bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human marrow stromal cells: response to interleukin-6 (IL-6) and control of IL-6 expression
Authors: Nemunaitis J , Andrews DF , Mochizuki DY , Lilly MB , Singer JW 
Published: October 2019

Abstract
Production of interleukin-6 (IL-6) by marrow stromal cells from human long-term marrow cultures and from stromal cells transformed with simian virus 40 was examined. As with other cultured mesenchymal cells, unstimulated stromal cells produced undetectable amounts of IL-6 mRNA when assayed by Northern blots. However, within 30 minutes after exposure of transformed marrow stromal cells to the inflammatory mediators, recombinant human interleukin-1 alpha (IL-1 alpha) or recombinant human tumor necrosis factor alpha (TNF alpha), significant increases in IL-6 expression were observed. The time course of IL-6 mRNA upregulation in transformed marrow stromal cells with IL-1 alpha and TNF alpha differed: The maximal response to TNF alpha was observed at 30 minutes whereas that to IL-1 alpha occurred at 8 hours. Although IL-6 at a concentration of 500 U/mL was inhibitory to adherent transformed marrow stromal cell proliferation, a concentration- dependent stimulation of anchorage-independent colony growth was observed when the cells were plated in semisolid medium with IL-6. The stromal cell colony-stimulating effect of IL-6 was abrogated by a neutralizing antibody to IL-6. Moreover, the heteroserum with anti-IL-6 activity and two anti-IL-6 monoclonal antibodies partially blocked autonomous and IL-1 alpha-induced colony formation, suggesting that colony formation by transformed marrow stromal cells may require IL-6. Clonal-transformed stromal cell lines were derived from the anchorage- independent stromal cell colonies. Both IL-6 mRNA and protein were constitutively produced at high levels. The addition of IL-6 to either long-term marrow culture adherent cells or transformed marrow stromal cells downregulated the expression of collagen I, a major stromal cell matrix protein. Thus, IL-6 affects proliferation of stromal cells and influences their production of extracellular matrix, suggesting that IL- 6 may have indirect as well as direct influences on hematopoietic cell proliferation.
DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor
Authors: Cattaneo M , Moia M , Delle Valle P , Castellana P , Mannucci PM 
Published: October 2019

Abstract
After infusion of cryoprecipitate, the very prolonged bleeding time of patients with severe von Willebrand disease (vWD) is shortened but not always normalized in spite of normalization of plasma von Willebrand factor (vWF) levels. Therefore treatments that further improve primary hemostasis in severe vWD patients are needed. Since DDAVP shortens the bleeding time in a variety of bleeding disorders, we investigated in a double-blind, placebo-controlled crossover study the effects of the intravenous (IV) infusion of DDAVP (0.3 microgram/kg) on the bleeding times of 10 patients with severe vWD treated with cryoprecipitate. Their very prolonged bleeding times (greater than 30 minutes), partially corrected by the infusion of cryoprecipitate (14 +/- 2 minutes, mean +/- SEM), were further shortened by the administration of DDAVP (9 +/- 2 minutes, P less than .01) but not of saline (15 +/- 3 minutes, ns). Plasma vWF levels, raised from unmeasurable to normal values by cryoprecipitate, were not changed after DDAVP or saline. The defective deposition of platelets from eight patients onto human umbilical artery subendothelium was increased but not normalized by cryoprecipitate and was not significantly affected by DDAVP or saline. Therefore the infusion of DDAVP after cryoprecipitate may be of clinical benefit for management of bleeding episodes in severe vWD patients. Since severe vWD patients do not have releasable tissue stores of vWF, DDAVP must shorten their prolonged bleeding times independently of released vWF.
A linear amino acid sequence involved in the interaction of t-PA with its endothelial cell receptor
Authors: Beebe DP , Miles LA , Plow EF 
Published: October 2019

