endogenous IκBα, were decreased when IκBα32/36A was induced, and the growth of IκBα32/36A-induced EBV-infected cells was slightly reduced. Loss of NF-κB activity was associated with decreased Bcl-2 protein levels. Finally, the induction of apoptosis was strongly increased in IκBα32/36A-overexpressing cells. Together these results show that it is possible to control IκBα32/36A levels, ie, NF-κB activity, in EBV-infected B-lymphocytes using a doxycycline-inducible vector. Moreover, our results indicate that NF-κB can protect EBV-infected cells from apoptosis by Bcl-2. Finally, our results suggest that a cellular model with doxycycline-inducible IκBα32/36A may be useful in the identification of genuine NF-κB target genes in EBV-infected B cells.