摘要:

AbstractNeoplastic transformation is one possible consequence of genomically disturbed intracellular feedback mechanisms normally governing life, differentiation, function and death of an individual cell. Neoplastic growth can be thought of as the abnormal activation of the mitotic program and/or the inactivation of programs for growth‐inhibition and apoptosis. This article reviews the current knowledge on three types, or families, of proteins that act on different levels of subcellular organization and are involved in controlling the integrity of the genome, survival and death: i) the DNA‐binding nuclear protein p53 inducing cell cycle arrest and apoptosis, ii) thebcl‐2 family of proteins acting as regulators of prolonged survival and programmed cell death and iii) APO‐1/Fas, a cell surface receptor transducing an apoptotic signal delivered either by the cell itself (cis death) or by another cell (trans death). Although much is still unknown, especially concerning the functional linkages of these three principles, the data available allow a fascinating insight into the society of cells, which we are, af

ISSN:1066-5099    

DOI:10.1002/stem.5530130729

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractWhile early radiation lesions might be a direct consequence of parenchymal cell loss, late‐radiation injury most probably develops as a consequence of functional perturbations that may involve both parenchymal and nonparenchymal elements. Damage to blood vessels and consequent perturbations in blood flow and endothelial physiology play an important role in the development of late effects. The development of late‐radiation damage has been studied in three different tissue systems: the skin, kidney and central nervous system. The results suggested that damage to vascular tissue played a major role in the development of radiation‐induced late ef

ISSN:1066-5099    

DOI:10.1002/stem.5530130730

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractImmature hemopoietic cells are heterogeneous with respect to repopulating capacity following exposure to ionizing radiation, growth factor receptor and surface marker phenotype as well as cycling state. In the present paper, the evidence from studies in subhuman primates and mice is reviewed, which demonstrates that the heterogeneity of immature stem cells is also reflected by a differential sensitivity to radiation, the most immature stem cells with long‐term repopulating capacity being less sensitive to radiation than assumed on the basis of 50% lethal dose (LD50) data, and the radiation sensitivity of immature hemopoietic cells measured by the spleen‐colony test. In addition, these immature cells appear to have a considerable repair capacity. These findings have a direct bearing on future strategies for the treatment of patients after accidental exposure to ionizing radiation, either by transplantation of (subsets of) stem cells or by administration of a specific combination of hemopoietic growth fact

ISSN:1066-5099    

DOI:10.1002/stem.5530130731

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractAmong the cytotoxic agents which particularly cause damage to cell renewal systems, ionizing radiation is one of the most effective ones since it leads to inactivation of all types of proliferating cells including resting stem cells. It is the aim of this paper to present the effects of continuous low dose rate total body irradiation (TBI) on hemopoiesis in dogs. The animals were exposed to γ‐rays from a 60‐Co source, receiving a daily radiation dose of 0.0188 Gy for indefinite times. Sequential hematological studies performed included determinations of peripheral blood cell counts and of total cell numbers in standardized bone marrow samples, assessments of progenitor cells GM‐CFC in the blood and bone marrow, and of colony‐stimulating activity (CSA) in the serum. The lymphocytes, the thrombocytes and neutrophilic granulocytes uniformly showed early decreases within the first 200 to 500 days corresponding to cumulative radiation doses in the range up to 3.8 to 9 Gy, but remained stable at subnormal levels in the period up to 1,700 days of exposure. The GM‐CFC numbers in bone marrow samples from the rib clearly showed a strong decrease within the first 150 days of exposure preceding the changes in the blood granulocyte concentration. A transient partial recovery of the GM‐CFC was observed at later times between 700 and 1,200 days of exposure, followed by another decrease to extremely low values at cumulative doses in the range of 32 Gy. Subnormal numbers of GM‐CFC in the peripheral blood within the whole period of exposure clearly signaled persistent alterations in the progenitor cell compartment, whereas increased levels of CSA in the serum were indicative of compensatory mechanisms operating under the influence of humo

ISSN:1066-5099    

DOI:10.1002/stem.5530130732

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe effects of chronic low‐dose irradiation on the immune system and the lymphocytes are largely unknown. The uranium miners in the former German Democratic Republic (GDR) were exposed mainly to a local low‐dose irradiation in the lung by radon and its progeny, but also to some whole‐body gamma irradiation. The local irradiation led to an increased rate of lung cancer and perhaps to some increase in extrapulmonary neoplasms. But little is known about the effects on the lymphocytes circulating and recirculating to the lung. As a prerequisite for the establishment of a biomathematical model to estimate lymphocyte fluxes, and to assess the radiation effects on the lymphocytic (and stem cell) populations passing through the lung, it was necessary to establish the current knowledge with respect to the physiology and pathophysiology of the lymphocytic cell renewal systems. The data concerning lymphopoiesis and lymphocyte kinetics, which are important for the development of this model, are summarized. The distribution of lymphocytes between different compartments including the lung is taken into consideration, as well as the effects of acute and chronic irradiation on the immune system. The extracorporeal irradiation of the blood (ECIB) may serve as a model of irradiation of blood in the lung. This review shows that many data necessary for development of a detailed biomathematical model are still missing, especially data concerning details on lymphocyte production rates of their different subsets and regulatory mechanisms of the lymphocytic s