Abstract
Endothelial cell receptors for tissue plasminogen activator (t-PA) have been demonstrated recently, and we have sought to identify a region of the t-PA molecule involved in its interaction with these receptors on human umbilical vein endothelial cells. Of three monoclonal antibodies against various regions of t-PA, one directed against the finger region inhibited 125I-t-PA binding to the cells. Synthetic peptides corresponding in amino acid sequences to segments from within the finger region were constructed, and one of these inhibited t-PA binding. This peptide corresponded to residues 7 through 17 of t-PA. The inhibition by this peptide was specific as other peptides from the finger region were inactive. The inhibitory peptide also did not affect the binding of another fibrinolytic ligand, urokinase, to the cells. Although a role for other regions of t-PA in binding to endothelial cells cannot be excluded, the results implicate a short span of linear amino acid sequence within the finger region in the interaction of t-PA with endothelial cells.
Nucleoside transport and proliferative rate in human thymocytes and lymphocytes
Authors: Smith CL , Pilarski LM , Egerton ML , Wiley JS 
Published: October 2019

Abstract
The thymus is a site of active T-lymphoid cell proliferation and DNA synthesis. In this study, the capacity of human thymocytes for nucleoside transport was assessed both by cytosine arabinoside influx and by equilibrium binding of nitrobenzylmercaptopurine riboside (NBMPR), a specific ligand for the equilibrative nucleoside transporter of leukocytes. The proportion of freshly isolated thymocytes synthesizing DNA was 8.6% +/- 2.1% (n = 12) by 3H-thymidine labeling index and 7.8% +/- 2.9% (n = 4) S-phase cells by flow cytometric analysis of DNA content. In comparison, both methods gave proliferation S-phase values less than 1% for peripheral blood lymphocytes (PBLs). Thymocytes expressed a high density of specific NBMPR binding sites (26,068 +/- 8,776 sites per cell, n = 12) as compared with PBLs (1,123 +/- 553 sites per cell, n = 8). The initial influx of cytosine arabinoside into thymocytes was 14-fold greater than into PBLs, and in both cell types the influx of nucleoside was totally inhibited by 0.5 mumol/L NBMPR, which is known to inhibit the major equilibrative nucleoside transporter in white blood cells. Depletion of mature CD3+ cells from the thymocyte preparation by anti-CD3 antibody left a residual population with both increased labeling index and up to twofold greater density of NBMPR binding sites. When PBLs were cultured for 48 hours with the T-cell mitogen phytohemagglutinin, a 40-fold increase in labeling index was observed, together with a 30-fold increase in the density of specific NBMPR binding sites. Thus, fresh thymocytes from human thymus are actively proliferating and express high densities of a functional nucleoside transporter. The more immature cells in the thymocyte population which are proliferating more actively have a greater density of nucleoside transporters than the whole population. In contrast, mitotically inactive PBLs-have few nucleoside transporters, but after mitogenic stimulation PBLs express large numbers of this transmembrane molecule.
Molecular evidence for a single clonal origin in biphenotypic concomitant chronic lymphocytic leukemia and multiple myeloma
Authors: Saltman DL , Ross JA , Banks RE , Ross FM , Ford AM , Mackie MJ 
Published: October 2019

Abstract
To establish the clonal origin of a case of concomitant B-cell chronic lymphocytic leukemia (IgM kappa) and multiple myeloma (IGA lambda), we analyzed the immunoglobulin (Ig) gene rearrangements in the patient's blood and bone marrow. Despite the different isotypes, pretreatment investigation of the heavy chain gene (JH) revealed a germline fragment and two identical rearrangements in the blood and marrow. Both kappa and lambda light-chain genes were rearranged in the blood, suggesting peripheral blood lymphocyte involvement in the myeloma. Analysis of the Ig genes after chemotherapy demonstrated no change in the JH or CK rearrangements; however, the lambda genes were now in a germline configuration. Our results suggest that in this patient both chronic lymphocytic leukemia and myeloma originated from the same B-cell progenitor.
Modulation of arabinosylcytosine metabolism by arabinosyl-2- fluoroadenine in lymphocytes from patients with chronic lymphocytic leukemia: implications for combination therapy
Authors: Gandhi V , Nowak B , Keating MJ , Plunkett W 
Published: October 2019

Abstract
Our previous studies indicated that K562 cells loaded with arabinosyl-2- fluoroadenine 5′-triphosphate (F-ara-ATP) accumulated arabinosylcytosine 5′-triphosphate (ara-CTP) at a threefold higher rate compared to the control cells. In the present study lymphocytes were obtained from patients with chronic lymphocytic leukemia before and after F-ara-A monophosphate therapy. The rate of ara-CTP accumulation after in vitro ara-C incubation was compared in lymphocytes obtained prior to therapy without any other manipulation, after ex vivo F-ara- ATP (100 mumol/L) treatment, and after in vivo F-ara-A monophosphate therapy. Lymphocytes showed a 2.2-fold (n = 23) and 1.7-fold (n = 23) median increase in the cellular concentration of ara-CTP after an ex vivo incubation with 100 mumol/L F-ara-A and 20 to 24 hours after the first dose (25 or 30 mg/m2) of F-ara-A monophosphate in vivo treatment, respectively. Although the rates of F-ara-ATP and ara-CTP accumulation varied among patients, a relationship was observed in individuals between the cellular concentration of F-ara-ATP at the beginning of the ara-C incubation and ara-CTP accumulation. These studies strongly suggest that a protocol designed to administer F-ara-A monophosphate prior to ara-C infusion will augment ara-CTP accumulation by leukemia cells.
Molecular heterogeneity in acute leukemia lineage switch
Authors: Gagnon GA , Childs CC , LeMaistre A , Keating M , Cork A , Trujillo JM , Nellis K , Freireich E , Stass SA 
Published: October 2019

Abstract
Six cases of acute leukemia that underwent lineage switch from acute lymphocytic leukemia to acute myelogenous leukemia are reported. The mean age of the patients was 24 years, time to conversion was 36 months, and survival after conversion was only 3 months. Of the three cases which showed abnormal metaphases at both diagnosis and conversion, two (cases 2, 5) showed related cytogenetic abnormalities, and the third showed (case 3) independent chromosomal changes. Molecular analysis for immunoglobulin heavy chain and T-cell receptor beta chain genes showed that five of the six cases had rearrangement of at least one of these lymphoid associated genes at conversion to acute myelogenous leukemia. The single case (case 3) in which there were no lymphoid gene rearrangements at conversion was also the only case in which independent karyotypic abnormalities at diagnosis and conversion were demonstrated. Our findings suggest that lineage switch can represent either relapse of the original clone with heterogeneity at the molecular level or the emergence of a second new leukemic clone without molecular heterogeneity.
Immunophenotypic analysis of clonogenic cells in acute lymphoblastic leukemia using an in vitro colony assay
Authors: Hudson AM , Makrynikola V , Kabral A , Bradstock KF 
Published: October 2019

Abstract
A culture system was used to analyze the expression of membrane differentiation antigens on the proliferative or clonogenic fraction of cells from cases of common (precursor B) acute lymphoblastic leukemia (c-ALL). Colonies of leukemic cells were obtained in 18 of 20 cases after 1 week in culture in a liquid layer containing recombinant interleukin-2 (IL-2), phytohemagglutinin (PHA), and B-cell growth factor over an agar feeder layer containing irradiated peripheral blood mononuclear cells plus fetal calf serum (FCS) and horse serum. Cultured cells expressed HLA-DR, CD-9, CD-10, CD-20, and CD-34 antigens, indicating conservation of precursor B phenotype. Differentiation antigen expression on the clonogenic subpopulation giving rise to leukemic colonies was assessed by treating cells prior to culture with selected cytotoxic monoclonal antibodies (MoAbs) and complement or by fluorescence-activated cell sorting. Lytic treatment with HLA-DR, CD- 10, CD-9, and CD-20 antibodies produced median reductions in colony formation of 93%, 81%, 73%, and 58% respectively. Combined treatment with CD-9 and CD-10 antibodies produced complete inhibition in 11 of 13 cases. Cell-sorting experiments after CD-10 staining indicated a good correlation with complement lysis studies and also demonstrated that the CD-19 antigen is expressed on a high proportion of clonogenic cells. Colony formation was also significantly reduced in 13 of 17 cases by lytic treatment of cells with the CD-33 antibody MY-9, suggesting expression of this “myeloid” lineage antigen on ALL clonogenic cells. The substantial case-to-case variation in expression of individual differentiation antigens indicates that leukemic cellular heterogeneity is a major consideration in ex vivo bone marrow purging using MoAbs and emphasizes the need for more critical evaluation of purging techniques.
Immunohistologic features predict clinical behavior of orbital and conjunctival lymphoid infiltrates
Authors: Medeiros LJ , Harmon DC , Linggood RM , Harris NL 
Published: October 2019

