Biomedical subjects
R E Moore
Publications and source records attributed to R E Moore.
Low doses of T3 induce a rapid metabolic response in young lambs.
Injection of 1 microgram/kg T3 resulted in an increase in metabolic rate (VO2) within an hour of administration to lambs (aged 27 to 180 h). A larger dose of 5 micrograms/kg T3 initially caused a slight inhibition of VO2, which was followed in the second post-injection hour by a significant increase. The increase in VO2 during the second post-injection hour after either 1 microgram/kg or 5 micrograms/kg T3 represented a rise of 22% above pre-injection VO2. The increase persisted and was slightly enhanced during the third post-injection hour. These changes were significantly greater than the smaller changes which followed control injection (P less than 0.005). No significant changes in Tre or Tesk occurred after any treatment. This rapid response to low, physiological doses of T3 emphasises a possible role for thyroid hormones in the short-term control of metabolism in young animals.
Administration of low doses of TSH result in a rapid increase in the metabolic rate of young lambs.
A low dose of TSH (Thyroid Stimulating Hormone) can induce a rapid increase in VO2 and the response is dose dependent. Lambs aged 36 to 289 h were used. 5.0 i.u./kg TSH, the highest dose used, caused an initial inhibition of response but during the second and third post injection hours VO2 increased to control level. The intermediate TSH dose, 1.0 i.u./kg TSH resulted in a clear increase in VO2 even in the first post-injection hour, which further increased in the second and third hours. This change was significantly greater than in controls. Animals treated with the lowest dose, 0.5 i.u./kg TSH divided themselves into 2 distinct populations: responders, where an immediate and significant increase in VO2 occurred and non responders, where a small inhibition of metabolism was evident. The responder group had a significantly lower pre-injection VO2 and a significantly lower mean body weight, than the non responders. In the responders, the stimulation of metabolism was greater than at either of the higher TSH doses. These results indicate that low, but not high doses of TSH induce a rapid metabolic response. The argument in favour of a short-term role for thyroid hormones is thus strengthened.
Chemistry of fluorocarbons in biomedical use.
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Potential application of perfluorochemicals in cancer therapy.
PFC emulsions, because of their excellent oxygen-transporting properties and possibly other properties as well, have broad and promising potential in cancer therapy. Although this potential is readily apparent to both laboratory and clinical investigators who are concerned with tumor hypoxia, it should be equally apparent that the formulations that are currently available are wholly inappropriate for such an application. The sublethal toxicities of these emulsions may appear to indicate a poor prognosis for this approach, but they may be a blessing in disguise. All known approaches to tumor hypoxia are limited by our inability to administer enough of the agents to be effective. In many cases, the limiting factor was not uncovered until the approach had been introduced into clinical trials. Had we relied on such parameters as lethality in the case of PFC emulsions, the same mistake might have been made here. Instead, the death of a single rat has caused us to focus our attention on what would surely have produced major problems in the initial clinical trials. Recognition of the sublethal toxic effects of PFC emulsions at this early stage should allow us to optimize our formulations at the preclinical stage, thereby increasing the likelihood that PFC emulsions will someday live up to their full potential.
Induced secretion of a Mr 46,000 protein by cultured human hepatoma cells treated with tumor promoters.
Human hepatoma cells, HuH-6 Cl-5, were treated with 12-O-tetradecanoylphorbol-13-acetate at concentrations of 1 ng/ml to 10 micrograms/ml for 6 h in the presence of [35S]methionine. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the labeled proteins secreted into the medium showed that this treatment induced marked secretion of a polypeptide with a molecular weight of about 46,000 (p46). When the labeled proteins were analyzed by two-dimensional polyacrylamide gel electrophoresis, p46 was composed of three isoproteins which had different isoelectric points. The two new classes of tumor promoters, teleocidin and aplysiatoxin, also induced secretion of this protein, although the amount of p46 induced by debromoaplysiatoxin was less than that induced by 12-O-tetradecanoylphorbol-13-acetate, teleocidin, and aplysiatoxin, judging from densitometric scanning of bands on a fluorogram. The nonpromoting phorbol esters, such as 4 beta-phorbol and phorbol-13-monoacetate, did not induce p46. The induction of p46 secretion involved de novo RNA synthesis, since actinomycin D (1 microgram/ml) completely and selectively blocked the incorporation of [35S]-methionine into the protein. "Pulse-chase" experiments indicated that p46 was not a degradation product induced by these potent tumor promoters. In an attempt to identify p46, the total proteins released were treated with two kinds of rabbit anti-human whole serum antisera, but although some proteins were precipitated, p46 was not.
