Search PubMed⌕ Search

Biomedical subjects

C J Conti

Publications and source records attributed to C J Conti.

At least 145 records · Page 8Linked to original sources
PubMed1986

Effects of chronic topical application of 12-O-tetradecanoylphorbol-13-acetate on the skin and internal organs of SENCAR mice.

Repetitive topical applications of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 37 to 52 weeks induced a sustained epidermal hyperplasia, hyperplasia of hair follicles, and increased dermal cellularity in SENCAR mice. In addition, after 52 weeks of protracted promoter treatment most animals developed generalized amyloidosis involving liver and spleen, as well as interstitial nephritis. Severe pyelonephritis and papillary necrosis were also frequently seen. Reactive lymphoid hyperplasia was also a frequent finding. Chronic administration of TPA is not an innocuous treatment affecting only the interfollicular epidermis. The general effect of the promoter on the animals was a marked decrease in their longevity, probably through impairment of the immune system.

Administration, Topical↗
PubMed1986

Critical genetic determinants and molecular events in multistage skin carcinogenesis.

Carcinogenesis can be operationally and mechanistically divided into at least three major stages--initiation, promotion, and progression. Variations among stocks and strains of mice to susceptibility to multistage skin and liver carcinogenesis appear to be more related to alterations in tumor promotion than tumor initiation; however, the critical events have not been determined. In the mouse skin model the first stage is thought to involve the interaction of a tumor initiator with the genetic material of stem cells leading to an alteration in some aspect of growth control, differentiation, or both. The major effect of tumor promoters, regardless of the type, is the specific expansion of the initiated stem cells in the skin. This appears to occur by both direct and indirect mechanisms that involve the loss of glucocorticoid receptors, differentiation alterations, a direct growth stimulation of the initiated cells, or selective cytotoxicity. The progression stage is characterized by a high level of genetic instability that produces a number of chromosomal alterations. These changes may be responsible for the loss of the high-molecular-weight keratin proteins and filaggrin, increase in gamma-glutamyl-transpeptidase activity, and changes in oncogene expression in squamous cell carcinomas. We have found that a high percentage of squamous cell carcinomas have a trisomy in chromosome 2 that carries both src and abl genes and an increased expression of src and abl. We have also found increased Ha-ras on RNA expression in both papillomas and squamous cell carcinomas. We suggest that the genetic instability of the initiated cells is responsible for most observed changes during skin carcinogenesis.

Animals↗
PubMed1986

Rapid detection of xenotransplanted human tissues using in situ hybridization.

A rapid and sensitive method for the identification of human tissues xenotransplanted in nude mice was developed. An in situ hybridization technique made it possible to distinguish between cells of human origin and cells of murine origin in formalin-fixed paraffin sections. High-molecular-weight DNAs extracted from human or mouse tissues were sonicated, nick-translated with 32P-dCTP, and used as hybridization probes. Dot blot hybridization of 32P-labeled probes revealed clear species-specific signals. Formalin-fixed paraffin-embedded tissue samples from repopulated tracheal transplants, containing either human tracheal epithelial cells or human renal tubular cells, were used. Cells of human and murine origin were distinguishable by in situ hybridization with sonicated DNA probes. This method has several advantages; simple preparation of probes, high sensitivity, and applicability to formalin-fixed paraffin-embedded tissue sections. In situ hybridization with sonicated DNA probes should provide a powerful tool for verifying the human origin of xenotransplanted tissues in nude mice.

Animals↗
PubMed1986

Cytogenetic evidence for gene amplification in mouse skin carcinogenesis.

Using our recently developed methodology for cytogenetic evaluation of solid tumors, we analyzed the occurrence of double minutes (DM) in chemically induced mouse skin carcinomas and papillomas. These studies revealed that DM were observed in 10% of the squamous cell carcinomas and in none of the papillomas screened. In addition, we analyzed four cell lines derived from mouse skin papillomas and one spontaneously transformed mouse epidermal cell line. The presence of DM was a consistent feature in all the studied cell lines. In the papilloma cell lines, the degree that DM occurred correlated with the cell line's capacity to form malignant tumors in immunosuppressed mice. DM were also observed in direct chromosomal preparations from tumors induced by one of the papilloma cell lines. Homogeneously staining regions were also present in metaphases from the spontaneously transformed cell line. We have shown here, for the first time, DM and homogeneously staining regions in mouse skin tumors and transformed cells derived from mouse skin. Since DM and homogeneously staining regions are the cytogenetic equivalents of gene amplification, which is a mechanism of increased expression of normal or altered gene products, these findings may play a relevant role in mouse epidermal carcinogenesis.