Abstract
The natural history of lymphoid infiltrates of the orbit and conjunctiva is poorly understood. To determine if immunohistologic features could predict clinical outcome, these features were evaluated in 61 patients with orbital and conjunctival lymphoid infiltrates, including 44 patients with lesions localized to one or both orbits or conjunctivae. Using histologic criteria, 20 infiltrates were classified as malignant lymphoma (cytologically atypical), 14 cases were classified as benign (follicular hyperplasia or inflammatory pseudotumor), and 27 infiltrates (44%) were dense infiltrates of small lymphocytes without cytologic atypia, which could not be confidently classified as benign or malignant (histologically indeterminate). Based on expression of monotypic immunoglobulin, 20 of these cases were reclassified as small lymphocytic lymphoma. For all cases, monotypic immunoglobulin expression correlated with reduced survival (P less than .05) and increased likelihood of dissemination (P less than .001). Monotypic immunoglobulin expression also correlated with increased risk of dissemination for all histologically indeterminate (small lymphocytic) infiltrates (P less than .05). Separate analysis of the localized infiltrates showed that monotypic immunoglobulin expression significantly correlated with an increased likelihood of dissemination for all 44 cases (P less than .005) and for the 22 histologically indeterminate lesions (P = .06). For the localized small lymphocytic infiltrates, monotypic immunoglobulin expression conferred a 50% risk of dissemination. In contrast, no patients with polytypic small lymphocytic infiltrates have disseminated, although one lesion locally recurred 30 months later as lymphoma. Thus, monotypic immunoglobulin expression significantly correlates with reduced patient survival and increased risk of dissemination by orbital and conjunctival lymphoid infiltrates. Monotypic small lymphocytic infiltrates without cytologic atypia behave as do low grade B-cell malignant lymphomas with a significant risk of dissemination and an indolent clinical course. The relationship of polytypic small lymphocytic infiltrates to lymphoma remains to be determined.
Prognostic implications of cytogenetic studies in an intensively treated group of children with acute lymphoblastic leukemia
Authors: Fletcher JA , Kimball VM , Lynch E , Donnelly M , Pavelka K , Gelber RD , Tantravahi R , Sallan SE 
Published: October 2019

Abstract
We assessed the prognostic significance of leukemia cell cytogenetics by analyzing bone marrow aspirates obtained at time of diagnosis in 165 children on a single protocol for acute lymphoblastic leukemia (ALL). These children were assigned to six mutually exclusive cytogenetic categories as follows: (1) hyperdiploid, with 50 or more chromosomes (n = 35); (2) hyperdiploid, with 47 to 49 chromosomes (n = 11); (3) diploid (n = 42); (4) pseudodiploid (n = 34); (5) hypodiploid (n = 9); and (6) insufficient data (n = 34). At a median follow-up of 5 years, there were no statistically significant differences between any of these cytogenetic categories in either event-free or overall survival. Those children with chromosomal translocations (n = 26) appeared to fare the same as those lacking translocations (n = 105). The absence of karyotypic prognostic significance was observed not only within the overall group, but also when the results were stratified by standard- risk and high-risk status. Of the specific structural chromosome changes that we studied, only the Philadelphia chromosome (Ph) appeared to confer a poor prognosis, although there were too few such cases to achieve statistical significance. Although we did not detect the event- free survival differences that have been described previously in hyperdiploid, hypodiploid, and pseudodiploid childhood ALL, our findings must be viewed as preliminary given the small number of children in some of the cytogenetic categories. We think that the prognostic implications of these cytogenetic features might have been nullified by improvements in therapy.
The breakpoint of a large deletion causing hereditary persistence of fetal hemoglobin occurs within an erythroid DNA domain remote from the beta-globin gene cluster
Authors: Feingold EA , Forget BG 
Published: October 2019

