35 results on '"Khaldoyanidi S"'
Search Results
2. Critical analysis of methods used for hematopoietic differentiation of embryonic stem cells
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Orlovskaya, I. A. and Khaldoyanidi, S. K.
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- 2011
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3. Formation of Immunodeficiency in Newborn Mice Exposed to Nicotine during Intrauterine Development
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Demina, D. V., Toporkova, L. B., Kozlov, V. A., Khaldoyanidi, S. K., and Orlovskaya, I. A.
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- 2005
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4. Correction of testosterone-induced changes in a population of hemopoietic precursors by a bone-marrow inhibitor of the proliferative activity of a hemopoietic stem cell
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Orlovskaya, I. A., Khaldoyanidi, S. K., Shklovskaya, E. V., Tsyrlova, I. G., and Kozlov, V. A.
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- 1995
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5. Two Different Functions for CD44 Proteins in Human Myelopoiesis
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Moll, J., Khaldoyanidi, S., Sleeman, J.P., Achtnich, M., Preuss, I., Ponta, H., and Herrlich, P.
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- 1998
6. Initial results from a phase I/IIa trial evaluating BMS-986158, an inhibitor of the bromodomain and extra-terminal (BET) proteins, in patients (pts) with advanced cancer
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Hilton, J., primary, Cristea, M.C., additional, Voskoboynik, M., additional, Postel-Vinay, S., additional, Edenfield, W., additional, Gavai, A., additional, Wee, S., additional, Srivastava, N., additional, Klippel, A., additional, Jackson, D., additional, Apfel, A., additional, Chasalow, S.D., additional, Williams, D., additional, Donovan, M., additional, Fischer, B., additional, Khaldoyanidi, S., additional, and Diamond, J.R., additional
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- 2018
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7. 411O - Initial results from a phase I/IIa trial evaluating BMS-986158, an inhibitor of the bromodomain and extra-terminal (BET) proteins, in patients (pts) with advanced cancer
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Hilton, J., Cristea, M.C., Voskoboynik, M., Postel-Vinay, S., Edenfield, W., Gavai, A., Wee, S., Srivastava, N., Klippel, A., Jackson, D., Apfel, A., Chasalow, S.D., Williams, D., Donovan, M., Fischer, B., Khaldoyanidi, S., and Diamond, J.R.
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- 2018
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8. Hematopoietic differentiation of embryonic stem cells
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ORLOVSKAYA, I, primary, SCHRAUFSTATTER, I, additional, LORING, J, additional, and KHALDOYANIDI, S, additional
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- 2008
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9. Involvement of CD44 variant isoform v10 in progenitor cell adhesion and maturation
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Roesel, M., Khaldoyanidi, S., Zawadzki, V., and Zoeller, M.
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- 1999
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10. Expression of CD44 variant isoforms in peripheral blood leukocytes in malignant lymphoma and leukemia: inverse correlation between expression and tumor progression
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Khaldoyanidi, S., Achtnich, M., Hehlmann, R., and Zoeller, M.
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- 1996
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11. Hyaluronan stimulates mobilization of mature hematopoietic cells but not hematopoietic progenitors
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Schraufstatter, I., Serobyan, N., Discipio, R., Natalia Feofanova, Orlovskaya, I., and Khaldoyanidi, S.
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Mice, Inbred BALB C ,food and beverages ,Bone Marrow Cells ,Hematopoietic Stem Cells ,Article ,Hematopoietic Stem Cell Mobilization ,Mice ,Hyaluronan Receptors ,Matrix Metalloproteinase 9 ,Cell Movement ,Animals ,Glucuronosyltransferase ,Hyaluronic Acid ,Hyaluronan Synthases ,Cells, Cultured - Abstract
Hyaluronan (HA) is expressed by cells in bone marrow where it contributes to the regulation of hematopoietic homeostasis. In this study, we have demonstrated that exogenous low molecular weight HA (LMW HA) polymers mobilize leukocytes, but not hematopoietic progenitor cells, to peripheral blood within a 3 hour time period following HA administration. Mobilization of leukocytes correlated with increased extracellular MMP-9 concentrations induced by LMW HA, but not high molecular weight (HMW) HA. In contrast, HMW HA up-regulated TIMP-1 expression in bone marrow cells. In vitro, HMW HA did not influence SDF-1 - mediated chemotaxis of hematopoietic progenitors, whereas LMW HA polymers demonstrated inhibitory activity. These findings suggest that the effects of HA on cell motility depend on the size of the HA polymers and on the type of target cells.
12. The influence of synthetic peptide from retroviral transmembrane protein p15E on murine spleen cell proliferation and bone marrow hemopoietic precursor colony formation
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Chernukkin, I. V., Khaldoyanidi, S. K., Kozlov, V. A., and Gaidul, K. V.
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- 1993
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13. Incidence of Elevated Aminotransferases With or Without Bilirubin Elevation During Treatment With Immune Checkpoint Inhibitors: A Retrospective Study of Patients From Community Oncology Clinics in the United States.
