KINETICS OF DEVELOPMENT OF EMBRYONIC ERYTHROID CELLS

Embryonic erythropoiesis is an intrinsically non-steady-state process. A method of non-steady-state analysis is employed to approximately determine the kinetics of maturation of embryonic erythroid cells during the hepatic phase of erythropoiesis in the mouse. It appears from this analysis that embryonic erythroid cells have significantly shorter maturation times than their adult counterparts. In the embryo, there is insufficient time for more than three divisions between the proerythroblast and the orthochromatic erythroblast.     

Optimum combination of targeted131I therapy and total-body irradiation for treatment of disseminated tumors of differing radiosensitivity

¹³¹I is the radionuclide most commonly used in biologically targeted radiotherapy at the present time. Microdosimetric analysis has shown that microtumors whose diameters are less than the β-particle maximum range absorb radiation energy inefficiently from targeted radionuclides. Micrometastases of diameters <1 mm are likely to be spared if targeted¹³¹I is used as a single modality. Because of this, combined modality therapy incorporating targeted¹³¹I, external beam total-body irradiation (TBI), and bone marrow rescue has been proposed. In this study, the minimum necessary TBI component is shown to depend on the radiosensitivity of the tumor cells. The analysis shows that the TBI component, to achieve radiocurability, increases directly with tumor radioresistance. For the most radiosensitive tumors, a whole-body TBI treatment dose 2×2 Gy is calculated to be obligatory, whereas practical tumors, the analysis implies that a TBI treatment delivery of 5×2 Gy is obligatory. In all situation, external beam TBI appears to be an essential factor in providing reasonable probability of cure of disseminated malignant disease. Reasonable prospects of tumor cure by combination strategies incorporating¹³¹I exist for the more radiosensitive tumor types (e.g., neuroblastoma, lymphoma, leukemia, myeloma, seminoma), but more resistant tumors are unlikely to be curable at present. Superior targeting agents, and the possible use of panels of different radionuclides, may be necessary to achieve high cure probabilities for less radiosensitive tumor types.     

Quantitative comparisons ofin situ microbial biodiversity by signature biomarker analysis

Microscopic examinations have convinced microbial ecologists that the culturable microbes recovered from environmental samples represent a tiny proportion of the extant microbiota. Methods for recovery and enzymatic amplification of nucleic acids from environmental samples have shown that a huge diversity existsin situ, far exceeding any expectations which were based on direct microscopy. It is now theoretically possible to extract, amplify and sequence all the nucleic acids from a community and thereby gain a comprehensive measure of the diversity as well as some insights into the phylogeny of the various elements within this community. Unfortunately, this analysis becomes economically prohibitive if applied to the multitude of niches in a single biome let alone to a diverse set of environments. It is also difficult to utilize PCR amplification on nucleic acids from some biomes because of coextracting enzymatic inhibitors. Signature biomarker analysis which potentially combines gene probe and lipid analysis on the same sample, can serve as a complement to massive environmental genome analysis in providing quantitative comparisons between microniches in the biome under study. This analysis can also give indications of the magnitude of differences in biodiversity in the blome as well as provide insight into the phenotypic activities of each community in a rapid and cost-effective manner. Applications of signature lipid biomarker analysis to define quantitatively the microbial viable biomass of portions of an Eastern USA deciduous forest, are presented.     

Optimum combination of targeted 131I therapy and total-body irradiation for treatment of disseminated tumors of differing radiosensitivity.

131I is the radionuclide most commonly used in biologically targeted radiotherapy at the present time. Microdosimetric analysis has shown that microtumors whose diameters are less than the beta-particle maximum range absorb radiation energy inefficiently from targeted radionuclides. Micrometastases of diameters < 1 mm are likely to be spared if targeted 131I is used as a single modality. Because of this, combined modality therapy incorporating targeted 131I, external beam total-body irradiation (TBI), and bone marrow rescue has been proposed. In this study, the minimum necessary TBI component is shown to depend on the radiosensitivity of the tumor cells. The analysis shows that the TBI component, to achieve radiocurability, increases directly with tumor radioresistance. For the most radiosensitive tumors, a whole-body TBI treatment dose 2 x 2 Gy is calculated to be obligatory, whereas practical arguments exist in favor of higher doses. For more radioresistant tumors, the analysis implies that a TBI treatment delivery of 5 x 2 Gy is obligatory. In all situations, external beam TBI appears to be an essential factor in providing reasonable probability of cure of disseminated malignant disease. Reasonable prospects of tumor cure by combination strategies incorporating 131I exist for the more radiosensitive tumor types (e.g., neuroblastoma, lymphoma, leukemia, myeloma, seminoma), but more resistant tumors are unlikely to be curable at present. Superior targeting agents, and the possible use of panels of different radionuclides, may be necessary to achieve high cure probabilities for less radiosensitive tumor types.     

NON-STEADY-STATE ANALYSIS OF CELLULAR DEVELOPMENT

A discrete, compartmental, representation is proposed for cellular development. Equations describing the kinetics of cellular development (with or without cell proliferation) are derived in both differential and integral form. Using an integral formulation, a method is proposed for the computation of compartment transit times (maturation times) which does not require the use of radioactive or other tracers. Although some restrictive conditions are imposed, the applicability of the method does not depend on strictly steady-state conditions, nor on purely exponential growth or decay. The method permits analysis of cellular development in certain non-steady cases for which existing analytical methods are inadequate. It is possible that patterns of cellular development during embryogenesis, recovery from insults, or growth in culture (e.g. of normal and leukaemic human granulocytes) could be examined using this method of analysis.