Abstract
The DNA juxtaposed to the gamma-globin genes as a result of a large deletion associated with hereditary persistence of fetal hemoglobin (HPFH) was studied to define the role it may play in maintaining active expression of these genes in adult erythroid cells. The DNA located immediately 3′ to the deletion breakpoint was found to function as an enhancer element in gene transfer experiments and to be specifically hypomethylated in normal erythroid cells of both fetal and adult origin. This DNA also contains a long open reading frame encoding a polypeptide chain 292 amino acids in length. Therefore, in this form of HPFH (HPFH-1), the continued expression of gamma-globin genes in adult life may result from the inclusion of these genes within a new chromosomal domain that is potentially transcriptionally active in adult erythroid cells. The 3′ breakpoint of another large deletion causing delta beta thalassemia rather than HPFH was also identified. This deletion (Spanish G gamma A gamma (delta beta) degrees thalassemia) is nearly identical in size and location to that of HPFH- 1, but extends an additional 8.5 to 9 kb in the 3′direction, and therefore results in loss of the sequences near the 3′ breakpoint of HPFH-1. Thus, the presence of these sequences appears to be important for the expression of the HPFH phenotype.
Food iron absorption in idiopathic hemochromatosis
Authors: Lynch SR , Skikne BS , Cook JD 
Published: October 2019

Abstract
The relationship between iron status and food iron absorption was evaluated in 75 normal volunteers, 15 patients with idiopathic hemochromatosis, and 22 heterozygotes by using double extrinsic radioiron tags to label independently the nonheme and heme iron components of a hamburger meal. In normal subjects, absorption from each of these pools was inversely correlated with storage iron, as measured by the serum ferritin concentration. In patients with hemochromatosis, absorption of both forms of iron was far greater than would be predicted from the relationship between absorption and serum ferritin observed in normal volunteers. Nevertheless, there was still a modest but statistically significant reduction in absorption of nonheme iron with increasing serum ferritin. This relationship could not be demonstrated in the case of heme iron absorption. In heterozygotes, nonheme iron absorption from a hamburger meal containing no supplementary iron did not differ significantly from that observed in normal volunteers. However, when this meal was both modified to promote bioavailability and supplemented with iron, absorption of nonheme iron was significantly elevated. These studies confirm the presence of excessive nonheme iron absorption even from unfortified meals in patients with idiopathic hemochromatosis and suggest in addition that they are particularly susceptible to iron loading from diets containing a high proportion of heme iron. Impaired regulation of nonheme iron absorption was also observed in heterozygous individuals, but a statistically significant abnormality was demonstrable only when the test meal contained a large highly bioavailable iron supplement.
Interleukin-1 enhances survival of lethally irradiated mice treated with allogeneic bone marrow cells
Authors: Oppenheim JJ , Neta R , Tiberghien P , Gress R , Kenny JJ , Longo DL 
Published: October 2019

Abstract
Interleukin-1 (IL-1) enhanced the capacity of allogeneic bone marrow (BM) cells to promote survival of mice given doses of radiation (1,200 to 1,350 cGy) that are significantly higher than those generally used for BM ablation (850 to 950 cGy). Three to five times greater numbers of lethally irradiated (1,200 to 1,350 cGy) C57B1/6 (H-2b) mice given 10(7) T-cell-depleted Balb/c (H-2d) BM cells survived over 6 weeks if also treated with a single intraperitoneal (IP) dose of 10 micrograms IL-1 20 hours before or from 1 to 3 hours after radiation. The spleens of these mice were reconstituted predominantly, but not exclusively, with donor cells (54% to 91%). Histologic examination of the epidermal and gastrointestinal tissues of mice surviving more than 6 weeks did not reveal any evidence of graft-versus-host (GVH) disease; however, since 10% to 43% of the mice died between days 30 and 46, the possibility of a GVH syndrome in these mice cannot be excluded. The spleen cells from irradiated mice given BM transplants and IL-1, which consisted of greater than or equal to 85% donor cells, were able to generate specific T-cell cytotoxic killing of unrelated allogeneic donor cells but were unreactive to target cells bearing either host or donor major histocompatibility complex (MHC) class I antigens. Thus, long-term mixed chimeric survivors were tolerant to recipient and donor alloantigens but exhibited immunologic competence. These results show that IL-1 promotes survival of lethally irradiated mice and that allogeneic hematopoietic cells in such animals develop tolerance to host MHC antigens. Although there are many unanswered questions, these data suggest that IL-1 may prove clinically useful in promoting BM engraftment.