Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.8 (thyroid peroxidase)
3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With the identification and recombinant production of the hematopoietic growth factors, these cytokines have been evaluated in the treatment of primary bone marrow failure states and after myelosuppressive chemotherapy or radiotherapy. A lot of clinical trials with hematopoietic factors have been performed in patients with haematologic and oncologic diseases within the last decade. Granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], interleukin-3, interleukin-2, erythropoietin and in phase I/II trials thrombopoietin [TPO] are available for the clinical use. At the present, there is a broad use of growth factors. Most studies have been done with G-CSF and GM-CSF, their beneficial effects are proven regarding improvement of hematopoietic recovery after chemotherapy. This results in a marked reduction of infectious risks and a shortening of drug- and radiation-induced myelosuppression. CSFs are most important in mobilizing peripheral blood progenitor cells [PBPC] and have allowed high dose therapy to be given to patients who would not have been able to undergo conventional bone marrow transplantation. However, an improved outcome and improved survival rates with standard chemotherapy protocols couldn't be documented by studies up to now, even though higher chemotherapy doses are possible by the use of hematopoietic factors.
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PMID:[Current status of the clinical application of hematopoietic growth factors in oncology]. 898 92

Heparin, a glycosaminoglycan (GAG) derivative has been widely used as an anticoagulation agent for more than 50 years. This study was conducted to demonstrate that, due to their modulatory effect on cytokines, heparin and other GAGs can favor megakaryocytopoiesis both in vitro and in vivo in mice. In vitro addition of heparin and other GAGs (excepting keratane sulfate) into plasma clot cultures induces a significant increase in the number of megakaryocyte colonies. Optimal heparin and GAG concentrations for maximal effect are approximately 50-100 micrograms/ml. In agar culture without serum, all GAGs do not have this stimulating effect on megakaryocyte colonies. This would suggest that the GAG action depends on the presence of one or more plasma factors. Interactions between GAGs and cytokines such as IL3, IL6, G-SCF, GM-CSF, aFGF, TPO and EPO as well as PF4 and TGFB1 were also conducted. The results demonstrate that heparin and chondroitin sulfate significantly increases the action of TPO, IL6 and aFGF but not the action of IL3, G-SCF and EPO. Heparin and other GAGs can also neutralize PF4 and TGFB1 inhibitory action. In vivo, the effect of low-molecular-weight heparin (Fraxiparine) injected in normal mice treated with 5-fluorouracil increases megakaryocytopoiesis. The findings demonstrate that heparin and its derivatives have a potentializing effect on megakaryocytopoiesis and could be used as therapeutic agents in the treatment of thrombocytopenia.
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PMID:[Effects of heparin on megakaryocytopoiesis. From fundamental data to clinical applications]. 923 40

A novel human myeloid leukaemia cell line (HNT-34) was established from the peripheral blood of a 45-year-old female patient with acute myelogenous leukaemia (AML) transformed from chronic myelomonocytic leukaemia (CMMoL) with 3q21q26 syndrome. Morphologically, the HNT-34 cells were undifferentiated blasts which were negative for myeloperoxidase. The HNT-34 cells were positive for CD4, CD13, CD33 and CD34, but negative for CD41a and CD42b. The cells actively proliferated in suspension with a doubling time of 26-27h in the absence of any growth factors. Neither proliferative advantage nor differentiation was observed with the addition of G-CSE GM-CSF, IL-3, TPO, DMSO or PMA. Cytogenetic analysis showed 46,XX. t(3;3)(q21;q26), t(9;22)(q34;q11),20q-. Molecular analysis showed expression of EVI1 gene, P210 and P190 BCR/ABL chimaeric transcripts. The chromosomal breakpoint at 3q26 of HNT-34 cell line was located to approximately 200 kb 5' of FIM3 locus and more upstream of the MDS1. which is the same region as that of somatic cell hybrid line H10C. The breakpoint at 3q21 was located within the 390 kb centromeric from the breakpoint cluster region. These results suggest that the HNT-34 cell line may be a useful tool for the elucidation of the mechanisms of leukaemogenesis which involve the 3q21q26 syndrome and Ph1 chromosome.
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PMID:Establishment of a novel human myeloid leukaemia cell line (HNT-34) with t(3;3)(q21;q26), t(9;22)(q34;q11) and the expression of EVI1 gene, P210 and P190 BCR/ABL chimaeric transcripts from a patient with AML after MDS with 3q21q26 syndrome. 926 39