ISSN:1066-5099    

DOI:10.1002/stem.5530130733

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractCytological analysis of bronchoalveolar lavage (BAL) and x‐ray energy dispersive spectrometry of intercellular compounds were evaluated in 19 workers (“liquidators”) commissioned to clean and contain the nuclear waste after the Chernobyl catastrophe in comparison with ten control subjects. Results showed a significant increase of neutrophils, small monocyte‐like alveolar macrophages (AM) and AM with large black cytoplasmic inclusions. In addition, such mineral elements as Zr, Ce, Pr, Sm, Pa, PU and Cs were detected in AM phagosomes in liquidators. These elements were reported as markers of Chernobyl‐type nuclear fuel. It is recognized that BAL gives access to particulate matter present in lung parenchyma. Thus, spectrometric analysis of AM inclusions can provide reliable information about the exposure to inhaled radionuclides seven years after the ca

ISSN:1066-5099    

DOI:10.1002/stem.5530130734

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractIn this paper a dynamic model of granulocytopoiesis is used to estimate stem cell numbers after acute and chronic irradiation. Regeneration data from irradiation accidents and bone marrow transplantation are investigated in the case of acute irradiation. Data from dogs living in a low‐dose irradiation field are investigated for the case of chronic irradiation. The effects of acute irradiation and bone marrow transplantation are interpreted as a change of the initial conditions of the model, while the effect of chronic irradiation is interpreted as a continuous cell loss in the proliferating cell compartments of the model. The unknown initial conditions of the model are computed on the basis of real patient and dog data with the help of a suitably constructed optimization problem. The numerical solution of this optimization problem will only be sketched in this paper. In all cases discussed in this paper, a very good agreement between the model and the real data is achieve

ISSN:1066-5099    

DOI:10.1002/stem.5530130735

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractFundamental principles for the development of a biomathematical model of lymphocytopoiesis are presented in this paper. The first step in this modeling approach is the definition of appropriate anatomical compartments in order to identify dominant locations of lymphocytes in the human body, and the definition of functional compartments in order to model different maturation stages. In the second step these compartment structures are combined, and thus form the basis of a dynamical model consisting of linear differential equations. Cell balance equations are used to derive the biomathematical dynamical model which is presented using the tools of modern systems theory.As a result of intensive discussions between engineers and medical doctors, our model of lymphocytopoiesis consists of six anatomical and six functional compartments. Virtual marking technique plays a key role for the interpretation of the simulation results which are in solid agreement with biological observations.Future work is directed towards implementation of radiation damages in order to meet the final goal, namely, the evaluation of our model against the data derived from a group of chronically irradiated uranium miners.Biomathematical modelLymphocytes

ISSN:1066-5099    

DOI:10.1002/stem.5530130736

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe aim of this contribution is to outline how methods of system analysis, control theory and computer science can be applied to simulate malignant and normal cell growth and to optimize cancer treatment. Based on biological observations and cell kinetic data, our group has constructed three types of computer models: 1) A cell cycle model describing the spatial (3D) and temporal growth of tumor spheroids; 2) A compartment model describing the growth of rapidly proliferating normal cells; 3) A compartment model simulating slowly proliferating normal tissues. These growth models have been extended by an irradiation model based on the linear‐quadratic survival function. Different clinical fractionation schemes (standard‐, super‐, hyperfractionation and weekly high single dose) have been applied to the tissues mentioned above. The simulation results show that in the case of irradiating a rapidly growing tumor spheroid the hyperfractionation (3 x 1–1.5 Gy per day) leads to a particularly good anti‐tumor effectiveness. On the other hand, the radiogenic response of rapidly growing normal tissue to a hyperfractionated treatment schedule is severe. The same result is observed when simulating the late reaction on slowly growing parenchymal tissue. Therefore, this therapeutic modality is ensured only if the overall dose is reduced from DTOTAL= 60 Gy to DTOTAL= 50 Gy. Thus, it is possible to study radiation effect on tumors, and on different normal tissues, and to construct treatment schedules via computer simulations with the aim of a maximum tumor cell kill and a minimum radiation effect on nor

ISSN:1066-5099    

DOI:10.1002/stem.5530130737

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe first panel discussion of the International Searle‐Foundation Workshop on Biological Indicators of Exposure to Ionizing Radiation was directed at identifying ‘common denominators’ for the development of somatic late effects. The presented accidents were analyzed in terms of occurrence of total body or partial body irradiation, external or internal contamination, onset of early signs or symptoms of acute radiation syndrome, reduction of life expectancy, and occurrence of neoplastic or non‐neoplastic disorders. Evidence of radiation effects was sought in the victims' cell systems and in any cellular or molecular response to ionizing radiation, and whether other complicating factors could be established. From the results presented during the meeting, as well as from a review of the relevant literature, it is, however, rather unlikely that a single parameter will emerge by which the late effects of ionizing radiation in man can be determined easily. Instead, a couple of acute and chronic effects of exposure to ionizing radiation could be identified which are more or less common to any given exposure s

ISSN:1066-5099    

DOI:10.1002/stem.5530130738

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY