The concept of negativity in experimental carcinogenesis

The problems that arise in the interpretation of experimental data on chemical carcinogenesis are addressed. In particular, the difficulties in demonstrating negative results are shown to present problems in delineating carcinogens from noncarcinogens. The use of the virtually safe dose estimated under the assumption of low dose linearity is shown to lead to potentially anomalous results if used indiscriminately in bioassays in which no statistically significant increase in tumor occurrence is induced. It is suggested that there is a need to establish an operational definition of negativity in carcinogenesis, with the realization that this definition may be revised in light of new information. The establishment of negativity in aligning data from positive and negative experiments and in considering possible thresholds is also discussed.     

The historical bases of the concept of allelopathy

Conclusion In the light of contemporary allelopathic research, the intuitively based statements of the early botanists stand up surprisingly well. The walnut tree is now understood to affect the growth of neighboring plants via juglone leached from the leaves, roots, and fruits.¹¹⁸ The replant or soil sickness problem of peach orchards has been related to the toxigenic breakdown of amygdalin, a constituent of peach roots.¹¹⁹ The declining yield of many crop species grown under continuous monoculture has been linked to the accumulation of allelopathic substances in the soil, especially through the mediation of microorganisms.¹²⁰ Numerous plants cited by de Candolle as being injurious, such as Erigeron,¹²¹ thistle (Cirsium),¹²² flax (Linum),¹²³ and various crucifers (such as Brassica nigra),¹²⁴ have been found to posses marked allelopathic activity. Over fifty years before the discovery of rhizobia, de Candolle considered the excretory material of legumes to be beneficial to cereals.¹²⁵ Modern reviews of allelopathy commonly credit de Candolle with an insight that was not equaled by the technology of his era.¹²⁶ In fairness to his detractors, his toxin theory of plant interactions was largely the by-product of an outdated and misconstrued notion of plant nutrition. His critics and most earlier botanists had similarly erred in seeking a single factor responsible for plant growth, much as had the alchemists sought the legendary philosopher's stone. Taking all this into account and considering the forceful personality of Liebig, one can readily appreciate how, 130 years ago, Liebig's theories preempted and stifled those of de Candolle.Today, with modern techniques of plant physiology and soil biochemistry, allelopathy has been shown to be a real but subtle factor in the dynamics of natural and agricultural plant communities. It is unfortunate that the single-mindedness characteristic of previous centuries still persists. The dichotomy between allelopathy and competition is exacerbated by the inherited bias toward the nutritional model of plant interaction fostered by Liebig, and is accentuated in the fact that in modern nutritional studies it is still basically unnecessary to consider plant-plant chemical interactions and their concomitant effects, whereas in allelopathic investigations the converse is regarded as axiomatic.In summary, de Candolle should not be seen as a prophet crying in the wilderness, as Fisher would have it.¹²⁷ The bases of de Candolle's concept of allelopathy were the dubious experiments of Macaire and his own obsolete theory of plant nutrition. Despite this, modern experimental work indicates that allelopathy is important in many plant interactions. De Candolle seems to have been right, at least in part—but for the wrong reasons.     

Immunity to the liver stage of malaria

The search for subunit vaccines against malaria has concentrated on asexual and sexual blood stage and sporozoite antigens. In recent years the search for the basis of the protection against sporozoite challenge obtained in mice immunized with irradiated sporozoites has focused attention on the liver or exoerythrocytic (EE) stage of the malaria life cycle. Here, Andreas Suhrbier looks at the various immune responses that appear to be active against this stage, which was once thought to be immunologically insignificant. The liver stage of malaria has thus emerged as a legitimate target for vaccine development.     

Dynamics of bases in hydrated [d(CGCGAATTCGCG)]2

Solid-state 2H NMR spectroscopy has been used to investigate the dynamics of a DNA oligonucleotide with a defined sequence, [d(CGCGAATTCGCG)]2, which contains the EcoRI binding site. Quadrupole echo line shapes and spin-lattice relaxation times were obtained as a function of hydration on two different deuterated samples, both in the form of the Na salt. In one sample, the C8 protons of all purines in the self-complementary dodecamer were exchanged for deuterons. In the other sample, a specifically labeled thymidine (C6 deuterated) was synthetically incorporated at the seventh position (counting 5' to 3') in the sequence. The general trends for both samples were quite similar. At all levels of hydration, the data reveal the presence of a rapid, small-amplitude libration of the bases (tau c less than or equal to 1 ns, 6 degrees-10 degrees amplitude). At the higher hydration levels (80% relative humidity or higher), the results indicate the presence of a much slower motion (tau c approximately 10-100 microseconds), which at 80% relative humidity is of small amplitude (approximately 5 degrees) and at higher hydration levels may be of larger amplitude. There is no evidence for large-amplitude (greater than +/- 10 degrees) motion on a nanosecond or faster time scale under any hydration condition. The 2H NMR results were analyzed with a dynamical model which treats the oligonucleotide as a deformable filament and which can include collective torsional fluctuations. The slow motion observed at high hydration levels is attributed to the uniform twisting mode (of the entire helix).(ABSTRACT TRUNCATED AT 250 WORDS)     