The 9;22 chromosomal translocation characteristic of CML results in a fused bcr/abl gene and an abnormal fusion protein, p210bcr/abl. Relative to normal c-abl, p210bc1/abl has elevated tyrosine kinase activity that is essential for its transforming activity. We recently reported a prominent 62 kDa GAP-associated P-tyr protein and five additional consistent but less prominent P-tyr proteins as well as five more minor P-tyr proteins that are constitutively tyrosine phosphorylated in primary primitive lineage negative (lin-) chronic phase CML blasts but not in comparable primary lin- normal blasts. The GAP-associated p62 protein has now been purified, sequenced and its gene has been cloned; it is a previously unidentified protein and is currently being characterized. In analyzing P-tyr proteins in primary lin- normal blasts in response to various hematopoietic cytokines, we found a striking similarity in the tyrosine phosphorylation of four major and three minor proteins after stimulation with c-kit ligand (KL) and the P-tyr proteins that are constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other cytokines tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand, TPO, EPO) were much less active or stimulated phosphorylation of other proteins. KL/c-kit and bcr/abl have some similar activities including enhancing survival and expansion of hematopoietic progenitor cells, probably acting primarily on early progenitors at the time of lineage commitment rather than on self-renewing stem cells. Activation of growth factor receptors promote a cascade of protein phosphorylations that can ultimately result in a wide range of cellular responses. Sustained activation of discrete signaling pathways in some types of cells results in differentiation, whereas transient activation instead causes a proliferative response; in other cell types, the converse is true. It may be postulated that stem cells and primitive progenitors are at a particularly susceptible stage of development that renders them especially responsive to sustained bcr/abl-induced phorphorylation of a number of signaling proteins that are components of critical regulatory pathways, including c-kit. The affected pathways control and coordinate multiple diverse cell processes including proliferation, differentiation, maturation and apoptosis, processes that are normally tightly regulated and integrated. Perturbation of these key pathways in primitive progenitors would be expected to seriously disrupt orderly hematopoiesis and could also explain the multiple subtle pleiotropic biological abnormalities characteristically observed in later maturing CML compartments that we have collectively designated 'discordant maturation'. The true situation is undoubtedly very complex and involves interaction of multiple cytokines and signaling pathways that we are now trying to define. Constitutive downstream activation of critical pathways in susceptible early progenitors that normally require KL or other factors for activation could explain most if not all features of the disease.
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PMID:New understanding of the pathogenesis of CML: a prototype of early neoplasia. 952 44