Normal childhood and early adolescent sexuality. A psychologist's perspective.
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A blue-green alga from Okinawa contains aplysiatoxins, the third class of tumor promoters.
The causative agents of swimmer's itch were isolated from the marine blue-green alga, Lyngbya majuscula, which grows off the coast of the Okinawa islands, Japan. Nuclear magnetic resonance and mass spectral studies revealed that these agents were identical with aplysiatoxin and debromoaplysiatoxin, which were previously shown to be the causative agents of swimmer's itch in Hawaii. Aplysiatoxin and debromoaplysiatoxin were recently found to be potent tumor promoters in two-stage carcinogenesis in mouse skin. This is the first report that humans are directly affected by these potent environmental tumor promoters in Japan.
Evidence that cyclosporine-incubated platelets retain function and release cyclosporine.
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A two-stage mouse skin carcinogenesis study of lyngbyatoxin A.
A strong skin irritant, lyngbyatoxin A, isolated from the marine blue-green alga Lyngbya majuscula is structurally related to teleocidin. Since lyngbyatoxin A satisfied our short-term screening tests for possible tumor promoters, viz. irritation of mouse ear, induction of ornithine decarboxylase (ODC) in mouse skin, and adhesion of human promyelocytic leukemia cells (HL-60), a two-stage carcinogenesis experiment was carried out. Tumor incidences in the groups treated with 7,12-dimethylbenz(a)anthracene (DMBA) plus lyngbyatoxin A and with DMBA plus 12-O-tetradecanoylphorbol-13-acetate (TPA) were 86.7% and 93.3% in week 30, respectively. The average number of tumors per mouse was 3.7 in the former group and 10.5 in the latter group. This paper reports for the first time the potent tumor-promoting activity of lyngbyatoxin A and also the histological examination of tumors.
Perfluorocarbon emulsions in cancer therapy: preliminary observations on presently available formulations.
Perfluorocarbon (PFC) emulsions, due to their favorable oxygen transporting properties, have been proposed as tumor sensitizers for application in both radiotherapy and chemotherapy. While this application is a very promising one it is by no means simple, and presently available formulations are inadequate. Intravenous administration of these emulsions can produce a severe hemodilution which tends to offset the desired effect; these emulsions can alter the pharmacokinetics of simultaneously administered drugs. Unless these variables are taken into account the risk of false negative and false positive results will be excessive. Of more serious concern are the profound disturbances produced by these emulsions in the reticuloendothelial system. Using two of the more popular PFC, Fluosol-DA and DMA/NONANE, we have shown that daily administration of these emulsions can produce 9-fold increases in liver size and 27-fold increases in spleen size. This problem appears to involve the surfactant used in both emulsions, pluronic F-68. It will be necessary to circumvent this problem before further study of their potential application can proceed.
Estimation of tumor promoting activity and structure-function relationships of aplysiatoxins.
Twelve aplysiatoxin compounds have been evaluated as possible tumor promoters in vivo by means of three biological tests: viz. irritation of mouse ear, induction of ornithine decarboxylase in dorsal skin of mice, and inhibition of specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to an epidermal particulate fraction. The potencies of these three biological activities correlate well for each derivative. Bromoaplysiatoxin shows biological activities that are similar to those of the strong tumor promoter, aplysiatoxin. The present studies suggest that the C-3, C-20 and C-30 hydroxyl groups of the aplysiatoxins are involved in binding to the specific receptor of TPA.
Auditory-evoked response in the clinically normal dog: early latency components.
