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E Vellenga

Publications and source records attributed to E Vellenga.

At least 199 records · Page 11Linked to original sources
PubMed1987

Effects of recombinant IL-3, GM-CSF, and G-CSF on proliferation of leukemic clonogenic cells in short-term and long-term cultures.

To further define the growth factors required for the in vitro proliferation of acute myeloblastic leukemic (AML) cells, we have compared the ability of recombinant interleukin-3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF) to support growth of AML colony forming cells (AML-CFU). IL-3, GM-CSF, and G-CSF are active as single growth factors in short-term colony cultures and have additive effects when used in combination in some cases. The effects of these CSFs on the proliferation of AML cells in long-term-cell-suspension cultures were also investigated. These cultures provide an estimate of the "self-renewal" capacity and long-term proliferation potential of AML cells. There was considerably heterogeneity with regard to the effects of individual growth factors, but in general, IL-3, GM-CSF, and G-CSF promoted self-renewal of AML cells, and combinations tended to be more effective in supporting long-term survival of AML-CFU. There was evidence of gradual differentiation, but this was evident in control cells and did not appear to be accelerated by CSF treatment. These results of short-term and long-term cultures indicate that each of the CSFs tested can be used by AML cells to support proliferation. The lack of evidence that the CSFs enhance in vitro differentiation does not suggest they will be valuable as therapeutic differentiation agents.

Cell Division↗
PubMed1987

The biology of acute myeloblastic leukemia.

Many questions about the biology of AML remain to be answered. The initial genetic lesions that inhibit differentiation and increase the likelihood of self renewal have yet to be identified. Given the heterogeneity of this neoplasm, it is possible that many different mutational events may be capable of triggering leukemia. Alternatively, there may be only a small number of possible initial leukemic mutations, and the heterogeneous phenotype of the disease is determined by the evolution of different subclones that have acquired different secondary mutations. Studies with retroviral oncogenes have suggested that a common secondary event in an evolving myeloid tumor is the development of growth factor independence by either leukemic cell production of CSF or possibly constitutive activation of a CSF receptor. These mechanisms have not yet been established as important in human AML, although there is intriguing evidence to suggest that CSF genes are inappropriately activated in many cases.

Animals↗
PubMed1987

The effects of GM-CSF and G-CSF in promoting growth of clonogenic cells in acute myeloblastic leukemia.

A small subset of leukemic cells from most patients with acute myeloblastic leukemia (AML) have properties of stem cells and can be assayed by colony formation in agar or methylcellulose. Colony formation generally requires the addition of exogenous growth factors, but the exact factors required are incompletely defined. The AML colony-promoting activities of two recombinant human colony-stimulating factors (GM-CSF and G-CSF) were investigated by using blasts from 48 patients with AML. In nine cases, no colonies formed with either CSF. In seven cases colonies formed only in response to G-CSF and in 11 cases only in response to GM-CSF. In 21 cases colonies formed in response to either GM-CSF or G-CSF, and in 12 of these cases there was an additive effect between the two CSFs in determining maximum colony size. For cases responding to both GM- and G-CSF, the total number of colonies formed in response to the combination of both CSFs was almost always less than additive compared with the number of colonies formed in response to the individual CSFs. Further, the AML-CFU responding to either GM-CSF or G-CSF could not be distinguished by surface markers or by the cytochemical staining pattern of the colonies. These results suggest that there is considerable overlap between the GM-CSF- and G-CSF-responsive AML-CFU subpopulations in most cases. For five of seven cases, the combination of GM-CSF and G-CSF could replace a leukocyte feeder layer in providing maximum growth stimulation. These results indicate that GM-CSF and G-CSF are active growth factors for AML cells and are frequently additive in promoting maximum colony size.

Adult↗
PubMed1987

Patterns of acute myeloid leukemia colony growth in response to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF).

In order to assess the response of acute myeloid leukemia colony-forming cells (AML-CFU) to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), AML blasts of 20 patients were cultured in a colony assay supplemented with titrated concentrations of rGM-CSF. In 16 cases rGM-CSF was able to induce AML colonies. In eight cases maximal clonogenic cell proliferation was obtained with 100 U rGM-CSF/ml alone (type I response). In eight other cases, however, maximal colony numbers were reached only after the addition of low concentrations of PHA-leukocyte conditioned media (PHA-LCM) to the rGM-CSF containing cultures (type II response). These values could not be obtained with higher doses of rGM-CSF (500 U/ml) or PHA-LCM separately. Thus in this subgroup, optimal AML colony formation depended on rGM-CSF plus an additional factor. Finally, in 4 of 20 cases rGM-CSF alone (100 U, 1000 U/ml) was not capable of inducing any AML colonies in vitro (type III). In these latter cases proliferation of AML-CFU could be achieved only by supplementing PHA-LCM. We conclude that GM-CSF is a stimulator of the in vitro proliferation of AML clonogenic cells. However, in a majority of these cases, i.e., 12 out of 20, AML-CFU require an additional factor for optimal proliferation which is produced by PHA-stimulated leukocytes.