We have developed an efficient serum free culture model for cloning human erythroid progenitors. Accordingly, human bone marrow or cord blood CD34+ cells if plated in our serum free medium and stimulated with a mixture of EpO + KL, grow erythroid colonies exclusively. Cells isolated from these cultures express glycophorin-A (GPA-A), are CD33-, IIb/IIIa-, and finally all become hemoglobinized. By employing this system we also found out that cord blood CD34+ mononuclear cells (MNC) contain more BFU-E than adult marrow CD34+ MNC, moreover, the erythroid colonies formed by cord blood progenitors are significantly larger then the ones formed by the marrow cells. We have also compared the influence of different cytokines and growth factors, which were reported in the literature to costimulate BFU-E growth on cloning efficiency of human BFU-E cultured in our serum free medium. We found that from 20 different growth factors and cytokines tested, EpO dependent bone marrow BFU-E growth is costimulated only by KL, and to lesser degree also by IL-3, GM-CSF, TpO and IL-9. In contrast to marrow cells we observed that cord blood BFU-E in addition to KL, IL-3, GM-CSF, TpO, LIF and IL-9 were also costimulated by NGF-beta, FGF-1, FGF-2 and STK-IL. We found simultaneously that TPO which possess only negligible costimulatory effect on erythroid colony formation by bone marrow CD34+ cells, significantly costimulated the formation of erythroid colonies grown by cord blood CD34+ cells. Therefore, the cord blood CD34+ cells are largely committed to erythroid differentiation, and, moreover, they respond to a wider spectrum of the growth factors than their bone marrow counterparts.
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PMID:An improved serum free system for cloning human "pure" erythroid colonies. The role of different growth factors and cytokines on BFU-E formation by the bone marrow and cord blood CD34+ cells. 960 18

We have developed an efficient and rapid method to analyze transduction in human hematopoietic cells and to select them. We constructed two retroviral vectors using the recombinant humanized S65T green fluorescent protein (rHGFP) gene. Transduced cells appeared with specific green fluorescence on microscopy or fluorescence-activated cell sorting (FACS) analysis. The rHGFP gene was placed under the control of two different retroviral promotors (LTR) in the LGSN vector and in the SF-GFP vector. Amphotropic retroviruses were tested on NIH/3T3 fibroblasts or human hematopoietic (K562, TF-1) cell lines. Then CD34+ cells isolated from cord blood were infected three times after a 48-h prestimulation with IL-3, IL-6, SCF or with IL-3, IL-6, SCF, GM-CSF, Flt3-L and TPO. After 6 days of expansion, a similar number of total CD34(+)-derived cells, CD34+ cells and CFC was obtained in non-transduced and transduced cells, demonstrating the absence of toxicity of the GFP. A transduction up to 46% in total CD34(+)-derived cells and 21% of CD34+ cells was shown by FACS analysis. These results were confirmed by fluorescence of colonies in methyl-cellulose (up to 36% of CFU-GM and up to 25% of BFU-E). The FACS sorting of GFP cells led to 83-100% of GFP-positive colonies after 2 weeks of methyl-cellulose culture. Moreover, a mean gene transfer efficiency of 8% was also demonstrated in longterm culture initiating cells (LTC-IC). This rapid and efficient method represents a substantial improvement to monitor gene transfer and retroviral expression of various vectors in characterized human hematopoietic cells.
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PMID:Rapid analysis and efficient selection of human transduced primitive hematopoietic cells using the humanized S65T green fluorescent protein. 961 82

We investigated the ability of endothelial cells (EC) to support hematopoiesis in contact and non-contact cocultures with isolated CD34+ or CD34/CD38low cells. In the absence of exogenous cytokines, umbilical vein EC (HUVEC) efficiently support proliferation of hematopoietic cells and generation of colony-forming cells (CFC). Cytokines (IL-6, LIF, G-CSF, GM-CSF, M-CSF, but not IL-1, IL-3, IL-7) were detected in HUVEC coculture supernatants. Neutralization of these cytokines profoundly inhibited the ability of EC supernatants to support the differentiation of hematopoietic progenitors and led to an accumulation of immature cells. Contact cocultures were significantly more efficient than non-contact cocultures. The expanded cell population essentially belonged to the myeloid and monocytic lineages. Contact cocultures generated cells expressing the CD61 or CD41 antigens. Interleukin-1alpha (IL-1alpha) augmented EC capacity to support hematopoiesis, this property resulting from the upregulation of cytokine expression. Glucocorticoids (GC) reduced this capacity by downregulating the biosynthesis of cytokines by EC and not by a direct effect on the progenitor cells. EC from the bone marrow microvasculature (BMEC) support the proliferation and the differentiation of hematopoietic progenitors. Synergistic increase in progenitor cells expansion and generation of CFC occurred when EC cocultures were added with exogenous cytokines. Supernatants of IL-1alpha-stimulated EC potentiated the effects of an association of IL-1, IL-3, IL-6, LIF, SCF, Flt3-ligand, TPO, G-CSF, GM-CSF, M-CSF and IL-11 on the proliferation of hematopoietic progenitors suggesting that EC may produce other soluble growth factors potentiating the action of the above set of cytokines.
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PMID:Endothelial cell support of hematopoiesis is differentially altered by IL-1 and glucocorticoids. 969 75