Early latency components (0 to 10 ms) of the auditory-evoked response, which is also called the brainstem auditory-evoked response (BAER), were recorded in 6 clinically normal adult dogs. Each dog responded to suprathreshold monaural clicks with a highly repeatable averaged waveform configuration consisting of 6 to 7 vertex positive waves. Configuration of the canine BAER consisted mainly of waves I, II, III, V, and VI. Wave IV was present in some records, but in most cases, it formed a complex with wave III and was not apparent as a separate wave. After a 90-dB hearing level (HL) stimulus (20/s), the positive peak of wave I in the averaged response appeared at approximately 1 ms after stimulation onset, and subsequent waves were spaced at approximately less than or equal to 1-ms intervals. Amplitudes of these waves were 4.0 microV when measured from positive peak to the following negative trough. Experiments were conducted to determine the effects of varying stimulus intensity (50- to 90-dB HL) on BAER wave amplitude and peak latency in nonanesthetized and anesthetized dogs and to determine the effects of increasing stimulus rate (10 to 50/s) in nonanesthetized dogs. As stimulus intensity was increased in 10-dB steps from 50 to 90 dB and as the stimulus rate remained at 20/s, amplitude increased and latency decreased for all waves (P less than 0.01). When stimulus intensity was held constant at 90 dB and stimulus rate increased from 5 to 50/s, amplitude decreased and latency increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Auditory-evoked response in the clinically normal dog: middle latency components.
The middle latency components (6 to 60 ms) of the auditory-evoked response were recorded in clinically normal mature dogs (n = 15 mixed breed). To record the middle latency response (MLR), a series of suprathreshold auditory clicks was presented monaurally to nonanesthetized and anesthetized dogs at a stimulus rate of 5/s. To determine effects of stimulus intensity on wave amplitude and latency in nonanesthetized dogs, clicks were presented at 90-, 70-, and 50-dB hearing level. Filtered electroencephalic activity during the first 100 ms after each click was recorded and averaged digitally for 1,024 consecutive stimuli. The response pattern in the nonanesthetized dog was a repeatable polyphasic configuration characterized by 3 to 4 major waves. Peaks of the waves were labeled, using a method developed in human beings. Mean latency ranges for the positive (P) or negative (N) peaks that comprised the waves across intensity levels were 7.43 to 7.77 ms (No), 11.07 to 11.57 ms (Po), 13.62 to 14.20 ms (Na), 20.04 to 20.68 (Pa), 39.08 to 39.37 ms (Nb), and 54.25 to 55.21 ms (Pb). The only variations in waveform morphologic features were the additional wave formed by peaks Nx (24.80 to 25.94 ms) and Px (30.0 to 30.62 ms), which occurred in 44% of the records, and the missing wave formed by No and Po in 6.6% of the records. Varying the stimulus intensity had no effect (P less than 0.05) on wave amplitude or latency.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of specific binding of [3H]phorbol-12,13-dipropionate to an epidermal fraction by certain irritants and irritant promoters of mouse skin.
Specific binding of [3H]phorbol-12,13-dipropionate ([3H]PDPr) to a particulate fraction of mouse skin is demonstrated (KD = 35 nM; Rt = 1.2 pmol/mg protein). A series of compounds of the diterpene ester, indole akaloid and polyacetate types with different degrees of activity as skin tumor promoters and/or irritants have been tested for their capacity to inhibit specific [3H]PDPr binding. Three main categories are found: (i) compounds which exhibit a positive correlation between their potency as irritants and promoters in vivo and their inhibition of specific binding in vitro: 12-O-tetradecanoylphorbol-13-acetate, 3-O-tetradecanoylingenol, pimelea factor P2, 'teleocidin', dihydroteleocidin B, and lyngbyatoxin are active in vivo and in vitro, whereas phorbol and ingenol are inactive and 4-O-methyl-12-O-tetradecanoyl-phorbol-13-acetate is weakly active; (ii) compounds which are strong irritants and inhibitors of binding but are weak or practically non-promoters: mezerein, 12-O-retinoylphorbol-13-acetate and milliamine C; (iii) strong irritants which are weak or marginally active inhibitors of binding: debromoaplysiatoxin and resiniferatoxin. Some consequences of these findings with respect to interpretations of the biochemical mechanism(s) of tumor promotion are discussed.
New classes of environmental tumor promoters: indole alkaloids and polyacetates.
