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Biomedical subjects

N G Testa

Publications and source records attributed to N G Testa.

At least 109 records · Page 6Linked to original sources
PubMed1989

Structure and regulation of the erythroid system at the level of progenitor cells.

Considerable ground has been covered since the first clonal assays for hemopoietic cells were described. The possibility of studying populations of progenitor cells and the regulatory factors that influence them has already thrown considerable light on our understanding of the structure and physiology of the normal erythroid system and its alterations in disease. The relative importance of humoral and short-range factors and of possible cell-to-cell interactions in the regulation of proliferation and differentiation in the erythroid cell lineage is now being studied actively in several laboratories. The possibility of analyzing possible regulatory networks involving such highly reactive cells as lymphocytes and monocytes-macrophages in defined in vitro conditions now exists. As these studies are being extended to the diseased state, concepts related to alterations in regulatory mechanisms in syndromes with abnormal cell proliferation can be tested. Clinical applications in the treatment of patients with hematological disease are being contemplated. The usefulness of Epo for the treatment of the anemia of renal disease has been demonstrated already.

Anemia↗
PubMed1989

Haemopoietic growth factors: their role in acute myeloblastic leukaemia.

The chromosome alterations specifically associated with leukaemia are found largely in the regions where the genes for the haemopoietic growth factors (as well as other regulatory molecules or their receptors) are located, indicating a crucial role of the growth factors in leukaemogenesis. However, growth factor genes per se do not generally induce leukaemia when inserted into normal haemopoietic cells, although they will do so if they are inserted into immortalized haemopoietic stem cell lines. The response of AML cells to these growth factors is extremely heterogeneous, and the tilting of the balance between self-reproduction (leading to perpetuation of the leukaemic process) and differentiation ('death' of the malignant cells) depends on several parameters, on the type and combination of factors to which the cells are exposed, with IL-3 and GM-CSF tending to favour self-renewal, and G-CSF and M-CSF tending to favour differentiation. These findings open the possibility to consider the use of growth factors to control the leukaemic process, although such treatment should be approached with considerable caution, and on an individual patient basis.

Animals↗
PubMed1989

Children in long-term remission after treatment for acute lymphoblastic leukaemia show persisting haemopoietic injury in clonal and long-term cultures.

Twenty children who were in unmaintained full haematological remission after treatment for acute lymphoblastic leukaemia (ALL) showed a significantly lower incidence of granulocyte-macrophage progenitor cells (GM-CFC) in the bone marrow compared to controls. This low incidence lasted for up to at least 3 years after the cessation of chemotherapy. There was no tendency to higher values with longer times after treatment, and the low incidence was not predictive of relapse. Long-term cultures from ALL bone marrows and from controls achieved similar levels of production of mature cells through the whole period of culture (6 weeks). However, cultures from patients' bone marrow had on average about 5 times lower numbers of GM-CFC, indicating that the level of mature cell production was achieved by a higher level of post-GM-CFC amplification than needed in the controls. This is taken to be due to compensatory mechanisms operative during stressed haemopoiesis which appears to be a long-lasting effect after current chemotherapy of ALL.

Adolescent↗
PubMed1989

The radiation response and recovery of bone marrow stroma with particular reference to long-term bone marrow cultures.

There is evidence for long-term haematopoietic dysfunction in some patients treated with radiotherapy. Although the underlying mechanisms are unclear, both stem cell and environmental defects have been implicated. In the present article we review the evidence concerning the role of stromal cells. According to the endpoints used, a wide range of radiosensitivities for the stroma have been reported. Long-term bone marrow cultures provide a system in which both functional and regenerative aspects of the stroma can be studied. A dose of 5 Gy applied prior to the establishment of long-term bone marrow cultures decreases both the formation of a confluent adherent stromal layer and its capacity to support haematopoiesis. In contrast, in its fully established phase, the adherent layer displays a high radioresistance due to the low proliferative stress applied to its stromal populations. A dose of 10 Gy given to a fully established adherent layer does not prevent haematopoietic engraftment and sustained haematopoiesis. At doses above 100 Gy a macrophage-like and epithelioid cell-type become dominant, which preserve their ability of producing growth regulatory molecules at doses as high as 500 Gy. These data suggest that the main effect on the stroma is a delayed expression of irradiation damage due to the slow rate of turnover of stromal cells. So far, there is little evidence for persistent deficiencies in the functional roles of stromal cell populations.

Animals↗
PubMed1989

Long-term hematopoietic damage: concepts, approaches, and results relevant to the study of environmental toxins.