Endothelial cell dysfunction is a classic consequence of radiation damage. Bone marrow endothelial cells (BMEC) are a critical component of the stroma in the regulation of haemopoiesis. In animal models, radiation-induced injury of BMEC has been described and a role for BMEC in haemopoietic regeneration after irradiation has been suggested. However, functions of BMEC involved in the haemopoietic regeneration have not been assessed. Therefore we studied the functional response of human BMEC to irradiation using the transformed human BMEC line (TrHBMEC) irradiated with 2. 5 or 10Gy. Our results showed a time- and a dose-dependent increase in damage to irradiated TrHBMEC measured by a decreased number of adherent cells which correlated with increased apoptosis and augmented release of soluble ICAM-1 and von Willebrand factor. 2 Gy irradiated TrHBMEC expressed more ICAM-1 on their surface than non-irradiated cells, whereas no change in VCAM-1, E-selectin and PECAM-1 expression was observed. An increased production of G-CSF, GM-CSF, IL-8, IL-6, IL-1alpha, IL-11, MIP-1alpha and SCF and no production of LIF, TNF-alpha, TPO and IL-3 by 2 Gy irradiated TrHBMEC was observed. The haemopoietic supportive function of TrHBMEC was not altered after a 2 Gy exposure. These results suggest that although radiation induces endothelial cell damage, irradiated cells still support the proliferation and the differentiation of CD34+ haemopoietic cells.
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PMID:Characterization of the response of human bone marrow endothelial cells to in vitro irradiation. 988 9

Anti-CD20 antibody is an established treatment for low-grade non-Hodgkin's lymphoma (NHL). Augmenting the expression of CD20 antigen on the tumor cells may increase the cell kill and therefore increase the effectiveness of the antibody. To study this, we incubated peripheral blood lymphocytes from CLL patients with the following cytokines: EPO, SCF, TNFalpha, TGFbeta, GMCSF, TPO, IL-1, IL-2, IL-3, IL-4, GCSF. CD20 expression was studied by flow cytometry at baseline, 24 and 72 h after exposure to these cytokines. Upregulation of CD20 antigen expression was observed with IL-4, TNFalpha and GMCSF.
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PMID:Effects of cytokines on CD20 antigen expression on tumor cells from patients with chronic lymphocytic leukemia. 1120 84

Myeloid differentiation is a highly regulated process governed by various cytokines, such as EPO, TPO, G-CSF, IL-3, IL-5 and GM-CSF. These cytokines act in part through activation of the STAT transcription factor family. In particular, various isoforms of STAT3 and STAT5 are activated during myeloid differentiation in a cell-type and maturation-state dependent fashion. In vitro studies have shown that STAT proteins are essential for cytokine-regulated processes such as cellular proliferation, differentiation as well as survival. Similarly, various STAT knock-outs have highlighted the role of STATs in myeloid differentiation in vivo. STATs also appear to play an important role in various myeloid malignancies, which are characterized by arrested maturation and cytokine-independent proliferation of myeloid progenitors. Constitutive activation of STAT3 and/or STAT5 resulting in enhanced transcription of anti-apoptotic- cell-cycle progression genes is likely to contribute to the pathogenesis of various myeloid leukemia's. Oncogene (2000).
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PMID:The role of STATs in myeloid differentiation and leukemia. 1085 Oct 50


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