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Biomedical subjects

E Frindel

Publications and source records attributed to E Frindel.

At least 73 records · Page 4Linked to original sources

Cell proliferation in EMT6 tumours treated with single doses of X-rays or hydroxyurea. II. Computer simulations.

A computer simulation technique was used to analyse data on the proliferation of clonogenic cells in EMT6 tumours treated with 5 mg/mouse of hydroxyurea (HU) or 3.0 Gy (300 rads) X-rays. This simulation technique is able to determine the respective roles of selective killing, blocks in cell progression and recruitment of the treated population. When the technique was applied to tumours treated with HU, it was possible to prove that both a G1/S block and recruitment occurred. These phenomena could not have been demonstrated quantitatively, or even qualitatively, without the use of the simulation. After irradiation, blocks in cell progression and differences in the proliferative patterns of the surviving clonogenic cells and the total tumour cell population were found.

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The effect of partial body irradiation on haemopoietic stem cell migration.

Data obtained after various types of partial body irradiation support the concept of a small rapidly exchangeable pool of CFUs which seems to be exhausted rapidly after irradiation. The depletion of this pool is the most plausible explanation for the decrease in stem cell migration observed 3 hr after exposure in C3H mice. After partial body irradiation the size of the rapidly mobilizable pool is reduced in proportion to the areas of bone marrow irradiated. When only one marrow area is shielded, the recovery of this pool does not occur during the first 24 hr after exposure.

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Study of a CFUs stimulating factor liberated by bone marrow cells after total and partial body irradiation.

Data reported in this paper show that a long range stimulating factor is released by irradiated bone marrow 15 minutes after exposure and that the secretion of the factor precedes CFUs proliferation. The factor seems to be elaborated by liver cells as is demonstrated by dose effect experiments as well as by the fact that protected bone marrow secretes a factor, albeit with different kinetics of secretion from those of irradiated bone marrow. The liberation of the factor seems to be regulated by the size of the stem cell compartment.

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Mathematical analysis of bone marrow erythropoiesis: application to C3H mouse data.

A mathematical analysis of normal bone marrow erythropoiesis is investigated under the following assumptions: there is no correlation for a cell between its position in cell cycle and its maturation level; the transition between proliferant and quiescent cells along the erythroid line occurs at a critical point in its cell cycle when a certain maturation level is reached; there is no net migration between the bone marrow and other hemopoietic tissues. Relationships are derived between model parameters (cell flows and cell number) and kinetic parameters, namely, the classic proliferation parameters (cell cycle time duration and growth fraction) and the maturation parameters (maturation time duration and amplification coefficient). This model, when applied to normal C3H mouse experimental data, provides a complete description of bone marrow erythropoiesis from pluripotent stem cells up to mature red blood cells. No differentiation from the pluripotent stem cells to the erythroid line is necessary to explain our experimental data. The number of erythroid-committed stem cells is estimated to be 3.4 x 10(5). Their maturation is characterized by eight divisions and a transit duration time of approximately 2.5 days. No ineffective erythropoiesis is found. Moreover, important red blood cell production is found in some other hemopoietic tissues. The 55Fe-labeling experiment of proerythroblasts is interpreted, assuming variability among cells for cell cycle and maturation time durations. For our experimental data, neglecting such a variability jeopardizes parameter estimations for proerythroblast population.

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Restoration by serum thymic factor of colony-forming unit (CFU-S) entry into DNA synthesis in thymectomized mice after T-dependent antigen treatment.

Adult thymectomy prevents stimulation of hematopoietic stem cells as measured by colony-forming units (CFU-S) if T-dependent antigens are injected, but not when T-independent antigens are used. This can be observed as soon as 10 to 15 days after thymectomy. The serum thymic factor can restore CFU-S response to T-dependent antigens in thymectomized mice.

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Some effects of chemotherapeutic drugs on bone marrow stem cells. I. The long-term effects of phase-specific drugs on mouse bone marrow stem cells.

Two phase-specific drugs, cytosine arabinoside and hydroxyurea, were studied with regard to their effects on various murine hematologic cell compartments of the same mouse. Effects of single and multiple injections of Ara-C were compared. Following a significant decrease in the first few days, and a subsequent overshoot of pluripotential stem cells (CFU-S), colony-forming cells (CFC), bone marrow nucleated cells, and leukocytes, the number of these cells returned to normal values with a time sequence that varied with the cell type. During the 6-month observation period the number of these cells oscillated around control values after both drugs and both types of protocols.

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Some effects of chemotherapeutic drugs on bone marrow stem cells. II. Effect on non-Hodgkin lymphoma chemotherapy on various hemopoietic compartments of the mouse.

