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Biomedical subjects

M A Moore

Publications and source records attributed to M A Moore.

At least 217 records · Page 12Linked to original sources
PubMed1991

Purification and partial characterization of a human hematopoietic precursor population.

This study reports the development of an assay, the Pre-colony-forming unit (CFU) assay, which detects human hematopoietic precursors. The Pre-CFU assay is based on the observation that precursors to CFU-granulocyte-macrophage (CFU-GM) that are undetectable in clonogenic assays differentiate into CFU-GM preferentially following treatment in suspension culture with recombinant human interleukin-1 alpha (rhIL-1 alpha) combined with rhIL-3. Using the Pre-CFU assay, hematopoietic precursors were detected in human bone marrow depleted of CFU-GM progenitors and differentiated hematopoietic elements via 4-hydroperoxycyclophosphamide treatment coupled with selection for CD34+ cells (4-HCresistant/CD34+ marrow). Additionally, the Pre-CFU assay detected recovery of hematopoiesis substantially earlier than the CFU-GM assay in primates following myeloablation with 5-fluorouracil. The Pre-CFU assay was used to asses purification of a phenotypically defined hematopoietic precursor population, the lin-CD34+ population. The lin-CD34+ population lacks detectable surface markers for T-cell, B-cell, natural killer cell, and myeloid lineage, possesses the CD34 antigen, is devoid of CFU-GM progenitors, and yields Pre-CFU assay values comparable with 4-HCresistant/CD34+ marrow. Using a combination of phenotypic analysis and Pre-CFU assay analysis, the action of rhIL-1 alpha plus rhIL-3 treatment on lin-CD34+ cells was further characterized. The data indicate that rhIL-1 alpha plus rhIL-3 treatment induces proliferation and differentiation of early hematopoietic precursors into progenitors and terminally differentiated cells, without inducing a significant expansion of the precursor population itself.

Animals↗
PubMed1991

Modulation of granulocyte colony-stimulating factor receptors on murine peritoneal exudate macrophages by tumor necrosis factor-alpha.

Modulation of granulocyte CSF (G-CSF) receptors on murine peritoneal exudate macrophages (PEM) by various cytokines was investigated. At 4 degrees C, 125I-G-CSF receptor binding on PEM reached a plateau after 6 h and was specifically competed by unlabeled human rG-CSF but not by other cytokines, including human rG-CSF-1, murine recombinant granulocyte-macrophage CSF, murine rIFN-gamma, human rIL-1 beta, and murine rTNF-alpha. 125I-G-CSF bound to PEM has a half-life of 30 min at 37 degrees C. Preincubation of PEM with murine rTNF, murine recombinant granulocyte-macrophage CSF, CSF-1, or G-CSF for 30 min at 37 degrees C resulted in partial reduction of 125I-G-CSF binding capacity, whereas IL-1 or IFN-gamma did not inhibit G-CSF binding. Further studies indicated that reduction of G-CSF binding caused by TNF was a dose- and time-dependent process and did not require FCS. The reduction was transient, and receptor binding was recovered by incubation at 37 degrees C for 8 h. The recovery of G-CSF binding was inhibited in the presence of cycloheximide. In addition, G-CSF binding studies suggested that the TNF-induced decrease in G-CSF binding to PEM was probably due to a reduction in receptor number rather than receptor affinity. Modulation of G-CSFR by TNF was also observed on nonelicited macrophages from various strains of mice. Our results demonstrate a physiologic response of G-CSFR on macrophages that is modulated by TNF. This phenomenon may play an important, as yet unknown, role in the macrophage inflammatory response.

Animals↗
PubMed1991

Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid-specific monoclonal antibodies and drugs in combination.

