[Nutrition, toward new shores].
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Dietary Carbohydrates↗
Biomedical subjects
W Lutz
Publications and source records attributed to W Lutz.
A vasopressin analog that binds but does not activate V1 or V2 vasopressin receptors is not internalized into cells that express V1 or V2 receptors.
To assess whether receptor binding is sufficient to initiate vasopressin receptor endocytosis in cells expressing the vasopressin V1 or V2 receptors, we synthesized a novel fluorescent-labeled vasopressin analog, [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid), 2-(O-ethyl)-D-tyrosine, 4-valine, 8-lysine-N6-carboxytetramethylrhodamine] vasopressin (R-CLVP), that binds to vasopressin receptors but does not activate intracellular events such as the mobilization of intracellular calcium or the activation of adenylate cyclase. We compared the manner in which this analog was endocytosed in cells expressing V1 (A-10, rat smooth muscle cells) or V2 (LLC-PK1, porcine kidney cells) receptors with that of a full agonist, [1-(beta-mercaptopropionic acid), 8-lysine-N6-carboxytetramethylrhodamine] vasopressin (R-MLVP) [Lutz et al. (1990) J. Biol. Chem. 265, 4657-4663; Lutz et al. (1990) Proc. Natl. Acad. Sci. U.S.A. 87,6507-6511]. We showed that R-CLVP bound to both types of receptors with good affinity. It failed to increase cyclic AMP concentrations in LLC-PK1 cells and did not increase the mobilization of intracellular calcium in A-10 cells. It bound to the surface of both these cell types in a diffuse manner and it did not undergo receptor endocytosis in either cell type. In contrast, R-MLVP, an agonist that bound to both receptor subtypes and elicited changes in intracellular cyclic AMP and calcium, bound to the surface of these cells in a diffuse manner at early times after exposure, and rapidly underwent endocytosis. We conclude that binding of vasopressin to its receptors alone is insufficient to cause receptor endocytosis, and other events distal to the receptor are required to initiate endocytosis. R-CLVP should be a useful analog in determining the factors responsible for initiating receptor endocytosis.
Amino Acid Sequence↗
[Acetylation phenotype as a biomarker of sensitivity to the carcinogenic effect of aromatic amines].
The feasibility of genetic screening used for the determination of the acetylation phenotype in workers exposed to carcinogenic aromatic amines seems to be well-grounded. A conclusion like that is supported by numerous epidemiologic observations which show that the slow acetylators are more prone to bladder cancer under the conditions of exposure to aromatic amines than the fast acetylators. The significance of the acetylation phenotype for the processes which start the transformation of the normal bladder epithelium cells into the neoplasm was explained by studying the metabolism of the carcinogenic amines in the cells of mammals, including humans. Further tests are required to explain to what degree the genetic inclination is associated with the occurrence of the slow acetylation phenotype dependent on the tobacco smoking and on other factors, such as diseases, past or present.
Acetylation↗
Biological monitoring of risk of bladder cancer in persons occupationally exposed to aromatic amines.
Recent advances in molecular biology and toxicology have greatly contributed to the early diagnosis of biological changes which may evoke neoplasms. This paper reviews the issues regarding the screening of persons occupationally exposed to carcinogenic aromatic amines. The screening was designed for an early detection of bladder cancer by means of biochemical tests. The applied tests facilitated the estimation of the level of aromatic amines which penetrate an organism (biomarkers of exposure), early diagnosis of the biochemical disorders which may influence cancer development (biomarkers of early effects) and the detection of genetic predispositions which enhance risk of such disorders (biomarkers of susceptibility).
Amines↗
[Changes in the levels of tissue polypeptide antigen and carcinoembryonic antigen in the blood of workers exposed to aromatic amines].
The tissue polypeptide antigen (TPA) and carcinoembryonal antigen (CEA) are the markers used for screening and treatment monitoring of the bladder cancer. A study was carried out in a group of 38 workers chronically exposed to aromatic amines in a dye factory. The findings were compared with those of he study on CS2 exposure and for the non-exposed workers. The results revealed a statistically significant differences between TPA values in the exposed and non-exposed workers. This finding does not apply to CEA. No significant differences between the markers' values were found in the group of workers exposed to CS2. The highest percentage of abnormal values, 29.2%, refers to the workers with a low acetylation phenotype; taking into account the smoking habit the TPA value would amount to 102 U/L in the smokers and to 64.8 U/L in the non-smokers. The studies indicate the higher usefulness of TPA as a marker of the effects of exposure to aromatic amines than that of CEA.
Adult↗
[Biological markers--a new trend in evaluating the effects of the environment on the body].
Deepening changes in the environment, resulting from the industrialization process, have a negative effect upon human health. They increase specific health effects and bring about higher incidence of common diseases. Biomarkers make it possible to evaluate the organism's reaction toward the hazardous effects of exposure to noxious chemicals of the environmental origin. Biomarkers reflect the changes in the exposed organisms and make it possible to assess exposure, its health effects and susceptibility to toxic agents. At the moment, research is under was aimed at finding biomarkers for the neoplastic process and determining the neurotoxic effects, changes in the reproductive system, immunotoxic effects as well as toxic changes in such organs as liver, kidneys and lungs.
Biomarkers↗
[Expression of cytochrome P-450 genes].
Cytochromes P-450 are important in the oxidative metabolism of many endogenous substrates, as well as innumerable drugs, chemical carcinogens, and environmental pollutants. Biochemical analyses of cytochrome P-450 have revealed multiple isoenzymes. Information for synthesis of these isoenzymes is contained in different genes. Based on the degree of relatedness in DNA sequence, the genes for cytochrome P-450 have been classified into different families, constituting cytochrome P-450 multigene superfamily. Particular chemicals induce expression of one or more genes belonging to definite cytochrome P-450 family. Expression of these genes may have served as a mechanism by which the cell respond to specific chemical signals (xenobiotic or hormonal).
Animals↗
Vasopressin receptor-mediated endocytosis: current view.
A number of peptide hormones have been shown to undergo receptor-mediated endocytosis (RME). RME involves the internalization of receptor-ligand complexes followed by delivery to an intracellular compartment, the endosome, from which ligands or receptors can be delivered to lysosomes or other cellular destinations. Vasopressin, a peptide hormone that plays a role in kidney and vascular physiology, has recently been demonstrated to undergo RME in LLC-PK1 and A10 cells, which express V2- and V1-type vasopressin receptors, respectively. Fluorescent vasopressin analogues are internalized by RME from the basolateral surface of polarized LLC-PK1 cells. The precise role of RME in vasopressin action is uncertain, but it is likely that it is involved in the desensitization of target cells by altering the number of cell surface vasopressin receptors. Alterations in the rate of RME may alter the response of the cell to vasopressin. Fluorescent and biotinylated vasopressins are useful tools for the study of this process.
Animals↗
[Aromatic amines, oncogenes and cancer of the bladder].
The role of aromatic amines in cancer inducing is mainly connected with their metabolism in the organism. During successive cell changes certain adducts are generated which may bind DNA. Their ability to cause mutations depends on whether a given adduct was generated with a free form or an acetylated amine. Adducts generated with non-acetylated amines are the main cause of mutations, i.e. changes of base in a DNA-coding triplet. Also, an important effect in cancerogenic activity of aromatic hydrocarbons is attributed to recently discovered oncogenes. Changes in oncogene expression may result in proliferations of the cells of the urinary bladder epithelium, which may induce their transformation into neoplastic cells. Diagnostic tests based mainly on cytological studies do not make it possible to detect early changes of the proliferation process in the cells of the urinary bladder epithelium. Only the recently introduced methods using monoclonal antibodies, which facilitate determination of oncogene protein products in organism's fluids, are sensitive indicators of initiating the neoplastic process in the urinary bladder.
Air Pollutants, Occupational↗
[The role of testing DNA adducts and proteins in monitoring cancer risk].
This paper is a review of methods used for determination of adducts of chemicals or their metabolites with DNA of different cells or with blood proteins in humans and animals. Advantages and disadvantages of methods currently used have been discussed. The relationship between adducts formation and genotoxic, mutagenic and carcinogenic properties of chemicals has been shown. An attempt was made to indicate the usefulness of DNA or protein adducts monitoring in humans to detect their exposure to carcinogenic substances and to assess the risk of cancer.
Animals↗
[Life expectancy--the Japanese experience].
The author thinks that the rise in Japanese life expectancy since the end of world war I is due to the increase of fat and animal matter in Japanese diet by American influence. Even the "West" should consider a "paleolithization" of its diet as up to now all "field studies" failed to show a positive effect of a low cholesterol diet on total mortality; this the more the epidemiological relations between fat intake and coronary and cancer mortality can be explained by adaptation to carbohydrates since the neolithic.
Adaptation, Biological↗
[Laboratory diagnosis of renal changes caused by occupational chemical factors].
The problem of early detection of the consequences of toxic action of chemical substances on the kidneys at the working place is becoming one of more important problems in the prophylaxis of renal diseases. The introduction of new sensitive diagnostic methods such as enzyme activity determination or low-molecular-weight proteins measurement in urine has made possible detection of renal damage in the reversible stage. As yet the observations demonstrate that workers exposed in their occupation to heavy metals (cadmium, lead, metalic mercury) and organic solvents should be subjected to special control for detection of renal changes.
Air Pollutants, Occupational↗
Interstitial thermoradiotherapy of brain tumors: preliminary results of a phase I clinical trial.
A Phase I clinical trial has been initiated to determine the feasibility, tolerance, and toxicity of interstitial thermoradiotherapy in the treatment of high-grade supratentorial brain gliomas. Hyperthermia was delivered by means of thermally-regulating ferromagnetic implants afterloaded into stereotactically placed plastic catheters. Heat treatments were given immediately before interstitial irradiation; in addition, five patients received a second heat treatment at the completion of brachytherapy. The desired target temperature for the 60-minute hyperthermia session was between 42 degrees C and 45 degrees C. Following hyperthermia, the catheters were afterloaded with Ir-192, which delivered a variable radiation dose of 14-50 Gy depending on the clinical situation. Interstitial irradiation was supplemented with external beam radiotherapy (40-41.4 Gy) in patients with previously untreated tumors. A total of 14 patients (4 males, 10 females) have been treated to date on this protocol. Eleven of the patients had a diagnosis of glioblastoma multiforme, whereas three had anaplastic astrocytoma. The mean implant volume was 61.5 cm3 (range: 9-119 cm3); the median number of interstitial treatment catheters implanted was 19 (range: 7-33). Continuous temperature monitoring was performed by means of multisensor thermocouple probes inserted in the center as well as in the periphery of the tumor. Of the 175 monitored intratumoral points, 83 (47%) had time-averaged mean temperatures of greater than 42 degrees C, and only 12 sensors (7%) exceeded a temperature of 45 degrees C. Among the 19 heat treatments attempted, there have been four minor acute toxicities, all of which resolved with conservative medical management and one major complication resulting in the demise of a patient. These preliminary results indicate that ferromagnetic implants offer a promising new approach to treating brain tumors with hyperthermia.
Adult↗
Treatment planning of template-guided stereotaxic brain implants.
We have initiated a Phase I clinical trial of interstitial hyperthermia induced with inductively heated ferromagnetic implants in combination with Ir-192 implants for glioblastomas and anaplastic astrocytomas of the brain. For speed and accuracy of the implant procedure, and to control the radiation and thermal dose, a stereotaxic frame is used to position a template. We have modified the Brown-Roberts-Wells frame to be used with a variety of templates which we designed. On the morning of the implant procedure, a CT scan is done, and a CT-based treatment plan is then completed before the patient goes to the operating room. We also describe the CT-based treatment planning system developed to accommodate the template-guided implant and illustrate its clinical use.