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Kim C, Zhu S, Kouros-Mehr H, and Khaldoyanidi S
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Introduction The elevation of aminotransferase levels is regarded as an indicator of hepatocellular injury. The objective of this study was to describe real-world incidence of elevated aminotransferase levels with or without bilirubin elevation among patients treated with immune checkpoint inhibitors (ICIs) for solid tumors. Methods This retrospective cohort study used an electronic health record database representing > 1.5 million active United States (US) cancer patients and included patients diagnosed with any cancer between January 1, 2014 and March 31, 2019, and treated with one or more ICIs such as ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The frequency, onset, duration, management of grade ≥ 3 elevation of aminotransferase levels with or without bilirubin elevation events, progression rate from isolated elevation of aminotransferase levels (IAT) to elevated aminotransferase levels with elevated bilirubin (ATWB), and mortality were described. Results Overall, 69,140 patients received 85,433 treatment courses. A total of 1,799 (2.11%) IAT and 441 (0.52%) ATWB events were observed during treatment courses. The median onset was 51 and 42 days for IAT and ATWB, respectively, across treatment courses, and the median duration of both was approximately seven days. Approximately 5% (n=96) of IAT events progressed to ATWB in a median time of 11 days. The proportion of patients who received corticosteroids after elevated aminotransferase levels with or without bilirubin was ~37% (n=671/1,799 of IAT and n=147/441 of ATWB) and ~8% discontinued ICI treatment (n=118/1,799 of IAT and n=43/441 of ATWB). About 46% (n=68/147) of ATWB and and 25% (n=172/671) of IAT events treated with steroids led to death within 45 days. Similarly, 49% (n=21/43) of ATWB and 35% (n=42/118) of IAT events leading to treatment discontinuation led to death within 45 days. Conclusions Real-world data from oncology clinics in US suggest low incidence of grade ≥ 3 elevated aminotransferase levels with or without bilirubin elevation following treatment with ICIs. In most cases, ICI treatment was not discontinued and management of elevated aminotransferases consisted of corticosteroid treatment in one-third of cases., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Kim et al.)
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- 2022
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14. Immune Biology of Acute Myeloid Leukemia: Implications for Immunotherapy.
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Khaldoyanidi S, Nagorsen D, Stein A, Ossenkoppele G, and Subklewe M
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- Animals, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Humans, Immunologic Surveillance, Tumor Escape, Immunotherapy methods, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute therapy
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- 2021
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15. New insights into the role of Plg-RKT in macrophage recruitment.
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Miles LA, Lighvani S, Baik N, Parmer CM, Khaldoyanidi S, Mueller BM, and Parmer RJ
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- Amino Acid Sequence, Animals, Humans, Macrophages pathology, Molecular Sequence Data, Peritonitis pathology, Plasminogen chemistry, Proteomics, Receptors, Cell Surface chemistry, Macrophages metabolism, Plasminogen metabolism, Receptors, Cell Surface metabolism
- Abstract
Plasminogen (PLG) is the zymogen of plasmin, the major enzyme that degrades fibrin clots. In addition to its binding and activation on fibrin clots, PLG also specifically interacts with cell surfaces where it is more efficiently activated by PLG activators, compared with the reaction in solution. This results in association of the broad-spectrum proteolytic activity of plasmin with cell surfaces that functions to promote cell migration. Here, we review emerging data establishing a role for PLG, plasminogen receptors and the newly discovered plasminogen receptor, Plg-RKT, in macrophage recruitment in the inflammatory response, and we address mechanisms by which the interplay between PLG and its receptors regulates inflammation., (© 2014 Elsevier Inc. All rights reserved.)
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- 2014
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16. Hyaluronan expressed by the hematopoietic microenvironment is required for bone marrow hematopoiesis.
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Goncharova V, Serobyan N, Iizuka S, Schraufstatter I, de Ridder A, Povaliy T, Wacker V, Itano N, Kimata K, Orlovskaja IA, Yamaguchi Y, and Khaldoyanidi S
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- Animals, Cell Adhesion drug effects, Cell Adhesion physiology, Cells, Cultured, Chemokine CXCL12 genetics, Chemokine CXCL12 metabolism, Chemotaxis drug effects, Chemotaxis physiology, Glucuronosyltransferase genetics, Glucuronosyltransferase metabolism, Hematopoiesis drug effects, Hematopoietic Stem Cells cytology, Humans, Hyaluronan Synthases, Hyaluronic Acid genetics, Hymecromone analogs & derivatives, Hymecromone pharmacology, Mice, Mice, Knockout, Stem Cell Niche drug effects, Bone Marrow metabolism, Hematopoiesis physiology, Hematopoietic Stem Cells metabolism, Hyaluronic Acid metabolism, Stem Cell Niche physiology
- Abstract
The contribution of hyaluronan (HA) to the regulatory network of the hematopoietic microenvironment was studied using knock-out mice of three hyaluronan synthase genes (Has1, Has2, and Has3). The number of hematopoietic progenitors was decreased in bone marrow and increased in extramedullary sites of Prx1-Cre;Has2(flox/flox);Has1(-/-);Has3(-/-) triple knock-out (tKO) mice as compared with wild type (WT) and Has1(-/-);Has3(-/-) double knock-out (dKO) mice. In line with this observation, decreased hematopoietic activity was observed in long term bone marrow cultures (LTBMC) from tKO mice, whereas the formation of the adherent layer and generation of hematopoietic cells in WT and dKO cultures was not different. 4-Methylumbelliferone (4MU) was used to pharmacologically inhibit the production of HA in LTBMC. Treatment with 4MU inhibited HA synthesis, decreased expression of HAS2 and HAS3, and eliminated hematopoiesis in LTBMC, and this effect was alleviated by the addition of exogenous HA. Exogenous HA also augmented the cell motility in LTBMC, which correlated with the HA-stimulated production of chemokines and growth factors. Conditioned media from HA-induced LTBMC enhanced the chemotaxis of hematopoietic stem/progenitor cells (HSPC) in response to SDF-1. Exposure of endothelial cells to 4MU decreased their ability to support HSPC rolling and adhesion. In addition, migration of transplanted HSPC into the marrow of 4MU-pretreated mice was lower than in untreated mice. Collectively, the results suggest that HA depletion reduces the ability of the microenvironment to support HSPC, and confirm a role for HA as a necessary regulatory element in the structure of the hematopoietic microenvironment.
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- 2012
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17. The plasminogen receptor, Plg-R(KT), and macrophage function.