We report the results of a preclinical study comparing four different purging protocols using a promyelocytic human cell line HL-60 and myeloid leukemic progenitor cells (colony-forming unit-leukemic [CFU-L]) from acute myelogenous leukemia (AML) patients assayed in semisolid culture. We studied the antileukemic effect of (1) Single-cycle complement-mediated lysis by two different monoclonal antibodies (MoAbs) (M195 [CD33] and F23 [CD13] 40 micrograms/mL), reactive with distinct antigens found on early myeloid cells and monocytes, used alone and in combinations; (2) 4-Hydroperoxycyclophosphamide (4-HC) (80 mumol/L or 100 mumol/L) alone; or (3) combined with VP-16 (5 micrograms/mL) and (4) a cocktail of 1 through 3 as above (combined immunochemotherapy). More than 4 logs of HL-60 tumor cell elimination were observed after 1 hour of incubation with both MoAbs plus 4-HC + VP-16 while the single treatment (immunotherapy or chemotherapy) provided 1.5 and 3.5 logs of colony-forming inhibition, respectively. When the same protocols were tested on cryopreserved leukemic cells from eight patients with AML, we observed a mean value of CFU-L inhibition of 92.3% +/- 2.5% SD, 95.5% +/- 1.4% SD, and 99% +/- 0.8% SD after MoAbs and complement lysis, 4-HC, and 4-HC + VP-16 treatment, respectively. The combined treatment of MoAbs and 4-HC + VP-16 produced more than 3-log reduction of CFU-L colony formation. By comparison, the mean recovery of committed normal bone marrow progenitors after incubation with MoAbs and complement was 12% for CFU-granulocyte-macrophage (CFU-GM), 22.9% for burst-forming unit erythroid (BFU-E), and the recovery following 4-HC + VP-16 treatment was 4.4% for CFU-GM and 5.6% BFU-E. In subsequent experiments, highly purified CD34+ blast cells, enriched by positive selection, and stimulated in liquid culture by cytokines (interleukin-1 [IL-1], IL-3, and combination of both) or MO-conditioned medium (MoCM), demonstrated that immunochemotherapy spares hematopoietic colony-forming cells earlier than day 14 CFU-GM, in vitro.

Adult↗
PubMed1991

Characterization of a cDNA for chicken osteopontin: expression during bone development, osteoblast differentiation, and tissue distribution.

The chicken bone phosphoprotein (approximately 66-kDa BPP) is a major noncollagenous component of bone and is the major phosphoprotein synthesized by cultured chicken embryo osteoblasts [Gotoh, Y., Gerstenfeld, L. C., & Glimcher, M. J. (1990) Eur. J. Biochem. 87, 49-58]. A cDNA clone for this protein was isolated from an expression library made from embryonic chicken bone mRNA. The complete primary protein sequence of 264 amino acids was deduced from the cDNA sequence inclusive of a 16 amino acid signal peptide sequence and terminated by 4 in-frame stop sequences. A sequence alignment indicated an approximate 35% overall similarity in protein sequence between the avian approximately 66-kDa BPP and the mammalian protein osteopontin, while at the nucleotide level 60% similarity was observed. Features of this sequence which showed the greatest similarity to mammalian osteopontin included a region in which seven of nine consecutive residues are aspartic acid, a recognition sequence for integrin-mediated cell binding (-Arg-Gly-Asp), and four possible recognition sequences for phosphorylation by casein kinase II. Hybridization analysis indicated a message of 1.5 kb found predominantly in bone and kidney. The mRNA was inducible in phorbol ester treated primary cultures of chondrocytes which show no expression under normal growth conditions. A temporal induction was seen during osteoblastic differentiation both in vivo and in vitro, thus suggesting that regulation of the approximately 66-kDa BPP is under transcriptional control during osteoblast development. In summary, both the protein's primary structure and its biological features suggest that it is the avian homologue to mammalian protein osteopontin.

Amino Acid Sequence↗
PubMed1991

The use of colony stimulating factors in combination.

More gene products that influence hematopoiesis continue to become available. As a result, is now possible to carry out both in vivo and in vitro studies with purified erythropoietin, various colony stimulating factors and 11 interleukins. The identification and availability of the ligand for the c-kit gene product has had a profound influence in the past year.

Animals↗
PubMed1991

Depression of Hoffmann reflexes following voluntary contraction and implications for proprioceptive neuromuscular facilitation therapy.

Postcontraction depression of Hoffmann-reflex (H-reflex) amplitudes was examined to study the rationale underlying proprioceptive neuromuscular facilitation relaxation techniques. The time course of H-reflex amplitude depression was used to assess postcontraction changes in motoneuron reflex excitability. Sixteen healthy female subjects performed voluntary isometric plantar-flexion contractions (65%-75% of maximal voluntary contraction) in a prone position. H-reflex stimulation began at a postcontraction delay of 0.05, 0.1, 0.5, 1, or 5 seconds and continued every 10 seconds for 1 minute. Reflexes were depressed (mean = 67% decrease) by 0.05 second postcontraction, reached maximal depression (mean = 83.3% decrease) from 0.1 to 1 second postcontraction, recovered to 70% of control amplitudes (mean = 30% decrease) by 5 seconds postcontraction, and reached 90% control amplitudes (mean = 10% decrease) by 10.05 seconds postcontraction. The results indicate that proprioceptive neuromuscular facilitation techniques (eg, hold-relax) purported to produce a phase of relaxation following voluntary contraction do appear to produce a strong, but brief, neuromuscular inhibition that may be clinically useful for applying stretch.