Animals↗
PubMed1985

Survival curves and incidence of neoplastic and non-neoplastic disease in SENCAR mice.

The survival curves and the incidence of spontaneous diseases were studied in a population of SENCAR mice, a stock derived by a selected breeding protocol for enhanced susceptibility to chemical carcinogenesis in the skin. SENCAR mice proved to be as long-lived as other mouse strains or stocks, including one of their parental lines, Charles River CD-1. The most frequently occurring neoplasias in SENCAR mice were lymphoma, myeloid leukemia and reticulum cell sarcoma. Other frequently occurring neoplastic diseases included lung adenomas and carcinoma and mammary gland carcinoma. However, the incidence of these tumors was not higher than the incidence in CD-1 mice or other mouse strains or stocks. A variety of non-neoplastic diseases, both inflammatory and degenerative, were also observed in old mice. The most common were liver, spleen and kidney amyloidosis, pyelonephritis and papillary necrosis. These data indicate that selective breeding for susceptibility to chemical carcinogenesis has not produced a concomitant increase in the incidence of spontaneous neoplastic and non-neoplastic disease.

Animals↗
PubMed1985

Cutaneous changes during prolonged application of 12-O-tetradecanoylphorbol-13-acetate on mouse skin and residual effects after cessation of treatment.

The epidermal and dermal effects of protracted 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment (2 micrograms TPA twice weekly) of Sencar mouse skin were studied using cell kinetics and morphometric techniques. In addition, regression of TPA-induced changes was evaluated after cessation of 56 topical applications. During the first week of treatment a reactional hyperplasia, characterized by cell damage, edema, and acute inflammation in both epidermis and dermis, occurred. This picture changed gradually during the following 3 weeks: an epidermal hyperplasia devoid of involutional or inflammatory features was accompanied by a moderate to mild chronic inflammation of the dermis and a hyperplasia of the hair follicles. This remained throughout the experimental period until the topical TPA treatment ceased. Although TPA induced papillomas in only 5% of the animals (maximum = 2 papillomas/animal and no carcinomas), all sustained marked epidermal hyperplasia of approximately 4 to 5 times the normal thickness, and increased the number and volume of hair follicles. The [3H]thymidine pulse-labeling index of the basal layer was approximately 32% (normal congruent to 6%). The level of dark keratinocytes remained constant; i.e., 8% of the basal cells were identified as dark cells during the entire experiment. At the subepidermal level the dermal thickness and total cellularity increased, although the proportion of the different cell types changed during the treatment. The mast cell population increased remarkably. After TPA treatment ceased, most of these parameters regressed abruptly during the first 2 weeks. Two to 4 months later, the epidermis was slightly thinner, and the labeling index was 50% lower than normal (2.8%). This study shows that prolonged repetitive TPA applications induced a steady-state hyperplasia without tachyphylaxis, and that this alteration regressed rapidly after treatment ceased. In addition, labeling-index values lower than normal were reached soon after normalization, suggesting that a possible selection of keratinocytes, dependent on TPA for proliferation, took place during the chronic administration of topical TPA. The number of hair follicle, capillary vessels, mast cells, and the dermal thickness never reached normal values after treatment. These important changes in the dermis and hair follicles indicate that the target cells for tumor promoters are not confined to the epidermis alone, and that these tissues could participate actively in carcinogenesis directly, either as tumor-originating tissues (hair follicles), or as inducers or helpers of neoplastic growth (connective tissue cells).

Animals↗
PubMed1985

Immunohistochemical detection of filaggrin in preneoplastic and neoplastic lesions of the human oral mucosa.