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Miles LA, Lighvani S, Baik N, Andronicos NM, Chen EI, Parmer CM, Khaldoyanidi S, Diggs JE, Kiosses WB, Kamps MP, Yates JR 3rd, and Parmer RJ
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- Amino Acid Sequence, Animals, Conserved Sequence, Humans, Inflammation metabolism, Inflammation pathology, Lysine metabolism, Macrophages cytology, Molecular Sequence Data, Plasminogen metabolism, Receptors, Urokinase Plasminogen Activator chemistry, Receptors, Urokinase Plasminogen Activator genetics, Macrophages metabolism, Receptors, Urokinase Plasminogen Activator metabolism
- Abstract
When plasminogen binds to cells its activation to plasmin is markedly enhanced compared to the reaction in solution. Thus, cells become armed with the broad spectrum proteolytic activity of plasmin. Cell-surface plasmin plays a key role in macrophage recruitment during the inflammatory response. Proteins exposing basic residues on the cell surface promote plasminogen activation on eukaryotic cells. We have used a proteomics approach combining targeted proteolysis with carboxypeptidase B and multidimensional protein identification technology, MudPIT, and a monocyte progenitor cell line to identify a novel transmembrane protein, the plasminogen receptor, Plg-R(KT). Plg-R(KT) exposes a C-terminal lysine on the cell surface in an orientation to bind plasminogen and promote plasminogen activation. Here we review the characteristics of this new protein, with regard to membrane topology, conservation of sequence across species, the role of its C-terminus in plasminogen binding, its function in plasminogen activation, cell migration, and its role in macrophage recruitment in the inflammatory response.
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- 2012
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18. Regulation of macrophage migration by a novel plasminogen receptor Plg-R KT.
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Lighvani S, Baik N, Diggs JE, Khaldoyanidi S, Parmer RJ, and Miles LA
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- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Biocompatible Materials, Cell Movement drug effects, Collagen, Disease Models, Animal, Drug Combinations, Female, Fibrinolysin metabolism, Fibrinolysin pharmacology, Humans, Laminin, Macrophages immunology, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Monocytes cytology, Monocytes immunology, Peritonitis chemically induced, Peritonitis metabolism, Plasminogen genetics, Plasminogen metabolism, Proteoglycans, Receptors, Cell Surface metabolism, Receptors, Urokinase Plasminogen Activator immunology, Receptors, Urokinase Plasminogen Activator metabolism, Thioglycolates toxicity, Cell Movement immunology, Macrophages cytology, Peritonitis immunology, Plasminogen immunology, Receptors, Cell Surface immunology
- Abstract
Localization of plasmin on macrophages and activation of pro-MMP-9 play key roles in macrophage recruitment in the inflammatory response. These functions are promoted by plasminogen receptors exposing C-terminal basic residues on the macrophage surface. Recently, we identified a novel transmembrane plasminogen receptor, Plg-R(KT), which exposes a C-terminal lysine on the cell surface. In the present study, we investigated the role of Plg-R(KT) in macrophage invasion, chemotactic migration, and recruitment. Plg-R(KT) was prominently expressed in membranes of human peripheral blood monocytes and monocytoid cells. Plasminogen activation by urokinase-type plasminogen activator (uPA) was markedly inhibited (by 39%) by treatment with anti-Plg-R(KT) mAb. Treatment of monocytes with anti-Plg-R(KT) mAb substantially inhibited invasion through the representative matrix, Matrigel, in response to MCP-1 (by 54% compared with isotype control). Furthermore, chemotactic migration was also inhibited by treatment with anti-Plg-R(KT) mAb (by 64%). In a mouse model of thioglycollate-induced peritonitis, anti-Plg-R(KT) mAb markedly inhibited macrophage recruitment (by 58%), concomitant with a reduction in pro-MMP-9 activation in the inflamed peritoneum. Treatment with anti-Plg-R(KT) mAb did not further reduce the low level of macrophage recruitment in plasminogen-null mice. We conclude that Plg-R(KT) plays a key role in the plasminogen-dependent regulation of macrophage invasion, chemotactic migration, and recruitment in the inflammatory response.
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- 2011
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19. Mesenchymal stem cells and their microenvironment.
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Schraufstatter IU, Discipio RG, and Khaldoyanidi S
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- Animals, Cell Differentiation, Cell Proliferation, Cytokines physiology, Extracellular Matrix physiology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells physiology, Humans, Intercellular Signaling Peptides and Proteins physiology, Models, Biological, Neoplasms etiology, Neoplasms pathology, Neoplasms therapy, Signal Transduction, Wound Healing physiology, Wounds and Injuries pathology, Wounds and Injuries physiopathology, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells physiology
- Abstract
Mesenchymal stem cells (MSC) are multipotent stem cells that hold promise for an expanding list of therapeutic uses, not only due to their ability to differentiate into all connective tissues including bone, fat and cartilage, but additionally due to their trophic and anti-inflammatory effects which contribute to healing and tissue regeneration. Ongoing research is starting to illuminate important aspects of the microenvironmental niche, which supports MSC self-renewal. In this review, we summarize recent findings on cellular structures and molecular pathways that are involved in regulation of MSC self-renewal versus differentiation, and in retention of MSCs within the niche versus mobilization and recruitment to sites of injury. In addition, the contribution of MSCs to the structure and function of hematopoietic and cancerous niches is discussed.
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- 2011
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20. 5-Androstene-3β,7β,17β-triol (β-AET) slows thermal injury induced osteopenia in mice: relation to aging and osteoporosis.
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Malik AK, Khaldoyanidi S, Auci DL, Miller SC, Ahlem CN, Reading CL, Page T, and Frincke JM
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- Absorptiometry, Photon, Adult, Aged, Aged, 80 and over, Animals, Bone Diseases, Metabolic etiology, Burns complications, Cell Differentiation, Cell Line, Tumor, Female, Flow Cytometry, Humans, Male, Mice, Mice, Inbred BALB C, Middle Aged, Aging, Androstenols pharmacology, Bone Diseases, Metabolic physiopathology, Burns physiopathology, Osteoporosis physiopathology
- Abstract
5-Androstene-3β,7β,17β-triol (β-AET), an active metabolite of dehydroepiandrosterone (DHEA), reversed glucocorticoid (GC)-induced suppression of IL-6, IL-8 and osteoprotegerin production by human osteoblast-like MG-63 cells and promoted osteoblast differentiation of human mesenchymal stem cells (MSCs). In a murine thermal injury model that includes glucocorticoid-induced osteopenia, β-AET significantly (p<0.05) preserved bone mineral content, restored whole body bone mineral content and endochondral growth, suggesting reversal of GC-mediated decreases in chondrocyte proliferation, maturation and osteogenesis in the growth plate. In men and women, levels of β-AET decline with age, consistent with a role for β-AET relevant to diseases associated with aging. β-AET, related compounds or synthetic derivatives may be part of effective therapeutic strategies to accelerate tissue regeneration and prevent or treat diseases associated with aging such as osteoporosis.