Adult↗
PubMed1991

The clinical use of colony stimulating factors.

Colony stimulating factors and interleukins regulate proliferation, differentiation, and functional activation of hematopoietic cells of multiple lineages. These hematopoietic growth factors are proving effective in vivo in stimulation of granulopoiesis in clinical situations associated with myelosuppression. G-CSF and GM-CSF promote accelerated granulocyte recovery following chemotherapy, or allogeneic or autologous bone marrow transplantation, in patients with cancer. In congenital defects of granulocyte production or in acquired disorders such as idiopathic neutropenia or aplastic anemia, CSF administration can lead to recovery of functioning granulocytes. This has resulted in a reduction in the morbidity and mortality associated with these diseases and now permits both a dose and a schedule intensification of chemotherapy. In myeloid leukemia and myelodysplastic syndromes, CSF treatment, particularly G-CSF, has proved effective for certain patients in improving neutrophil, platelet, and occasionally red cell production while reducing blast cells. The recombinant growth factors are generally well tolerated with few limiting toxicities at dose levels that effectively stimulate hematopoiesis.

Acquired Immunodeficiency Syndrome↗
PubMed1990

GABA receptor modulation of tyrosine hydroxylase gene expression in the rat adrenal gland.

Chromaffin cell gamma-aminobutyric acid (GABA) receptors play a role in modulating catecholamine secretion. The present experiments examined the role of GABA receptors in modulation of tyrosine hydroxylase (TH) induction in rat adrenal gland. Administration of bicuculline, a GABA antagonist, had no effect on TH activity or TH mRNA. However, bicuculline potentiated reserpine's effect on TH activity and TH mRNA induction. These data suggest that GABA receptors modulate induction of TH and TH mRNA in the adrenal gland.

Adrenal Glands↗
PubMed1990

Modulation of tyrosine hydroxylase gene expression in the rat adrenal gland by age and reserpine.

Tyrosine hydroxylase (TH), TH messenger RNA (TH mRNA) and dopamine (DA) were measured simultaneously in adrenal glands of individual Fischer 344 rats aged 2, 6, 13 and 23 months. Between 2 and 23 months TH activity rose 2-fold as compared to the youngest group. TH mRNA content of the adrenal gland rose 3-fold between 2 and 23 months. A 3-fold increase in adrenal DA content, the first catecholamine product of TH, provides evidence that the increases in TH gene expression are functionally significant. To determine if mechanisms that regulate gene expression are altered by aging, the effects of reserpine on induction of TH mRNA and TH activity were compared in another group of rats aged 2, 12 and 27 months. Consistent with the results of the first experiment, there were age-related increases in both TH activity and TH mRNA in the age-matched control groups. TH activity rose 2-fold and TH mRNA rose more than 6-fold between 2 and 27 months. The discrepancy in the relative magnitudes of increases in TH mRNA and TH protein suggest an uncoupling of regulation of TH mRNA and TH protein levels. Moreover, there were significant age-related differences with respect to modulation of TH gene expression by reserpine treatment. TH activity was induced by reserpine in the youngest group, but not in the two older age-groups. In contrast, reserpine caused significant induction of TH mRNA in all age groups. These results provide evidence that aging is accompanied by alterations in transcriptional and post-transcriptional mechanisms involved in regulation of TH gene expression.

Adrenal Glands↗
PubMed1990

Protective effects of tumor necrosis factor on murine hematopoiesis during cycle-specific cytotoxic chemotherapy.

Tumor necrosis factor (TNF) is a pleiotropic cytokine which exerts a wide range of effects when administered in vivo. Using a murine model, we have investigated the effect of pretreatment with 1 microgram (2.6 x 10(4) units) per mouse of recombinant murine TNF-alpha on hematopoietic recovery following administration of cyclophosphamide, 5-fluorouracil, methotrexate, or vinblastine. TNF pretreatment results in enhanced regeneration of circulating neutrophils and hematopoietic progenitors, as measured by in vivo and in vitro assays, in animals given cycle-specific chemotherapeutic agents. The results may suggest that TNF affects cycle kinetics in hematopoietic progenitor cell populations, thus making these cells less prone to the cytocidal effects of the chemotherapeutic agents. As myeloablation is a frequent and often critical side effect following cancer treatment, these findings may have clinical implications.