Tumor promoters are known to induce ODC activity in mouse skin and that this induction can be inhibited by the application of 13-cis-retinoic acid. These two properties of tumor promoters were utilized for screening new tumor promoters in our environment. Two new classes of tumor promoters are presented: indole alkaloids (teleocidin and lyngbyatoxin A) and polyacetates (aplysiatoxin and debromoaplysiatoxin). Teleocidin from streptomyces and lyngbyatoxin A, from the blue-green alga, Lyngbya majuscula, were able to induce ODC activity in mouse skin and showed various biological activities similar to those of TPA. Teleocidin and lyngbyatoxin A are indole alkaloids. Their tumor promoting activities became apparent in the mouse skin through a two-stage carcinogenicity test. The tumor incidence of the group treated with DMBA plus teleocidin was 100% at week 30, which was similar to that of the group given DMBA and TPA. The in vivo carcinogenicity test with lyngbyatoxin A is still underway. The tumor incidence of the group treated with DMBA plus lyngbyatoxin A is 80% at week 21. A second new class of tumor promoter is polyacetate. Aplysiatoxin and debromoaplysiatoxin were isolated from another variety of blue-green alga. Aplysiatoxin and debromoaplysiatoxin induce ODC to the same degree of potency. However, aplysiatoxin induced various membrane effects, such as adhesion of cells and turnover of phospholipid with a similar concentration of TPA, teleocidin and lyngbyatoxin A. On the other hand, debromoaplysiatoxin required an amount almost 100 times greater to achieve the same effects. We are convinced of the possibility that various classes of tumor promoters exist in our environment.
Nakahara memorial lecture. New classes of tumor promoters: teleocidin, aplysiatoxin, and palytoxin.
Teleocidin and aplysiatoxin, which are structurally different from 12-O-tetradecanoylphorbol-13-acetate (TPA), were found to be potent tumor promoters in two-step mouse skin carcinogenesis. The class of teleocidin includes dihydroteleocidin B, teleocidin, and lyngbyatoxin A. Teleocidin, which is a mixture of 93% teleocidin A and 7% teleocidin B, was isolated from Streptomyces mediocidicus as a strong skin irritant. Teleocidin A consists of C-14S-teleocidin A and C-14R-teleocidin A. One teleocidin A-isomer corresponds to lyngbyatoxin A, which was isolated from the blue-green alga, Lyngbya majuscula. Teleocidin B has four isomers, C-14, C-17-diastereomers. The two teleocidin A-isomers and three of the teleocidin B-isomers (all but one, which was obtained in too low yield) were shown to be biologically active and also potent tumor promoters. Synthetic analogues (indolactams) of teleocidin were obtained and their structure-activity relations were examined by several biological tests. The finding that only (-)-indolactam-V was active showed that the S, S configuration of native teleocidin was necessary for expression of the activity. The class of aplysiatoxin, which was isolated from the blue-green alga, L. majuscula, includes debromoaplysiatoxin, aplysiatoxin, bromoaplysiatoxin, and oscillatoxin A (nordebromoaplysiatoxin). The former three were potent tumor promoters, while oscillatoxin A was a moderate one. Dibromoaplysiatoxin, which is a chemically brominated derivative of debromoaplysiatoxin, in addition to aplysiatoxin and bromoaplysiatoxin, possessed the same promoting activity as that of oscillatoxin A.(ABSTRACT TRUNCATED AT 250 WORDS)
Structure-activity studies of aplysiatoxin-type tumor promoters.
The cellular activities and responses of aplysiatoxin in vitro and in vivo are very similar to those of the diterpene 12-O-tetradecanoylphorbol-13-acetate (TPA) and the indole aklaloids teleocidin B and lyngbyatoxin A. Even though aplysiatoxin, TPA, and teleocidin B are chemically and structurally quite distinct from one another, all three compounds produce essentially the same plethora of biological effects by apparently binding to the same receptor on the cell membrane, the so-called phorboid receptor. Several aplysiatoxin-type compounds have been studied in three test systems for evaluating potential tumor-promoting activity, viz. mouse ear skin for irritation, murine dorsal skin for the induction of ornithine decarboxylase (ODC) activity, and an epidermal particulate fraction of dorsal mouse skin for the inhibition of specific binding of [3H]-TPA. Some of the compounds were tested in a 30-week two-step carcinogenesis experiment in mice. In most cases the results of the 30-week test correlated with the activities of the three preliminary tests. The overall study indicated that the hydroxyl groups on C-3, C-20, and C-30 are essential for maximum activity. Inspection of Dreiding models showed that the oxygens on C-27, C-3, and C-30 of aplysiatoxin are aligned with the oxygens on C-3, C-4, and C-20 of TPA, respectively. The latter oxygens are in functional groups that are known to be necessary for the high activity of TPA.