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- 2010
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21. Visualization of the hematopoietic microenvironment: an alternative approach using the dorsal skinfold chamber model.
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Sikora L and Khaldoyanidi S
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- Animals, Back, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Microvessels physiology, Models, Biological, Cellular Microenvironment physiology, Hematopoiesis physiology, Microscopy methods, Microvessels cytology, Prostheses and Implants, Skin pathology, Tissue Culture Techniques instrumentation, Tissue Culture Techniques methods
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- 2010
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22. Down-regulation of epidermal growth factor receptor by selective expansion of a 5'-end regulatory dinucleotide repeat in colon cancer with microsatellite instability.
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Baranovskaya S, Martin Y, Alonso S, Pisarchuk KL, Falchetti M, Dai Y, Khaldoyanidi S, Krajewski S, Novikova I, Sidorenko YS, Perucho M, and Malkhosyan SR
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- 5' Untranslated Regions genetics, Base Sequence, Cell Line, Tumor, Colonic Neoplasms pathology, DNA Mutational Analysis, Down-Regulation, Flow Cytometry, Gene Frequency, Genes, ras genetics, Genotype, Humans, Mutagenesis, Insertional, Mutation, Poly A genetics, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Proto-Oncogene Proteins B-raf genetics, Sequence Deletion, Stomach Neoplasms genetics, Stomach Neoplasms pathology, Tumor Suppressor Protein p53 genetics, Colonic Neoplasms genetics, Dinucleotide Repeats genetics, ErbB Receptors genetics, Microsatellite Instability
- Abstract
Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in several tumor types, and its expression is influenced by the length of a 5'-end microsatellite repeat (CA)n: the longer the repeat, the lower the expression. Dinucleotide repeats accumulate insertion/deletion types of mutations in tumors with microsatellite instability. We designed this study to estimate the occurrence of these mutations in EGFR(CA)n and their relevance in carcinogenesis of microsatellite instability-positive colon and gastric tumors., Experimental Design: We analyzed the frequency of EGFR(CA)n mutations in vivo in 55 colorectal and 14 gastric microsatellite instability-positive cancers, and in vitro in single-cell clone cultures of microsatellite instability-positive colon tumor cell line LS174. Single-cell clone cultures with different repeat lengths were analyzed by fluorescent-activated cell sorter for EGFR cell-surface expression. A correlation analysis was done between EGFR(CA)n mutations and mutations in KRAS, BRAF, and p53., Results: Unlike single-cell clone cultures, which exhibited higher rate of deletions compared with insertions, most of EGFR(CA)n mutations in colon and gastric tumors were insertions. Longer EGFR(CA)n correlated with lower EGFR cell-surface expression in single-cell clone cultures. In colon cancers, the elongation of the repeat was associated negatively with mutations in KRAS and BRAF, but not in p53., Conclusions: The EGFR(CA)n elongation observed in tumors cannot be explained by an intrinsic property of this repeat favoring insertions versus deletions. Instead, a selection for repeat elongation occurs in microsatellite instability-positive tumors, leading to EGFR down-regulation. These findings suggest that in microsatellite instability-positive tumors current therapies targeting EGFR overexpression may have either no effect or an opposite to the expected effect.
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- 2009
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23. Directing stem cell homing.
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Khaldoyanidi S
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- Animals, Bone Marrow blood supply, Bone Marrow metabolism, Cell Adhesion physiology, Humans, Mesenchymal Stem Cells cytology, Hyaluronan Receptors metabolism, Mesenchymal Stem Cells physiology, Regeneration physiology
- Abstract
Stem cell-based regeneration depends partly on the delivery of stem cells to the damaged area. Recently in Nature Medicine, Sackstein et al. (2008) report that ex vivo fucosylation of surface CD44 promoted efficient adhesive interactions of manipulated mesenchymal stem cells with marrow vasculature and subsequent homing to endosteal surfaces.
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- 2008
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24. The cholinergic system is involved in regulation of the development of the hematopoietic system.