Bone Marrow Cells↗
PubMed1987

Secretion of interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors.

The interaction of acute myeloblastic leukemia (AML) cells with stromal cells was investigated by adding AML-conditioned media to cultures of human endothelial cells. This conditioned media contained factors that induced expression of both the granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte CSF (G-CSF) genes and release of colony stimulating activity from endothelial cells. The conditioned media contained interleukin-1 (IL-1) bioactivity and the endothelial cell stimulatory activity was partially neutralized by anti-IL-1 antiserum. Constitutive expression of the IL-1-beta gene was detected in ten of 17 AML cases analyzed. These results suggest that the unregulated secretion of IL-1 by AML cells can induce stromal cells in vitro to overproduce CSFs. This could contribute to the unrestricted growth of AML cells.

Acute Disease↗
PubMed1986

A syndrome of liver damage and intravascular coagulation in the last trimester of normotensive pregnancy. A clinical and histopathological study.

Six women without hypertension or proteinuria, admitted for severe upper abdominal pain in the third trimester of pregnancy had elevated serum liver enzymes (SGOT, SGPT), markedly increased serum LDH levels, thrombocytopenia and abnormal blood coagulation tests, in particular low antithrombin III levels, indicating disseminated intravascular coagulation (DIC). Liver biopsies showed periportal and/or focal parenchymal lesions with large fibrin deposits, comparable to the liver lesions in eclampsia. Immunofluorescence (IF) showed microthrombi and large fibrin deposits. Three of the six women recovered spontaneously before delivery; in the remaining three all signs and symptoms rapidly disappeared after delivery. Perinatal outcome was poor. Seven women with pregnancy-induced hypertension and elevated serum liver enzymes constituted a reference series. Histopathological examination of liver biopsies in the reference group revealed periportal and/or focal parenchymal lesions in three whereas IF showed fibrin deposition in all seven, but less extensive than in the study group. The present findings indicate that upper abdominal pain in the last trimester of pregnancy can be caused by a syndrome of (pre)-eclamptic liver damage and DIC, even when hypertension and proteinuria are lacking.

Abdomen↗
PubMed1986

The mutual relationship between the two molecular forms of the major fibrinolysis inhibitor alpha-2-antiplasmin in blood.

Alpha-2-antiplasmin, a major inhibitor of fibrinolysis, is synthesized in the liver and occurs in blood in two molecular forms: a very active plasminogen-binding (PB) form and a less active nonplasminogen-binding (NPB) form. This study investigates the origin and mutual relationship of these two forms in vivo and in vitro. Despite wide variation in plasma concentration of the inhibitor (16% to 138%), the ratio between the two forms in vivo was found to be, in the main, constant among healthy volunteers, heterozygotes for a congenital deficiency of alpha-2-antiplasmin, and patients with a stable liver cirrhosis: PB/NPB = 2.41 +/- 0.34 (SD). Resynthesis after depletion or increased synthesis in the acute-phase reaction showed a specific increase of the PB form of the molecule in blood after discontinuation of L-asparaginase or streptokinase therapy and after myocardial infarction. In vitro studies demonstrated that only the PB form was present after one day in the culture medium of the human cell line Hep G2, while the NPB form appeared after 11 days. Clearance after inhibition of synthesis by L-asparaginase therapy revealed a more rapid decrease in the PB form relative to the NPB form in blood, demonstrated by a change in the PB-NPB ratio from 2.86 +/- 0.55 to 1.74 +/- 0.24 (mean of 6, SD). An apparently spontaneous first order conversion from the PB to NPB form, with an apparent half-life of about eight days, was demonstrated at 37 degrees C in plasma and serum in vitro. The conversion was found to be temperature dependent and uninfluenced by the fibrinolytic components fibrinogen, fibrin, and plasminogen. Additions of a variety of enzymes or inhibitors did not interfere with the process. These results demonstrate that the PB form of alpha-2-antiplasmin is produced by the liver and that the NPB form is formed in the circulation.

Asparaginase↗
PubMed1986

Retinoic acid as antileukemic therapy in a patient with acute promyelocytic leukemia and Aspergillus pneumonia.

A patient with acute promyelocytic leukemia (APL) and laboratory evidence of fibrinolysis who could not be treated with aggressive cytostatic regimens because of Aspergillus pneumonia was treated with cis-retinoic acid (RA), a substance that can induce differentiation and maturation of APL cells. After seven weeks of daily oral treatment, he went into complete remission, and signs of coagulopathy disappeared. Meanwhile, the Aspergillus pneumonia could be treated adequately. Based on the experience in this single patient, RA deserves further evaluation in the treatment of APL.