The hematopoietic tissue is one of the prime examples of hierarchical tissues, where mature cells with a limited life span are continually replaced as a result of proliferation and differentiation from stem and progenitor cells. In the bone marrow, these processes are controlled by growth factors and by cell to cell interactions, the latter being specially important for the regulation of the stem-cell population. In the study of long-term hematopoietic damage, we have to distinguish between deleterious effects of the environmental toxins on the stem and progenitor cells, and on the stromal bone marrow cells which are part of the regulatory hematopoietic microenvironment. In some experimental situations, the function of the tissue may be subnormal, not because of stem cell damage (which may also be present), but because of damage to regulatory environmental populations. Because of the high degree of organization of the hematopoietic tissue (not immediately obvious from histological sections), the heterogeneity of the stromal cell populations, and their different capacities to regenerate after cytotoxic insult, the stromal damage is likely to be heterogeneous and would tend to be expressed functionally at later times than acute hematopoietic injury. While microenvironmental damage may be of importance in the induction of hematopoietic failure, the primary target in leukemogenesis is likely to be the stem cell. However, experimental data support the concept that regulatory microenvironmental influences may hinder or favor the development of leukemia.

Animals↗
PubMed1989

The use of bone marrow cells grown in long-term culture for autologous bone marrow transplantation in acute myeloid leukaemia: an update.

Eleven patients with acute myeloid leukaemia have been transplanted with autologous marrow grown in long-term bone marrow culture. In the high risk group (six patients who had all previously relapsed) the procedure induced a remission in two patients who were in florid relapse at the time of the transplant. Five patients were transplanted in first remission and they remain well and disease-free between 150 and 12 weeks after their autologous transplant.

Adolescent↗
PubMed1988

Haemopoietic growth factors: their relevance in osteoclast formation and function.

The major recent advance in our knowledge of the haemopoietic system has been the purification and characterization of a family of haemopoietic growth factors, and their availability in recombinant form. In the bone marrow the sequences of differentiation and proliferation leading to the production of mature cells that these factors regulate may be determined by the relative availability of the factors in microenvironmental domains. The observation that growth factor-producing cells and haemopoietic progenitor cells are not evenly distributed in the bone marrow leads us to expect that the overall effect of growth factors (and other regulatory molecules) on the production and function of macrophages and osteoclasts may differ when in vivo or in vitro assays are used as end-points and, in the latter case, when whole marrow or purified cell populations are tested. The availability of an in vitro assay in which osteoclast-like cells are generated will allow these concepts to be tested.

Animals↗
PubMed1988

In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients.

Twelve patients with small cell lung cancer were treated with recombinant human granulocyte colony-stimulating factor, rhG-CSF, given by continuous infusion at doses ranging from 1 to 40 micrograms kg-1 day-1. Patients received the rhG-CSF before the start of intensive chemotherapy and after alternate cycles of chemotherapy. Several in vitro assays were performed using peripheral blood neutrophils and marrow progenitor cells collected from patients prior to and after infusion of the growth factor. Peripheral blood neutrophils were tested for mobility and phagocytic activity. In addition, in vitro clonogenic assays of marrow haemopoietic progenitor cells and analysis of bone marrow trephines and aspirates were carried out. We found that rhG-CSF in vivo has at least two main effects: (a) an early fall in peripheral neutrophils, within the first hour, followed by a rapid influx of mature neutrophils into the circulatory pool; (b) stimulation of proliferation and differentiation of neutrophil precursors in the bone marrow. Neutrophils released into the circulation were normal in tests of their mobility and phagocytic activity.

Antineoplastic Agents↗
PubMed1988

Persistent dose-dependent increases in cycling of haemopoietic precursor cells after irradiation.

Between 3 weeks and 36 months after irradiation of mice, there was a dose-dependent increased level of cycling in haemopoietic stem cells (CFU-S) and in granulocyte-macrophage precursor cells (GM-CFC). For CFU-S the percentage kill measured using the thymidine suicide technique increased from about 10% in controls to a high and persistent average level of about 45% after 10 Gy gamma-rays, and for GM-CFC the increase was from about 30% to about 50%.

Animals↗
PubMed1988

Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer.