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Serobyan N, Jagannathan S, Orlovskaya I, Schraufstatter I, Skok M, Loring J, and Khaldoyanidi S
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- Acetylcholinesterase metabolism, Animals, Bone Marrow Cells cytology, Bone Marrow Cells drug effects, Bone Marrow Cells metabolism, Cell Differentiation drug effects, Cell Line, Choline O-Acetyltransferase metabolism, Embryonic Stem Cells cytology, Embryonic Stem Cells drug effects, Embryonic Stem Cells metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Flow Cytometry methods, Gene Expression drug effects, Granulocyte Colony-Stimulating Factor metabolism, Hematopoietic System embryology, Hematopoietic System growth & development, Humans, Immunohistochemistry, Injections, Intravenous, Leukocyte Common Antigens analysis, Mice, Mice, Inbred BALB C, Nicotine administration & dosage, Nicotine pharmacology, Nicotinic Agonists administration & dosage, Nicotinic Agonists pharmacology, Phosphorylation drug effects, Platelet Endothelial Cell Adhesion Molecule-1 analysis, Receptors, CXCR4 metabolism, Receptors, Nicotinic metabolism, Reverse Transcriptase Polymerase Chain Reaction, Acetylcholinesterase genetics, Choline O-Acetyltransferase genetics, Hematopoietic System metabolism, Receptors, Nicotinic genetics
- Abstract
Gene expression profiling demonstrated that components of the cholinergic system, including choline acetyltransferase, acetylcholinesterase and nicotinic acetylcholine receptors (nAChRs), are expressed in embryonic stem cells and differentiating embryoid bodies (EBs). Triggering of nAChRs expressed in EBs by nicotine resulted in activation of MAPK and shifts of spontaneous differentiation toward hemangioblast. In vivo, non-neural nAChRs are detected early during development in fetal sites of hematopoiesis. Similarly, in vivo exposure of the developing embryo to nicotine resulted in higher numbers of hematopoietic progenitors in fetal liver. However postpartum, the number of hematopoietic stem/progenitor cells (HSPC) was decreased, suggesting an impaired colonization of the fetal bone marrow with HSPCs. This correlated with increased number of circulating HSPC and decreased expression of CXCR4 that mediates migration of circulating cells into the bone marrow regulatory niche. In addition, protein microarrays demonstrated that nicotine changed the profile of cytokines produced in the niche. While the levels of IL1alpha, IL1beta, IL2, IL9 and IL10 were not changed, the production of hematopoiesis-supportive cytokines including G-CSF, GM-CSF, IL3, IL6 and IGFBP-3 was decreased. This correlated with the decreased repopulating ability of HSPC in vivo and diminished hematopoietic activity in bone marrow cultures treated with nicotine. Interestingly, nicotine stimulated the production of IL4 and IL5, implying a possible role of the cholinergic system in pathogenesis of allergic diseases. Our data provide evidence that the nicotine-induced imbalance of the cholinergic system during gestation interferes with normal development and provides the basis for negative health outcomes postpartum in active and passive smokers.
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- 2007
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25. Constitutive overexpression of IL-5 induces extramedullary hematopoiesis in the spleen.
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Khaldoyanidi S, Sikora L, Broide DH, Rothenberg ME, and Sriramarao P
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- Animals, Bone Marrow Cells cytology, Bone Marrow Cells drug effects, Cell Movement drug effects, Chemokine CXCL12, Chemokines, CXC pharmacology, Chemotaxis drug effects, Eosinophils cytology, Eosinophils drug effects, Interleukin-5 biosynthesis, Interleukin-5 genetics, Mice, Mice, Transgenic, Spleen cytology, Stromal Cells cytology, Stromal Cells drug effects, Hematopoiesis, Extramedullary drug effects, Interleukin-5 pharmacology, Spleen drug effects
- Abstract
The differentiation of eosinophils from hematopoietic precursors and their subsequent maturation, chemotaxis, and activation is primarily regulated by interleukin-5 (IL-5). To examine the effect of chronic IL-5 exposure on hematopoiesis, IL-5 transgenic (IL-5trg) mice and wild-type BALB/c (WT) mice were examined. In comparison to WT mice, a significant alteration in bone marrow hematopoiesis was observed in IL-5trg mice. Although the total number of myeloid progenitors in the bone marrow of IL-5trg mice was not significantly altered, the number of long-term culture-initiating cells (LTC-ICs) was 1.5-fold lower than that observed in WT mice. Furthermore, IL-5trg mice failed to demonstrate hematopoietic activity in long-term bone marrow cultures, which correlated with a significant decrease in the number of bone marrow mesenchymal/stromal progenitor (MSP) cells in these mice. In comparison to WT mice, a 10-fold decrease was observed in the number of fibroblast colony-forming units (CFU-Fs) in IL-5trg bone marrow. Hematopoietic activity of IL-5trg bone marrow cells was rescued by cultivation on preestablished layers of bone marrow-derived stromal cells. However, in contrast to bone marrow, increased hematopoietic activity was observed in the spleen and peripheral blood of IL-5trg mice. Likewise, the numbers of LTC-ICs and granulocyte-macrophage, macrophage, eosinophil, B-lymphocyte progenitors in the peripheral blood and spleen of IL-5trg mice were approximately 20-fold higher than in WT mice. A significant increase in CFU-F numbers was also observed in the spleens of IL-5trg mice compared with WT mice. Overall, our results suggest that constitutive overexpression of IL-5 can potentially induce colonization of spleen with MSP cells, which provides the necessary microenvironment for establishment of hematopoiesis in extramedullary sites.
- Published
- 2003
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26. CD44 variant-specific antibodies trigger hemopoiesis by selective release of cytokines from bone marrow macrophages.
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Khaldoyanidi S, Karakhanova S, Sleeman J, Herrlich P, and Ponta H
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- Amino Acid Sequence, Animals, Antibody Specificity, Cells, Cultured, Colony-Forming Units Assay, Crosses, Genetic, Epitopes pharmacology, Flow Cytometry, Granulocyte-Macrophage Colony-Stimulating Factor biosynthesis, Hyaluronan Receptors immunology, Interleukin-6 biosynthesis, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Molecular Sequence Data, Antibodies pharmacology, Bone Marrow Cells physiology, Cytokines metabolism, Genetic Variation, Hematopoiesis physiology, Hyaluronan Receptors genetics, Macrophages physiology
- Abstract
Hemopoiesis is regulated by the complex interplay between the bone marrow microenvironment and hemopoietic stem cells and progenitors. The local production of cytokines plays a critical role in this process. Using long-term bone marrow cultures, we show here that monoclonal antibodies directed against the CD44 v4 and CD44 v6 epitopes stimulate myelopoiesis (CD44 v4 and CD44 v6) and lymphopoiesis (CD44 v6). In the bone marrow cell population, CD44 v4 and CD44 v6 epitopes are found virtually exclusively on double-positive bone marrow macrophages. The anti-CD44 v4 and v6 antibodies act on bone marrow macrophages to stimulate granulocyte-macrophage colony-stimulating factor (GM-CSF) production (v4 and v6) and interleukin-6 (IL-6) production (v6). This profile of cytokine production explains the differential stimulation of hemopoiesis by the 2 antibodies. We suggest that the antibodies mimic ligand(s) that stimulate GM-CSF or IL-6 production by bone marrow-derived macrophages by binding to CD44 family members that bear CD44 v4 and CD44 v6 epitopes on these cells.