Animals↗
PubMed1990

Hematologic effects of interleukin-1 beta, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in tumor-bearing mice treated with fluorouracil.

Myelosuppression following intensive chemotherapy in cancer patients is associated with increased morbidity and mortality. Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), alone or in combination with interleukin-1 (IL-1), have been shown to counteract myelosuppression resulting from some, but not all, chemotherapeutic regimens. In an attempt to apply these findings to intensive therapy with proliferation-dependent chemotherapeutic drugs such as fluorouracil (5-FU), we investigated combination biochemotherapy in a murine model. Female CD8F1 [(BALB/c X DBA/8)F1] mice bearing first-passage transplants of spontaneous CD8F1 breast tumors were treated intraperitoneally once a week for 3 successive weeks with a course of 5-FU alone or with a course of 5-FU in combination with recombinant human interleukin-1 beta (rHuIL-1 beta) alone or in combination with CSFs. rHuIL-1 beta alone or in combination with rHuG-CSF or recombinant murine GM-CSF significantly improved tumor growth inhibition (60% vs. 90%) and survival (20% vs. 90%-100%), increased the maximally tolerated dose of 5-FU, accelerated recovery of neutrophil counts in peripheral blood, and reduced duration of significant neutropenia and loss of body weight (29% vs. 10% loss). Clinical trials of IL-1 have been initiated in patients with advanced cancer receiving multiple courses of high-dose 5-FU.

Animals↗
PubMed1990

Lipolyzed hypertriglyceridemic serum and triglyceride-rich lipoprotein cause lipid accumulation in and are cytotoxic to cultured human endothelial cells. High density lipoproteins inhibit this cytotoxicity.

The cytotoxic effect of hypertriglyceridemic (HTG) serum and triglyceride-rich lipoprotein (TG-rich lipoprotein) lipolyzed in vitro by purified lipoprotein lipase on cultured human umbilical vein endothelial cells (HUVECs) was studied. When confluent cultures of HUVECs (8.4 x 10(4)/cm2) were incubated in the presence of control (non-lipolyzed HTG serum) or lipolyzed HTG serum or TG-rich lipoprotein, the lipolyzed HTG serum or TG-rich lipoprotein was cytotoxic to the HUVECs as indicated by their detachment from the culture dish; the lipolyzed serum at 10% of the culture medium or lipolyzed TG-rich lipoprotein at 75 micrograms cholesterol/ml caused the detachment of all (100%) of the cells from the culture dish after a 24 h incubation. Control (non-lipolyzed) HTG serum or non-lipolyzed TG-rich lipoprotein at the same or higher concentration was not cytotoxic to the cells. The HUVECs incubated for 48 h with low (sublethal) doses of lipolyzed TG-rich lipoprotein (10-50 micrograms cholesterol/ml) contained massive lipid inclusions; no lipid inclusions were seen within the cells when the culture medium contained control non-lipolyzed TG-rich lipoproteins. Finally, when high density lipoprotein (HDL) was added to the culture medium at the same concentration as the cytotoxic lipolyzed TG-rich lipoprotein (75 micrograms cholesterol/ml), the cytotoxic effect of the lipolyzed TG-rich lipoprotein was inhibited. These data suggest that the interaction of endothelial cells with lipolytic remnants of TG-rich lipoprotein may play a role in the pathogenesis of atherosclerosis and that HDL may play an important role in inhibition of the endothelial cell injury produced by the lipolytic remnants of TG-rich lipoprotein.

Azo Compounds↗
PubMed1990

Interactions of serum proteins with small unilamellar liposomes composed of dioleoylphosphatidylethanolamine and oleic acid: high-density lipoprotein, apolipoprotein A1, and amphipathic peptides stabilize liposomes.

