Mass in the infratemporal fossa.
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Ameloblastoma↗
Biomedical subjects
G T Gallagher
Publications and source records attributed to G T Gallagher.
Depletion of eosinophil infiltration by anti-IL-5 monoclonal antibody (TRFK-5) accelerates open skin wound epithelial closure.
Wound healing is critical to the survival of the species after injury. Using hamsters as an experimental model, we have shown that eosinophils infiltrate prominently into skin wounds and that they express transforming growth factor-alpha and -beta 1 mRNAs and proteins. We hypothesized that eosinophils are important in wound healing. As no animal model is genetically deficient in eosinophils, a suitable way to test the hypothesis is to selectively reduce and/or deplete the influx of eosinophils into the wound sites. In this study, we report that anti-interleukin-5 monoclonal antibody (TRFK-5) treatment can deplete eosinophils in cutaneous healing wounds. We found that wound closure by re-epithelialization in the experimental group was 4 days faster than in the control group (P < 0.01). The density of eosinophils in day-9 wounds was significantly lower in the experimental group (P < 0.01). Wound-associated eosinophils in each of the TRFK-5-treated hamsters were depleted to the level comparable to unwounded hamster skin. These results demonstrate that anti-interleukin-5 monoclonal antibody treatment can effectively decrease eosinophil infiltration into hamster cutaneous healing wounds and indicate a role for eosinophils in negatively affecting wound re-epithelialization.
Animals↗
Lack of TGF-alpha and TGF-beta 1 synthesis by human eosinophils in chronic oral ulcers.
We recently demonstrated that eosinophils infiltrate prominently into cutaneous wounds in the Syrian hamster and represent a source of transforming growth factor-alpha and transforming growth factor-beta. In this study, we assessed the role of the eosinophil and eosinophil-derived transforming growth factors in human oral ulcers that exhibit delayed healing, descriptively termed traumatic ulcerative granuloma with stromal eosinophilia. Our aim was to determine whether eosinophils, which characteristically infiltrate traumatic ulcerative granuloma with stromal eosinophilia lesions, produced transforming growth factor-alpha or transforming growth factor-beta. Twelve cases of traumatic ulcerative granuloma with stromal eosinophilia were examined for transforming growth factor-alpha and transforming growth factor-beta mRNA and cellular protein by in situ hybridization and immunohistochemistry. Eosinophils in 92% of the cases did not express detectable cellular levels of mRNA for either of the transforming growth factors. In addition, only a small percentage of the many eosinophils infiltrating these lesions produced transforming growth factor-alpha or transforming growth factor-beta. The lack of significant synthesis of transforming growth factors by eosinophils in most of the cases of traumatic ulcerative granuloma with stromal eosinophilia is in striking contrast to the expression of transforming growth factors by the eosinophils that infiltrate the animal wound-healing model. Our findings may help to explain the delayed healing that is typical of TUGSE lesions.
Adult↗
Salivary EGF regulates eosinophil-derived TGF-alpha expression in hamster oral wounds.
Using hamster as an oral wound healing model, we examined eosinophils and their expression of transforming growth factor-alpha (TGF-alpha) and transforming growth factor-beta 1 (TGF-beta 1). Oral wounds healed approximately two times faster than their cutaneous counterparts. Eosinophils infiltrated prominently into oral wounds; however, unlike the dual expression of TGF-alpha and TGF-beta 1 in skin wounds, oral wound-associated eosinophils expressed TGF-beta 1, but not TGF-alpha. Because saliva is present in oral environments and contains epidermal growth factor (EGF) and TGF-alpha, sialoadenectomy was performed in this model to determine whether the lack of TGF-alpha expression by eosinophils in oral wounds is due to the presence of salivary EGF and/or TGF-alpha. We found that eosinophils in sialoadenectomized hamsters did express TGF-alpha during oral wound healing but that such expression was suppressed when EGF was added to their drinking water. Taken together, our findings suggest that eosinophil-derived TGF-alpha and salivary TGF-alpha/ EGF may have complementary roles in contributing to TGF-alpha in oral wound healing.