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- 2002
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27. Correlation between nicotine-induced inhibition of hematopoiesis and decreased CD44 expression on bone marrow stromal cells.
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Khaldoyanidi S, Sikora L, Orlovskaya I, Matrosova V, Kozlov V, and Sriramarao P
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- Animals, Blood Platelets drug effects, Bone Marrow Cells immunology, Bone Marrow Cells physiology, Cell Adhesion Molecules analysis, Cell Line, Cells, Cultured, Endothelium, Vascular drug effects, Endothelium, Vascular immunology, Flow Cytometry, Hematopoietic Stem Cells cytology, Humans, Mice, Mice, Inbred BALB C, Plants, Toxic, Smoke adverse effects, Stromal Cells drug effects, Stromal Cells physiology, Nicotiana, Umbilical Veins, Bone Marrow Cells drug effects, Hematopoiesis drug effects, Hyaluronan Receptors analysis, Nicotine pharmacology
- Abstract
This study demonstrates that in vivo exposure to cigarette smoke (CS) and in vitro treatment of long-term bone marrow cultures (LTBMCs) with nicotine, a major constituent of CS, result in inhibition of hematopoiesis. Nicotine treatment significantly delayed the onset of hematopoietic foci and reduced their size. Furthermore, the number of long-term culture-initiating cells (LTC-ICs) within an adherent layer of LTBMCs was significantly reduced in cultures treated with nicotine. Although the production of nonadherent mature cells and their progenitors in nicotine-treated LTBMCs was inhibited, this treatment failed to influence the proliferation of committed hematopoietic progenitors when added into methylcellulose cultures. Bone marrow stromal cells are an integral component of the hematopoietic microenvironment and play a critical role in the regulation of hematopoietic stem cell proliferation and self-renewal. Exposure to nicotine decreased CD44 surface expression on primary bone marrow-derived fibroblastlike stromal cells and MS-5 stromal cell line, but not on hematopoietic cells. In addition, mainstream CS altered the trafficking of hematopoietic stem/progenitor cells (HSPC) in vivo. Exposure of mice to CS resulted in the inhibition of HSPC homing into bone marrow. Nicotine and cotinine treatment resulted in reduction of CD44 surface expression on lung microvascular endothelial cell line (LEISVO) and bone marrow-derived (STR-12) endothelial cell line. Nicotine treatment increased E-selectin expression on LEISVO cells, but not on STR-12 cells. These findings demonstrate that nicotine can modulate hematopoiesis by affecting the functions of the hematopoiesis-supportive stromal microenvironment, resulting in the inhibition of bone marrow seeding by LTC-ICs and interfering with stem cell homing by targeting microvascular endothelial cells.
- Published
- 2001
- Full Text
- View/download PDF
28. Tissue- and epitope-specific mechanisms account for the diverse effects of anti-CD44 antibodies on the maintenance of primitive hematopoietic progenitors in vitro.
- Author
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Müller-Sieburg CE, Deryugina E, Khaldoyanidi S, and O'Rourke A
- Subjects
- Animals, Cell Adhesion drug effects, Cell Communication drug effects, Cells, Cultured, Coculture Techniques, Epitopes immunology, Female, Hematopoietic Stem Cells cytology, Ligands, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Signal Transduction, Stromal Cells cytology, Antibodies, Monoclonal pharmacology, Hematopoietic Stem Cells drug effects, Hyaluronan Receptors immunology
- Abstract
The identification of rare stromal cells that support high levels of stem cells has opened avenues to identify molecules that contribute to the maintenance of these cells. We show that the maintenance of long-term culture initiating cells (LTC-IC) in stromal cell-supported cultures can be modulated via mAbs specific for CD44. mAb IM7.8.1 suppressed while mAb RAMBM44 enhanced LTC-IC levels in culture. Genetic polymorphisms in CD44 were used to show that the stromal cell compartment is targeted by mAb RAMBM44 and the hematopoietic compartment by mAb IM7.8. Neither of the CD44-specific mAbs inhibited adhesion of LTC-IC to the stroma, suggesting alternative mechanisms of action. In support of this interpretation, we show that mAb RAMBM44 directly induces signal transduction in the stromal cell line S17 but not in hematopoietic cells. Conversely, mAb IM7.8 elicited the appearance of phosphorylated bands in hematopoietic cells, but not in stromal cells. Collectively, the data indicate that the opposing effects of CD44-mediated regulation can be explained by different cellular programs that are elicited in distinct cell compartments. The binding of the enhancing mAb RAMBM44 to CD44 is specifically inhibited by collagen IV, while binding of the suppressive mAb IM7.8.1 is inhibited by a substance contained in the supernatant of the stromal cell line AC3.U. Thus, the CD44 epitopes defined by the mAbs bind distinct ligands and the ligands provide a potential physiological counterpart for the regulatory actions of the mAbs., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
- View/download PDF
29. Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release of interleukin-1beta and interleukin-6 from bone marrow macrophages.
- Author
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Khaldoyanidi S, Moll J, Karakhanova S, Herrlich P, and Ponta H
- Subjects
- Animals, Bone Marrow Cells physiology, Cell Line, Hematopoiesis drug effects, Hyaluronic Acid pharmacology, Hyaluronoglucosaminidase pharmacology, Mice, Rats, Hematopoiesis physiology, Hyaluronan Receptors physiology, Hyaluronic Acid physiology, Interleukin-1 physiology, Interleukin-6 physiology, Macrophages physiology
- Abstract
The glycosaminoglycan hyaluronate (HA) is part of the extracellular environment in bone marrow. We show here that HA activates signal transduction cascades important for hemopoiesis. In myeloid and lymphoid long-term bone marrow cultures (LTBMC), treatment with hyaluronidase (HA'ase) results in reduced production of both progenitor and mature cells. Exogeneous HA added to LTBMC had the opposite effect: it enhanced hematopoiesis. The effect of HA is mediated through two different HA receptors on bone marrow macrophage-like cells, one of which is CD44 while the other is unknown. HA induces bone marrow macrophages to secrete IL-1beta (CD44-dependent) and IL-6 (CD44-independent). The two receptors address different signal transduction pathways: CD44 links to a pathway activating p38 protein kinase while the other yet unknown receptor induces Erk activity. There was no difference of the effect of HA and HA'ase on hematopoiesis in LTBMC and on cytokine production by macrophages in CD44-deficient mice compared with wild-type mice, indicating that the CD44 hyaluronate receptor and its signal transduction can be compensated for. Our data suggest a regulatory role for the extracellular matrix component HA in hematopoiesis and show the induction of signal transduction by HA receptors.