Small unilamellar liposomes composed to dioleoylphosphatidylethanolamine (DOPE) and oleic acid (OA) are stabilized by incubation with normal human serum or plasma [Liu, D., & Huang, L. (1989) Biochemistry 28, 7700-7707]. The present report describes a systematic study of interactions of purified serum proteins and lipoproteins with these liposomes. Albumin destabilized liposomes by extracting OA from the liposomes, whereas immunoglobulins and lipoproteins (HDL, LDL, and VLDL) had no effect. However, HDL and, to some extent, VLDL showed a rapid stabilization activity against the lytic effect of albumin. HDL added together with or shortly after the addition of albumin completely abolished the liposome leakage and aggregation effects induced by albumin. SDS-PAGE analysis of the HDL-stabilized liposomes revealed that apolipoprotein A1 was associated with liposomes. Purified apolipoprotein A1, but not a lipid mixture resembling the lipid composition of HDL, showed comparable liposome stabilization activity as HDL. Furthermore, synthetic peptides resembling the amphipathic helices found in apolipoprotein A1 also showed strong liposome stabilization activity. Peptides which were able to form amphipathic helixes of a wedge shape were more effective stabilizers than those which could not. These data indicate that HDL plays a major role in human serum or plasma for the liposome stabilization activity. HDL exerts its activity probably by the interactions of the amphipathic helices of apolipoprotein A1 with the hydrophobic voids found on the outer surface of the highly curved, small liposomes.

Apolipoprotein A-I↗
PubMed1990

Hematopoietic growth factors in cancer.

The family of colony stimulating factors and interleukins influence all aspects of hematopoietic cell proliferation and differentiation. In most instances these hematopoietic growth factors have overlapping, pleiotropic effects and frequently regulate early progenitor cell proliferation and mature cell function. Currently, seven of these factors are in clinical trial: erythropoietin for treatment of anephric anemia, IL-2 in conjunction with LAC therapy, and IL-1, IL-3, G-CSF, GM-CSF, and M-CSF for stimulation of myelopoiesis and granulocyte-macrophage function after chemotherapy, irradiation, or bone marrow transplantation in patients with cancer. G-CSF and GM-CSF have also proved effective in treatment of congenital and idiopathic neutropenias and have had some efficacy in treatment of myeloid leukemias, myelodysplastic disorders, aplastic anemia, and acquired immunodeficiency syndrome (AIDS).

Antineoplastic Agents↗
PubMed1990

Cytokine networks involved in the regulation of haemopoietic stem cell proliferation and differentiation.

Additive and synergistic interactions between haemopoietic growth factors and cytokines can be demonstrated in vitro in clonogenic and suspension cultures of murine and human bone marrow. Purification of early stem cells by combinations of purging with cytotoxic agents (5-fluorouracil, 4-hydroperoxy-cyclophosphamide) and selection with monoclonal antibodies for CD34+, CD33- cells permits analysis of factor interactions at the level of the primitive pluripotential stem cell. Interactions between interleukins, tumour necrosis factor and the colony-stimulating factors can be monitored. In vivo, IL-1 alone, or in combination with G-CSF produces accelerated reconstitution of haemopoiesis after chemotherapy, irradiation and bone marrow transplantation in murine and primate systems. IL-1 elicits cytokine cascades that may have positive or negative actions on lymphohaemopoiesis. Induction of products of the cyclooxygenase and lipooxygenase pathways, as well as tumour necrosis factor and TGF-beta, modulate haemopoiesis.

Animals↗
PubMed1990

High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates.

Because several human hematopoietic growth factors have been identified and shown to be effective for treatment of congenital or iatrogenic neutropenias, and cord blood contains stimulatory activities for blood-forming cells, we postulated that identification of these factors and analysis of their regulatory role in normal neonates would provide a rationale for their use in treating neonatal infections associated with neutropenia. We studied the plasma levels of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF, respectively) and the frequency of granulomonopoietic colony-forming cells (CFU-GM) in the umbilical cord blood of normal term neonates. Plasma growth factor levels were measured by a biologic assay. Circulating hematopoietic progenitors were assayed for colony formation with different recombinant growth factors used as exogenous growth stimulators. The cell cycle status of these progenitors was analyzed by the thymidine suicide technique. At birth the leukocyte count (mean +/- SD) was 11.0 +/- 3.9 x 10(9)L and the neutrophil count was 5.6 +/- 2.6 x 10(9)/L. The incidence of CFU-GM was significantly higher in umbilical cord blood than in normal adult peripheral blood (p less than 0.005) with up to 40% of the cells in S phase (less than 10% in normal adults). Plasma levels of G-CSF and GM-CSF at birth were 40.8 +/- 2.8 U/ml and 19.9 +/- 5.2 U/ml, respectively (normal adult plasma levels 2.5 +/- 1.5 U/ml for G-CSF and undetectable for GM-CSF). These high levels of G-CSF and GM-CSF in umbilical cord blood of normal neonates might play a role in maintaining adequate neutrophil production.

Adult↗