Twelve patients with advanced small cell carcinoma of the bronchus were treated by continuous infusion of recombinant human granulocyte colony-stimulating factor (rh G-CSF) at the following dose levels: 1 microgram, 5 micrograms, 10 micrograms, 20 micrograms and 40 micrograms/kg/day for 5 days. No toxicities resulted from the treatment and in all 12 patients the number of peripheral neutrophils increased rapidly to a maximum of 100 x 10(9)/l in one patient at 10 micrograms/kg/day. The neutrophils were shown to be functionally normal in tests of their mobility and bactericidal activity. During the Phase II part of the patients were treated using a combination of i.v. Adriamycin, Ifosfamide and Etoposide. The chemotherapy was repeated every 3 weeks. rh G-CSF was given to each patient for 14 days on alternate cycles of chemotherapy and reduced the period of absolute neutropenia considerably (median of 80%), with a return to normal, or above normal, neutrophil counts within 2 weeks after day 1 of chemotherapy. Ten severe infective episodes were observed during the 20 cycles of chemotherapy which did not include rh G-CSF, while only one infective episode occurred in 20 courses when treated with rh G-CSF. These results demonstrate the utility of rh G-CSF in restoring functional neutrophils to patients undergoing intensive chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

The effect of low dose rate on recovery of hemopoietic and stromal progenitor cells in gamma-irradiated mouse bone marrow.

Long-term recovery of mouse hemopoietic stem cells (CFU-S and CFU-S per colony), granulocyte-macrophage precursor cells (GM-CFC), and stromal colony-forming units (CFU-F) after doses up to 12.5 Gy was almost complete by 1 year when the dose rate was reduced to 0.0005 Gy/min compared to incomplete recovery after doses up to only 6.5 Gy given at greater than 0.7 Gy/min. This sparing effect of dose rate on long-term hemopoietic recovery is in contrast to the generally reported lack of dependence on dose rate for acute survival of hemopoietic progenitors after doses up to 5 Gy. The present results are compatible with the hypothesis that good recovery of the stroma should be reflected in the long-term recovery of hemopoiesis.

Animals↗
PubMed1987

The radiation sensitivity of the haemopoietic microenvironment--effect of dose rate on ectopic ossicle formation.

The haemopoietic microenvironment (HM) consists of a complex mixture of cellular types and extra-cellular matrix. It is essential for prolonged haemopoiesis in both the normal situation and after bone marrow transplantation. The competence of the HM can be assessed by ectopic grafting of femoral marrow. A complete haemopoietic organ develops at the site of implantation. Stem cells (CFU-S) which inhabit the ossicle formed after ectopic implantation can be measured, to assess the function of the engrafted HM to support haemopoiesis. Using this functional endpoint we have examined the radiation sensitivity of the HM at both high and low dose rates, and conclude that high doses of gamma-irradiation delivered at 4 Gy/min or 0.016 Gy/min have widely different effects on the HM, the former proving much more damaging than the latter.

Animals↗
PubMed1987

Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer.

Twelve patients with advanced small cell carcinoma of the bronchus were treated by continuous infusion of recombinant human granulocyte colony-stimulating factor (rhG-CSF) at the following dose levels: 1 microgram, 5 micrograms, 10 micrograms, 20 micrograms and 40 micrograms kg-1 day-1 for 5 days. No toxicities resulted from the treatment and in all 12 patients the number of peripheral neutrophils increased rapidly to a maximum of 100 x 10(9) l-1 at 10 micrograms kg-1 day-1. The neutrophils were shown to be functionally normal in tests of their mobility and bactericidal activity. During the phase II part of the study the patients were treated by a combination of intravenous adriamycin 50 mg m-2, ifosfamide 5 g m-2 by i.v. infusion with mesna 8 g m-2 on day 1, and etoposide 120 mg m-2 on days 1, 2 and 3 also intravenously. The chemotherapy regime was repeated every 3 weeks. RhG-CSF was given to each patient for 14 days on alternate cycles of chemotherapy and reduced the period of absolute neutropenia considerably (median of 80%), with a return to normal, or above normal, neutrophil counts within 2 weeks after day 1 of chemotherapy. Six severe infective episodes were observed during the cycles of chemotherapy which did not include rhG-CSF, while no infective episodes occurred when patients were treated with rhG-CSF. These results demonstrate the utility of rhG-CSF in restoring functional neutrophils to patients undergoing intensive chemotherapy.

Aged↗
PubMed1987

Standardization of procedures for ectopic marrow grafting. II. Influence on recipients of radiation dose and field size.

The ectopic implantation of mouse marrow to the kidney capsule offers considerable scope as an assay of the hemopoietic microenvironment. Our previous work has shown that whole-body irradiation of the graft recipient prior to implantation results in superior ossicle formation in the kidney of the host. Here we report that a range of irradiation doses over a 4-Gy threshold are equivalent with respect to conditioning the graft recipient. We also show that two distinct and separable influences affect graft growth in the irradiated recipient, namely, a local effect brought about in the irradiated kidney (and restricted to it) and secondly, a systemic effect resulting from irradiation of sites other than the kidney, which nevertheless affects ossicle growth in the shielded renal capsule.

Animals↗