Adult↗
PubMed1984

Prophylaxis of thrombosis in antithrombin III-deficient women during pregnancy and delivery.

Prophylactic treatment of two asymptomatic antithrombin III (AT III) -deficient women with oral anticoagulants and heparin during pregnancy and after delivery appeared to be feasible. Oral anticoagulants caused no change in plasma AT III levels in either woman. A high dose of heparin intravenously in one of them caused a strong reduction in the AT III level which was corrected by infusion of AT III concentrate during delivery. A low dose of heparin subcutaneously in the other caused no significant change in plasma AT III levels. There is probably no need for AT III substitution during an uncomplicated pregnancy.

Adult↗
PubMed1984

The influence of L-asparaginase therapy on the fibrinolytic system.

Fibrinolytic factors were assessed during L-asparaginase administration, to study whether their changes may predispose to a haemorrhagic or thrombotic diathesis. The total level of alpha 2-antiplasmin declined, as well as the ratio of the plasminogen-binding form of alpha 2-antiplasmin to the non-plasminogen-binding form. After cessation of L-asparaginase administration, the ratio increased to 1.6 times that of the pretreatment value. These data indicate that the plasminogen-binding form of alpha 2-antiplasmin is the form primarily synthesized in vivo. L-Asparaginase therapy reduced plasma levels of plasminogen and histidine-rich glycoprotein ( HRG ) and influenced the equilibrium between HRG , plasminogen and HRG -plasminogen complex, with a more pronounced decrease of plasminogen (62% +/- 8) and HRG (76% +/- 11) in comparison to the free-plasminogen levels (51% +/- 6). alpha 2-Macroglobulin was only slightly influenced by L-asparaginase and may consequently play a more pronounced role in inhibition. This is suggested by moderate declines in functional tests of plasmin, urokinase and tissue activator inhibition by patients plasma, and by the ratio of inhibition of these enzymes over alpha 2-antiplasmin. Thus the bleeding tendency described during L-asparaginase therapy can be ascribed not only to a temporary deficiency of coagulation factors but also to temporary alpha 2-antiplasmin deficiency.

Adolescent↗
PubMed1983

The significance of the aminoterminal propeptide of type III procollagen in paroxysmal nocturnal haemoglobinuria and myelofibrosis.

The level of the aminoterminal propeptide Col 1-3 of type III procollagen (PC-III) was determined in patients with paroxysmal nocturnal haemoglobinuria (PNH) and primary myelofibrosis (PMF), to study whether PC-III can be used as a parameter for the rate and/or degree of bone marrow replacement with collagen. Normal PC-III levels were found in PNH (6.6 +/- 1.1 micrograms/l; N: 8.6 +/- 1.8 micrograms/l), while significantly increased levels were found in PMF (24.8 +/- 2.2 micrograms/l). During a follow-up of 1 year, a slight increase of 2 micrograms/l occurred in three patients with a stable fibrosis, while one patient with more active disease demonstrated an increase of 25 micrograms/l. Treatment with acetylsalicylic acid led to a decline of PC-III as well as beta-thromboglobulin level, although normalization did not occur. It was demonstrated by means of gel filtration that the antigens related to the PC-III peptide were heterogenous, and that in PMF at least two main peaks were present, with molecular masses equal to and smaller than PC-III peptide. These data demonstrate that the radioimmunoassay cannot be used for the quantitative determination of PC-III; nevertheless it gives some insight in the process of bone marrow fibrosis.

Aged↗
PubMed1983

Lymphocyte characteristics and function in paroxysmal nocturnal haemoglobinuria.

In six patients with paroxysmal nocturnal haemoglobinuria (PNH) lymphocyte studies were performed to investigate whether the observed immunological dysfunction could be ascribed to a defect in lymphocytes as result of the PNH characteristics, or to an imbalance between T-cell subsets. The PNH characteristics were studied by means of the effect of serum and acidified serum on Indium111-oxine labelled lymphocytes. No increase in release of Indium111-oxine was found when lymphocytes were exposed to acidified sera. Thus a complement mediated lymphocyte lysis in PNH could not be demonstrated. T-cells were defined by monoclonal antibodies, directed at total T-cells (OKT3), helper T cells (OKT4) and suppressor/cytotoxic T-cells (OKT8). In two of the six patients a decreased proportion of OKT3 cells was found, while a significantly depressed ratio of OKT4/OKT8 cells was present in the whole group. No obvious correlation was found between a functional assay - the concanavalin-A suppressor cell activity - and the ratio of OKT4/OKT8 positive cells. It is concluded that the PNH characteristics could not be demonstrated in the lymphocytes; and that the immunological dysregulation in PNH may be ascribed to an imbalance of T-cell subsets, while a decreased number of monocytes, defined by the monoclonal antibody OKM1, may contribute to this defect.

Antibodies, Monoclonal↗