- Published
- 1999
30. Involvement of CD44 variant isoform v10 in progenitor cell adhesion and maturation.
- Author
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Rösel M, Khaldoyanidi S, Zawadzki V, and Zöller M
- Subjects
- 3T3 Cells, Animals, Antibodies, Monoclonal pharmacology, Bone Marrow Cells drug effects, Bone Marrow Cells metabolism, Cell Adhesion drug effects, Cell Communication drug effects, Cell Differentiation drug effects, Cell Division drug effects, Cell Line, Colony-Forming Units Assay, Flow Cytometry, Hematopoietic Stem Cells metabolism, Hyaluronan Receptors biosynthesis, Hyaluronan Receptors immunology, Interleukin-7 pharmacology, Ligands, Mice, Mice, Inbred BALB C, Stromal Cells cytology, Hematopoietic Stem Cells cytology, Hyaluronan Receptors physiology
- Abstract
CD44 has been described repeatedly to be involved in hematopoiesis. Here, we addressed the question of functional activity of CD44 variant isoform v10 (CD44v10) in progenitor cell maturation by in vivo and in vitro blocking studies with a monoclonal antibody and a receptor globulin. We became interested in this question by the observation that CD44v10 is expressed, although at a low level, on a subpopulation of bone marrow cells. Flow cytometry revealed that 15%-20% of hematopoietic cells in the fetal liver and 25%-35% of bone marrow cells in adult mice were CD44v10 positive. The majority of CD44v10+ cells was HSA+/J11d+ and CD43+. CD44v10 was not detected on CD4+, CD8+, IgM+, or IgD+ cells. A CD44v10 receptor globulin did not bind to hematopoietic progenitor cells, but to stromal elements. The CD44v10-CD44v10 ligand interaction had a major impact on the adhesion of progenitor cells to stromal elements. When healthy animals received repeated injections of either anti CD44v10 or the CD44v10 receptor globulin, committed progenitors were mobilized and significantly augmented numbers were recovered in the spleen and the peripheral blood. Furthermore, the CD44v10-CD44v10 ligand interaction, which had no impact on progenitor expansion, influenced progenitor maturation, particularly of the B-cell lineage. Although the nature of the CD44v10 ligand remains to be explored, the supportive role of CD44v10 in progenitor maturation and, importantly, the efficient mobilization of progenitor cells by anti-CD44v10 and a CD44v10 receptor globulin could be of clinical benefit in peripheral blood stem cell transplantation.
- Published
- 1999
- Full Text
- View/download PDF
31. Functional activity of CD44 isoforms in haemopoiesis of the rat.
- Author
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Khaldoyanidi S, Schnabel D, Föhr N, and Zöller M
- Subjects
- Animals, Antibodies, Monoclonal, Bone Marrow radiation effects, Bone Marrow Cells, Cell Division, Fluorouracil pharmacology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Hyaluronan Receptors chemistry, Rats, T-Lymphocytes cytology, T-Lymphocytes radiation effects, Thymus Gland cytology, Thymus Gland radiation effects, Hematopoiesis, Hematopoietic Stem Cells physiology, Hyaluronan Receptors biosynthesis
- Abstract
Expression of CD44 is involved in the maturation as well as the homing of haemopoietic progenitor cells. Whether these processes are mediated by CD44 standard (CD44s) or variant (CD44v) isoforms is unknown. To assign functional activities of CD44 in haemopoiesis of the rat to distinct isoforms, ligand binding of haemopoietic progenitor cells was inhibited by monoclonal antibodies recognizing an epitope on CD44s (Ox50) or CD44 exon v6, (1.1ASML). The vast majority of rat bone marrow cells (BMC) as well as stromal cells and non-adherent cells in long-term bone marrown culture (LTBMC) expressed CD44s. Bone marrow cells and non-adherent cells in LTBMC, but not the stromal cells, also contained a population of large and granulated cells, which stained with anti-CD44v6. In vivo and in vitro reconstitution experiments revealed that homing of BMC as well as settlement on stromal elements was influenced exclusively by anti-CD44s, which also inhibited proliferation of progenitor cells. Anti-CD44v6 had no influence on homing and seeding, but interfered with stroma formation and progenitor maturation. Finally, restoration of functional activity of T-lineage cells was impaired in the presence of anti-CD44v6. The data indicate that CD44s and CD44v6 fulfilled distinct functions in haemopoiesis of the rat. Although CD44s facilitated homing and expansion of stem cells, progenitor cells, CD44v6 was involved in differentiation processes, particularly of lymphoid progenitor cells.
- Published
- 1997
- Full Text
- View/download PDF
32. Requirement for CD44 in proliferation and homing of hematopoietic precursor cells.
- Author
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Khaldoyanidi S, Denzel A, and Zöller M
- Subjects
- Adipose Tissue cytology, Adipose Tissue drug effects, Animals, Antibodies, Monoclonal pharmacology, Bone Marrow drug effects, Bone Marrow Cells, Cell Adhesion, Cell Division, Cell Movement, Cells, Cultured, Colony-Forming Units Assay, Connective Tissue drug effects, Connective Tissue Cells, DNA Replication, Hematopoietic Stem Cells metabolism, Mice, Mice, Inbred BALB C, Specific Pathogen-Free Organisms, Hematopoietic Stem Cells cytology, Hyaluronan Receptors physiology
- Abstract
The hematopoietic form of the adhesion molecule CD44 is known to be involved in lymphocyte maturation and homing. To define lineage and stage of maturation, which requires expression of CD44, murine long-term bone marrow cultures were established. Stroma formation and proliferation of early as well as committed erythroid, myeloid, and lymphoid progenitors were evaluated under the influence of monoclonal anti-CD44 antibodies. Although the formation of stromal elements was not affected, formation of cobblestone areas was completely abolished. [3H]thymidine suicide confirmed that anti-CD44 treatment interfered with the proliferation of early and committed hematopoietic progenitor cells. In addition, homing and seeding of bone marrow cells was impaired by anti-CD44. The data are indicative of a dual functional mode of CD44 in adhesion and proliferation of hematopoietic progenitors and confirm an essential requirement for the molecule in early stages of hematopoiesis.