State of the erythrocyte surface (echinocytosis) in experimental carcinogenesis]

Characteristic red cell deformation, echinocytosis peculiar to mammary tumour susceptible C3H mice, were revealed by a comparative study of erythrocytes in animals with a different natural resistance to spontaneous carcinogenesis. 58.6% of spiny red cells was found at the early latent period (at the age of 3-4 months) and reached 91.1% at the late latent period (at the age of 11-12 months). In the blood of intact C57BL/6 mice resistant to mammary carcinogenesis, at the same ages the echinocyte count ranged from 16.0 to 18.7%. The tumour growth (spontaneous tumour in C3H mice and transplantable Ehrlich adenocarcinoma in C57BL/6 mice was accompanied by an increase in the echynocyte count and in the expression of echinocytosis (up to 96.6 and 65.3%, respectively). Possible pathogenetic mechanisms of echinocytosis in carcinogenesis are discussed.     

Physiological bases of oligotrophy of microorganisms and the concept of microbial community

Three groups of physiological processes in microorganisms are considered the physiological basis of oligotrophy: the greater substrate affinity of the oligotrophs' transport systems, efficient or “economical” metabolism, and existence of a “master reaction” or “rate-determining steps” controlling the rate of metabolism. Heterotrophic microorganisms are divided into three unequal groups according to “reaction norma.” Two groups representing the extremes are small groups with the “narrow” reaction norma, regarding the concentrations and structure of the assimilated organic compounds and variability limits of the physiological characteristics mentioned above. The third, intermediate group includes the majority of microorganisms with the “wide” reaction norma.     

Immunity to asexual blood stage malaria and vaccine approaches

The development of a malaria vaccine seems to be a definite possibility despite the fact that even individuals with a life time of endemic exposure do not develop sterile immunity. An effective malaria vaccine would be invaluable in preventing malaria-associated deaths in endemic areas, especially amongst children less than 5 years of age and pregnant women. This review discusses our current understanding of immunity against the asexual blood stage of malaria - the stage that is responsible for the symptoms of the disease - and approaches to the design of an asexual blood stage vaccine.     

Differentiation antigens in tumors: dependence on carcinogenesis mechanisms and progression (a hypothesis)

The data considered in the paper indicate that a tumor clone resulting from cell transformation, in order to develop, should overcome a microenvironmental constraint. This destroys intercellular contacts and cell interactions with extracellular matrix required for induction and maintenance of epithelium differentiation. The possible reasons for this lie in mutations of genes that control cell adhesion molecules and integrins, as well as proteases secreted by a tumor. These events lead to partial loss of differentiation antigens by a cell or to their incorrect localization in a cell. Simultaneously, the expression of embryo-specific genes is unblocked, leading to overexpression of embryonic antigens and their abnormal secretion into blood, which results in appearance of oncofetal markers in blood. Discussed from this point of view are alpha-fetoprotein, the carcinoembryonic antigen, and the prostate-specific antigen, which are used as tumor markers.     

Induction of experimental diabetes in frog (author's transl)]

The effect of diabetogenic agents, alloxan and streptozotocin, in frogs has been studied. These drugs were administered to the animals by injection into the dorsal lymph sac. Alloxan did not exert any effect at non-lethal doses. At 300 mg/kg alloxan caused death of most of the animals in an hyperglycemic state in less than 72 hours. Streptozotocin at doses lower than 1 g/kg was ineffective. At 1.5 g/kg, a non-lethal dose, about half of the animals became diabetic.     

Effect of vinblastine on experimental stomach carcinogenesis

The experiments on inbred male rats have been carried out to estimate the effect of parenteral vinblastine, an inhibitor of catecholamine axoplasmatic transport, on gastric tumour growth induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) added to drinking water. The maximum tolerance dose of vinblastine was determined in subchronic experiments on 30 rats (0.25 mg/kg subcutaneously, once per week). Chronic experiments with combined introductions of MNNG and vinblastine were performed on 70 rats. Vinblastine was shown to inhibit carcinogenesis on "intestinization" stake and to decrease three-fold the incidence of gastric adenocarcinomas. Vinblastine-induced changes in the behaviour of animals reflect the decreased activity of central adrenergic processes. The role of catecholamines in the mechanisms of specific action of chemical carcinogens is discussed.