Animals↗
Maxillary odontogenic carcinoma with distant metastasis to axillary skin, brain, and lung: case report.
We present a case of odontogenic carcinoma with ghost-cell keratinization of the right maxilla, with a history of 23 years after initial treatment. Within this period, multiple local recurrence, as well as metastasis to axilla, brain, and lung, was noted. Several attempts at resection of the primary lesion were unsuccessful at achieving local control, even when supplemented with chemotherapy and radiotherapy. Metastatic tumors were studied histologically, and their morphology coincided with that of the primary tumor. The medical history of the patient and pathologic findings of the tumor are reviewed.
Axilla↗
Identification of rabbit eosinophils and heterophils in cutaneous healing wounds.
The study of wound healing has traditionally used the rabbit as an experimental model. We have recently localized the production of the multifunctional cytokine, TGF-alpha, to eosinophils in rabbit skin wounds. It was evident that during the process of TGF-alpha localization, the distinction between the two granulocytic cell types, eosinophils and heterophils, was impossible by conventional histochemical techniques. This paper describes a rapid method to distinguish these two granulocytes by virtue of their endogenous peroxidases and differential resistance to blockade by inhibitors. In sections that have been blocked by hydrogen peroxide, the peroxidase substrate 3,3'-diaminobenzidine, together with nickel chloride (DAB-Ni), preferentially stained the cytoplasm of rabbit eosinophils while sparing those of heterophils. This selective DAB staining of rabbit eosinophil peroxidase in H2O2-blocked rabbit wounds was verified at the ultrastructural level by electron microscopy. We applied this technique to quantify eosinophil and heterophil infiltration into the 21-day rabbit cutaneous healing wound model. Heterophils were found infiltrated into all three layers of the wound (clot > granulation > base), but eventually all disappeared by day 21. As with the heterophils, eosinophils which had infiltrated into the clot and base of the wound had disappeared by day 21. Unlike the heterophils, eosinophils in the granulation layer of the wound continued to increase up to day 21. The continually increased and sustained presence of the eosinophils together with their demonstrated production of TGF-alpha, in the granulation layer of the healing would suggests that these cells play an important role in the organizational aspects of healing wounds.
3,3'-Diaminobenzidine↗
Eosinophils, tissue eosinophilia, and eosinophil-derived transforming growth factor alpha in hamster oral carcinogenesis.
Eosinophilia in tissues and/or circulating blood is known to be associated with a wide variety of malignancies but the role of the eosinophil in neoplastic conditions is not known. Using the cheek pouch of the Syrian hamster as an experimental model for oral carcinogenesis, it has recently been shown that eosinophils at sites of developing oral cancer express the multifunctional cytokine, transforming growth factor alpha (TGF-alpha). This study investigated the time course of eosinophil infiltration, tissue eosinophilia associated with malignant epithelium, and eosinophil-derived TGF-alpha mRNA during the 16-week 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral cancer development process. The results reveal that the occasional eosinophil is normally present in the lamina propria of hamster oral mucosa. With progressive DMBA treatments, there is an increase of eosinophils infiltrating into the lamina propria. By weeks 12-16, the number of eosinophils is significantly higher in DMBA-treated pouches than in control pouches treated with the vehicle mineral oil alone. Analysis of the infiltrating eosinophils into fully developed hamster oral carcinomas reveals that tissue eosinophilia is associated with 78% of the stromal areas associated with malignant epithelium, while only 7% of sites associated with non-tumor oral epithelium (normal, hyperplastic-dysplastic) exhibited eosinophilia. Furthermore, the majority of the eosinophils associated with malignant epithelium were found to contain TGF-alpha mRNA. The number of TGF-alpha mRNAs containing eosinophils associated with malignant oral epithelium is significantly higher than that associated with nonmalignant oral epithelium. Together, these results suggest that eosinophils are recruited to tumor-developing sites, that they predominantly associate with malignant epithelium, and that most tumor-associated eosinophils express the cytokine TGF-alpha.