- Published
- 1996
- Full Text
- View/download PDF
33. Endogenous retroviral envelope peptide expression is involved in a regulation of lymphocyte and hematopoietic precursor activity.
- Author
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Chernukhin IV, Khaldoyanidi SK, and Gaidul KV
- Subjects
- Animals, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Phenylhydrazines pharmacology, Hematopoietic Stem Cells metabolism, Lymphocytes metabolism, Retroviridae, Viral Envelope Proteins metabolism
- Abstract
A biological function of endogenously expressed MuLV p15E-related proteins for lymphocyte and hematopoietic precursor activity in mice was examined. A high level of endogenous p15E-related peptide expression in spleen cells of mice with hemolytic anemia rendered by phenylhydrazine (PHZ) treatment was observed, detected by hyperimmune rabbit antisera against amino acid sequence which compose the immunosuppressive domain (ISD) of exogenous viral transmembrane (TM) p15E protein. The conditioned medium of these cultured cells (PHZ/CM) was inhibitory for lymphocyte blastogenesis and granulocyte-macrophage (GM) precursor activity, but stimulatory for the erythroid colony growth. When added to PHZ/CM, anti-ISD/p15E antibodies were capable to abrogate these effects. These antibodies bound 14K and 48K structural peptides contented in PHZ/CM as presumably smaller components of env gene products. Given together, the results indicate that erythroid immature cells produce proteins appearing in cell culture medium which exert p15E-related properties. These peptides are suggested to exert a down regulation for both lymphocyte and GM precursor activities, and the colony-promoting effect towards erythroid compartment cells.
- Published
- 1995
- Full Text
- View/download PDF
34. Antisense oligonucleotide complementary to endogenous retroviral MCF env gene inhibits both BFU-E and CFU-S colony formation in mice.
- Author
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Chernukhin IV, Khaldoyanidi SK, Dikovskaya DV, Svinarchuk FP, Vlasov VV, and Gaidul KV
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Cell Division drug effects, Cells, Cultured, Colony-Forming Units Assay, Hematopoietic Stem Cells cytology, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Oligonucleotides, Antisense genetics, Genes, env, Hematopoietic Stem Cells drug effects, Mink Cell Focus-Inducing Viruses genetics, Oligonucleotides, Antisense pharmacology
- Abstract
A possible biologic activity of endogenously expressed env sequence of retroviral mink cell focus-forming virus (MCF) genome for hematopoietic colony formation was studied in mice. Antisense 20-mer complementary to MCF env sequence was used to detect the result of blockage of this gene translation on the potency of marrow cells to form colonies of erythroid (BFU-E), myeloid granulocyte-macrophage (CFU-GM), and stem cell (day 11 CFU-S) hematopoietic compartments. A large relative decrease in BFU-E number was found in bone marrow cell cultures preincubated with antisense oligonucleotide during 4 h, whereas CFU-GM colonies remained unaffected. A marked reduction of CFU-S colony formation was also registered under antisense oligomer influence. Following a decreased proliferation of erythroid progenitors, we suggest the mechanism by which antisense oligonucleotide could cause the loss of colony formation. Taken together, these data allow to propose that the expression of this gene is naturally significant for hematopoietic progenitor activity exerting some property of env gene products to regulate the growth of erythroid and multilineage hematopoietic precursors.
- Published
- 1994
- Full Text
- View/download PDF
35. The influence of synthetic peptide from retroviral transmembrane protein p15E on murine spleen cell proliferation and bone marrow hemopoietic precursor colony formation.
- Author
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Chernukhin IV, Khaldoyanidi SK, Kozlov VA, and Gaidul KV
- Subjects
- Animals, Dose-Response Relationship, Drug, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Peptides administration & dosage, Peptides chemical synthesis, Cell Division drug effects, Hematopoietic Stem Cells drug effects, Neoplasm Proteins, Peptides pharmacology, Retroviridae Proteins chemistry, Spleen cytology, Viral Envelope Proteins chemistry
- Abstract
The retroviral transmembrane p15E peptide is known to suppress a wide variety of immune cell functions, suggesting a role for immunosuppression associated with retroviral infection. The 10-amino acid sequence from the highly conserved portion of p15E (CKS-10) is capable of reproducing this inhibitory activity. In this study we set out to determine the influence of this decapeptide on murine spleen cell mitogen-induced proliferation and hematopoietic granulocyte-macrophage and erythroid precursor colony formation in vitro. A dose- and time-dependent suppression of spleen cell blastogenic response was produced by the CKS-10 peptide. When bone marrow cells were incubated with decapeptide, the significant decrease of CFU-GM colony number was also dose-dependent. In contrast, the same doses of CKS-10 peptide which induced a most significant inhibition of CFU-GM colony formation caused a marked increase of BFU-E colonies. A most pronounced effect of the peptide on bone marrow hematopoietic progenitor activity was produced by prolonged exposure to the peptide. Given the results of this study, it seems likely that, in addition to the cytopathic effect of retroviruses on the lymphocytes, viral peptide-mediated hematopoiesis disorders may also play an important role in the pathogenesis of immunodeficiency associated with retroviral infections.
- Published
- 1993
- Full Text
- View/download PDF
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