The distribution pattern of filaggrin in lesions of human oral mucosa was studied with the use of an anti-filaggrin serum raised in rabbits. A peroxidase-antiperoxidase method for the detection of filaggrin was applied to specimens from 9 cases of leukoplakia, 5 cases of verrucous carcinomas, 2 cases of carcinoma in situ, and 5 cases of invasive carcinoma. Areas of normal mucosa with different stages of keratinization were available in the same biopsy specimens. The granular layer of normal orthokeratinized epithelium was positive, whereas the horny layer was negative. Parakeratinized and nonkeratinized epithelia stained less than orthokeratinized epithelium. In leukoplakia and verrucous carcinoma, the reaction was irregular both in the granular and the cornified layers. Carcinoma in situ had a virtually negative reaction, and invasive carcinoma exhibited a slight positive reaction in the more differentiated areas. The immunohistochemical demonstration of altered filaggrin patterns in oral lesions correlates well with the degree of epithelial dysplasia and could be a helpful tool in grading white lesions and neoplasms of the oral mucosa.

Epithelium↗
PubMed1984

Keratinocyte damage produced by 12-O-tetradecanoylphorbol-13-acetate in rodent epidermis.

Cell damage produced by 12-O-tetradecanoylphorbol-13-acetate (TPA) was evaluated in keratinocyte suspensions obtained from TPA treated mouse epidermis using a dye-exclusion technique, and in tissue sections studied by light microscopy and quantitative enzyme histochemistry. TPA induced a maximum of approximately 25% of trypan blue stained basal keratinocytes using topical doses of 2, 20 and 200 micrograms. With the first two doses this effect was detectable at 12-24 h and disappeared 48-96 h after TPA treatment, whereas with 200 micrograms TPA the cell damage persisted for a longer time. Oxidative enzyme changes were moderate, and no changes in acid phosphatase levels could be detected. The facts that no signs of cell necrosis could be seen in tissue sections from epidermis treated with 2 and 20 micrograms TPA; that only a moderate change in oxidative enzyme pattern, without statistically significant variations in succinic dehydrogenase and cytochrome oxidase, could be detected, and that no shift of the damaged basal keratinocytes into the suprabasal compartment was evident, are indicative of moderate, probably sublethal damage induced by TPA. Although eventually committed to terminal differentiation, the epidermal cells do not show the cytologic and metabolic features of lethally damaged cells, suggesting that the membrane damage detected by the dye exclusion technique may be sublethal. Thus, it is possible that TPA can induce a reactive or regenerative type of epidermal hyperplasia without the prerequisite of extensive keratinocyte necrosis.

Animals↗
PubMed1984

Estrogen and progesterone regulation of proliferation, migration, and loss in different target cells of rabbit uterine epithelium.

We have explored the possibility that estrogens and progesterone could have different target uterine cell populations according to their cell cycle stage and localization in glands vs. lumen. Experiments were carried out in which rabbits were injected with [3H]thymidine for 3 days to label nuclei of dividing cells, then either 17 beta-estradiol, progesterone, or vehicle were administered. 17 beta-Estradiol induced a decrease in the percentage of cells with labeled nuclei or labeling index of either luminal or glandular epithelium. Since this steroid has been shown to have a significant proliferative effect on glands, the data suggest that its effect is exerted on unlabeled quiescent cells, which are then recruited into the cell cycle. Progesterone, on the other hand, was found to induce a significant increase in labeling index of both luminal and glandular epithelium. Therefore, it is concluded that dividing cells are a target for this hormone. Analysis of the number of nuclear grains according to cell location in luminal vs. glandular epithelia and the effect of hormone administration confirmed that each ovarian hormone acts on different target cell populations. Short and long term administration of estrogens resulted in a larger internal circumference of the uterus due to an increase in the number of luminal cells, whereas the number of glands and glandular cells per section did not appear to change. These findings, in combination with previous research, suggest that endometrial gland cells migrate towards the lumen and estrogen administration decreases the rate of cell loss in the luminal epithelium. The concept of cell migration is supported by experiments in which single administration of [3H]thymidine to rabbits was followed by determination at different times of the geographical distribution of cells with labeled nuclei. There was observed, as a function of time, a decrease in the number of labeled cells in the bottom of the glands with a concomitant increase in the same parameter in the upper part of the glands and luminal epithelia. Estradiol administration changed these kinetics.

Animals↗