The non-Hodgkin lymphoma chemotherapy protocol used at the Gustave-Roussy Institute was adapted, in terms of drug doses and interval between doses, to normal CBA mice. The numbers of pluripotential stem cells (CFU-S), unipotential stem cells (CFC), differentiated bone marrow cells, and circulating white cells were determined. Eight hours after each drug of the first chemotherapy cycle the number of pluripotent stem cells decreased while the proportion of these cells in DNA synthesis increased. Six hours after the end of each complete cycle, the stem cell compartments were found to be considerably depleted, and they were not completely restored when the next cycle was begun, while the other hematologic compartments were completely restored at this time.

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Influence of factors derived from EMT6 tumors and from bone marrow of tumor-bearing mice on tumor and bone marrow stem cell kinetics.

Untreated EMT6 tumors in BALB/c mice were used to assess the regulatory mechanisms of tumor growth in these animals. This tumor can be quantitated for clonogenic cells by in vitro techniques, and the hydroxyurea suicide method makes it possible to determine the kinetic status of the clonogenic cells. The untreated EMT6 tumor does not seem to have internal humoral regulatory mechanisms explaining tumor growth kinetics. However, the exponentially growing EMT6 experimental tumor releases a factor capable of stimulating quiescent splenic colony-forming units into cycle. This is also true of bone marrow taken from tumor-bearing mice. This study was made possible using an in vivo-in vitro technique which separates the effector cells from the responder cells by a Millipore filter floating on the culture medium. The relationship between tumor growth and normal hematopoietic tissue of the tumor-bearing animal is discussed.

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Humoral regulation of pluripotent stem cell differentiation.

Humoral regulators of CFU-S differentiation have been demonstrated in bone marrow of Ara-C treated animals. These factors are effective in vivo and are also capable of inducing erythropoietic differentiation of normal CFU-S in vitro. These results seem to indicate that the microenvironment acts at the committed stem cell level while the factors described in this paper act on the pluripotent stem cells.

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Stimulating factors and cell recruitment in murine bone marrow stem cells and EMT6 tumours.

The role of a stimulating factor in cell recruitment and the kinetics of its secretion were investigated by in vivo and in vitro techniques. The association of these two methods made it possible to demonstrate that a non-cycling population liberates a factor which in turn stimulates quiescent bone marrow stem cells into DNA synthesis. Moreover, it seems that undamaged cells are capable of secreting this factor. A stimulating factor responsible for cell recruitment was also demonstrated in an experimental EMT6 tumour and the kinetics of its secretion reported.

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Cell proliferation in EMT6 tumors treated with single doses of x-rays or hydroxyurea. I. Experimental results.

EMT6 mouse mammary tumors were treated in vivo with 5 mg/mouse of hydroxyurea (HU) or 300 rads of X-rays. The proliferation of the tumor cells was followed for 28 hr after treatment. Changes in the 3H-TdR labeling index, the mitotic index, the specific activity of the 3H-TdR-labeled DNA, and the proportion of suspended, clonogenic cells in the S phase of the cell cycle were examined and compared. Evidence was found for reassortment of the surviving cells in treated tumors into partially synchronous cohorts. The partial synchrony in the proliferation of the surviving cells was not accurately predicted by the changes in the labeling index and the mitotic index. The changes in DNA specific activity proved unacceptable as an indicator of cell proliferation in solid EMT6 tumors treated with low doses of radiation or HU.

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Inhibition of CFU-S entry into cell cycle after irradiation and drug treatment.

The cell cycle inhibition of pluripotent bone marrow stem cells (CFU-S) by a fetal calf bone marrow extract (BME) was studied. The normally quiescent cells were made to enter cell cycle by treatment with either irradiation or the phase specific drug cytosine arabinoside (Ara-C). Using the vitro-vivo system of Frindel et al., we have shown that when the BME was added to the incubation medium, no triggering of CFU-S into cycle could be observed. The inhibitory effect was also demonstrated when the BME was injected simultaneously with the drug. The possible relationships of BME with stimulating factors controlling CFU-S entry into cycle are discussed.

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Restoration of the bone marrow pluripotent stem cells in AKR mice after arabinosylcytosine treatment.

The hypothesis of repression of multipotent stem cells (CFU) by leukemic cells to explain their depletion, previously demonstrated in AKR leukemic mice, was tested. Using arabinosylcytosine to destroy leukemic cells, it was shown that the bone marrow CFU pool was acutely depressed between 2 h and 12 h after treatment. However, 5 to 7 days later, this pool was restored, surpassing the value of the bone marrow pool in normal mice. This seems to indicate that the CFU pool in leukemic mice is potentially capable of proliferating but is repressed by leukemic cells.

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