Brachytherapy↗
Internalization of vasopressin analogs in kidney and smooth muscle cells: evidence for receptor-mediated endocytosis in cells with V2 or V1 receptors.
To determine whether receptor-mediated endocytosis occurs in vasopressin-responsive cells, we developed a model system using synthetic fluorescent-labeled vasopressin analogs and A10 (smooth muscle) and LLC-PK1 (kidney epithelial) cells in culture; these cell lines express V1 and V2 vasopressin cell surface receptor types, respectively. We used epifluorescence microscopy to examine the binding, internalization, and intracellular destination of [1-(2-mercapto)propionic acid,8-lysine-N6-carboxytetramethylrhodamine] vasopressin (R-MLVP) and [1-(2-mercapto)propionic acid,8-lysine-N6-carboxyfluorescein]vasopressin (F-MLVP) in these cells. The rhodamine-labeled fluorescent vasopressin analog, R-MLVP, initially bound in a diffuse manner at the cell surface of both A10 and LLC-PK1 cells and could be displaced by excess unlabeled [8-arginine]vasopressin. After incubation at 37 degrees C, bound ligand rapidly aggregated into small clusters or patches, which were internalized in a manner consistent with receptor-mediated endocytosis. Subsequent processing of internalized ligand-receptor complexes appeared to differ between A10 and LLC-PK1 cells. In the case of LLC-PK1 cells, ligand was delivered to a tightly focused lysosome compartment in the perinuclear region of the cell, and receptor molecules were replenished at the cell surface. The lysosomal location of ligand was supported by the quenching of fluorescence in the internalized vesicles when F-MLVP was used as a fluorescent tracer. In the case of A10 cells, ligand became localized to a vesicular compartment and reappearance of receptor at the cell surface was limited. Our data are consistent with the occurrence of receptor-mediated endocytosis of vasopressin in cells with V1 and V2 receptors.
Animals↗
The oxidative phenotype as a marker of individual predisposition to neoplasm induced by chemical carcinogens.
The authors present a review of literature showing that the variations in xenobiotic oxidation phenotype, in the presence of cytochromes P-450, may be responsible, to a certain extent, for the varied individual susceptibility to neoplasm induced by chemical carcinogens. The evidence collected revealed that in the human population, one may distinguish individuals with high cytochrome activity and those in whom this reaction is low or even absent.
Biomarkers, Tumor↗
[Biochemical basis of the effect of organophosphate pesticides on humans].
The rapidly increasing use of organophosphorous compounds in everyday life causes that greater attention should be paid to the toxic effect exerted by these compounds on human organism. Acute toxic effects have been relatively well known whereas chronic effects require further studies. It is essential especially in view of progressive pollution of environment. The report presents data on the mechanism of action of organophosphorous compounds on human organism with particular regard to those effects which lead to the so called delayed neuropathy. The occurrence of that phenomenon as a result of single exposure to high concentrations of organophosphorous compounds as well as due to long-term exposure to the relatively low doses of those substances has been discussed.
Acetylcholinesterase↗
[Arteriosclerosis and cancer--fats or carbohydrates?].
The big field studies failed to yield the results expected from the lipid theory of arteriosclerosis. By only lowering the intake of animal fats and cholesterol (MRFIT) the death rate from cardiovascular disease was not significantly decreased whilst the use of strong drugs to lower the cholesterol level (LRC, Helsinki Heart) did not influence total mortality. The carbohydrate theory of arteriosclerosis according to epidemiological studies explains the results on the basis of evolutionary concepts through the different time spans a population had to adapt to the new foodstuff, carbohydrate appearing in the Neolithic Age. Studies on the effect of carbohydrates in humans are proposed.
Arteriosclerosis↗