9,10-Dimethyl-1,2-benzanthracene↗
Cellular sources of transforming growth factor-alpha in human oral cancer.
Aberrant expression of TGF-alpha is associated with human malignant oral epithelium. Experiments were initiated to determine the cellular sources of transforming growth factor-alpha (TGF-alpha) in human oral cancer. Ten freshly resected human oral cancers and four specimens of normal human oral epithelium were studied by in situ hybridization and immunohistochemistry. Tissues were probed with 35S-labeled sense and antisense riboprobes to (i) human TGF-alpha (hTGF-alpha), (ii) human epidermal growth factor receptor (EGFR) to determine the distribution of TGF-alpha responsive cells, and (iii) histone H3 to examine TGF-alpha and/or EGFR's possible contribution to altered proliferation in transformed epithelium. Results of our experiments showed that TGF-alpha mRNA could be detected in normal and transformed human oral epithelium. More surprising, we have identified the major source of TGF-alpha mRNA to be the infiltrating eosinophils. A monoclonal antibody to the mature human TGF-alpha peptide stained similar areas in normal and malignant specimens. Eosinophils associated with tumors exhibited positive cytoplasmic immunostaining for TGF-alpha protein. Labeling of EGFR mRNA in human oral epithelium demonstrated uniform labeling of basal layers in normal, hyperplastic, and mildly dysplastic epithelium. In severely dysplastic epithelium and carcinomas (particularly moderate to poorly differentiated types), cellular levels of EGFR mRNA were significantly higher. The profile of altered cellular levels of EGFR mRNA correlated well with the profile of altered proliferation as indicated by H3 mRNA labeling. We hypothesize that the overproduction of EGFR mRNA in tumor epithelium--together with the localized delivery of high amounts of TGF-alpha by eosinophils at tumor-developing sites--is responsible for the increased proliferation of the tumor epithelium.
Antibodies, Monoclonal↗
Localization of transforming growth factor-alpha in adult Syrian hamster tissues.
Using the cheek pouch of the Syrian hamster as an experimental model for oral carcinogenesis, it has been shown that the expression of transforming growth factor-alpha (TGF-alpha) is consistently associated with the malignant transformation process. We have recently shown that production of TGF-alpha has been localized to normal hamster oral epithelium and bone marrow eosinophils. In this study we investigated the production of this cytokine in other normal hamster adult tissues. By using an EGF-radioreceptor assay, immunohistochemistry, Northern blot analysis, and in situ hybridization we have now further detected the presence of TGF-alpha mRNA and/or protein in the kidney, stomach, and pancreas of normal adult hamster. Together with the previously reported detection of TGF-alpha in oral mucosa and bone marrow eosinophils, these adult normal tissue/cellular sources can serve as sites of TGF-alpha production. The availability of hamster specific reagents (cDNA and monoclonal antibodies) and the delineation of the various adult tissues that could produce TGF-alpha make the Syrian hamster a suitable model for the study of how this multifunctional cytokine can influence normal and pathological processes.
Animals↗
Oral mucous membrane reactions to drugs and chemicals.
This article reviews recent reports of interest to practitioners concerned with the damaging effects of drugs and exogenous substances on the oral mucosa. Major topics include the incidence of the use of dentally important drugs in selected populations, lichenoid reactions in oral mucosa, diagnosis and management of mucositis related to cancer therapy, and issues relating to the diagnosis of oral foreign body reactions.
Anticonvulsants↗
The eosinophil as a cellular source of transforming growth factor alpha in healing cutaneous wounds.
Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are known to promote the healing of epithelial wounds. Eosinophils are present in healing wounds and have recently been shown to be capable of producing TGF-alpha. This investigation was done to determine if eosinophils infiltrated into healing wounds are capable of expressing this cytokine. Using the rabbit cutaneous open wound model, the study found that the eosinophil is one of the predominant cell types in the healing wound, beginning from the seventh day and thereafter. Most surprisingly, the majority of the eosinophils present in the healing wound were found to contain TGF-alpha mRNA and protein by in situ hybridization and immunohistochemistry. Thus it is proposed that the delivery of TGF-alpha by eosinophils to epithelial wound healing sites represents a normal body mechanism whereby this multifunctional cytokine can accelerate the wound healing process.
Animals↗
Human eosinophils express transforming growth factor alpha.
Transforming growth factor alpha (TGF-alpha) is a pleuripotential cytokine with diverse biological effects, including the ability to influence the proliferation of normal cells or neoplastic epithelial cells. Eosinophils are a subset of granulocytes that normally enter the peripheral tissues, particularly those beneath gastrointestinal, respiratory, and urogenital epithelium, where they reside in close proximity to the epithelial elements. In this study, we demonstrate that the great majority of eosinophils infiltrating the interstitial tissues adjacent to two colonic adenocarcinomas and two oral squamous cell carcinomas labeled specifically by in situ hybridization with a 35S-riboprobe for human TGF-alpha (hTGF-alpha). No other identifiable leukocytes in these lesions contained detectable hTGF-alpha mRNA. We also examined leukocytes purified from a patient with the idiopathic hypereosinophilic syndrome. 80% of these eosinophils, but none of the patient's neutrophils or mononuclear cells, were positive for hTGF-alpha mRNA by in situ hybridization, and 55% of these eosinophils were positive by immunohistochemistry with a monoclonal antibody directed against the COOH terminus of the mature hTGF-alpha peptide. Finally, the identification of the purified eosinophil-associated transcript as hTGF-alpha was confirmed by polymerase chain reaction product restriction enzyme analysis followed by Southern blot hybridization. In contrast to eosinophils from the patient with hypereosinophilic syndrome, the peripheral blood eosinophils from only two of seven normal donors had detectable TGF-alpha mRNA and none of these eosinophils contained immunohistochemically detectable TGF-alpha product. Taken together, these findings establish that human eosinophils can express TGF-alpha, but suggest that the expression of TGF-alpha by eosinophils may be under microenvironmental regulation. Demonstration of TGF-alpha production by tissue-infiltrating eosinophils and the eosinophils in the hypereosinophilic syndrome identifies a novel mechanism by which eosinophils might contribute to physiological, immunological, and pathological responses.
Adenocarcinoma↗
Use of intracellular H3 messenger RNA as a marker to determine the proliferation pattern of normal and 7,12-dimethylbenz[a]anthracene-transformed hamster oral epithelium.
One of the major goals in cancer research and diagnosis is to identify in a tissue the population of actively dividing cells and their pattern of growth and to differentiate the proliferation patterns of normal and transformed tissues. We now describe a method for determining the proliferation pattern of any tissue (normal, diseased, or transformed), applicable in any mammalian species. This method is based on the fact that the transcription of histone H3 gene in mammalian cells is tightly coupled to DNA synthesis during cellular division. Resting cells or cells that just exited the cell cycle will have no detectable H3 mRNA. The presence of H3 mRNA in a cell is thus a good indicator of its proliferation status. We carried out in situ hybridization of H3 mRNA in hamster oral epithelia exhibiting a variety of altered growth patterns as a consequence of exposure to the chemical carcinogen, 7,12-dimethylbenz[a]anthracene to demonstrate the usefulness of this technique. This application does not require in vitro manipulation of tissues nor does it require the prior administration of a tracer. The proliferation pattern at a single moment in time instead of an accumulated pattern over a period of time is produced. Finally, since the technique of in situ hybridization can be applied to archival tissues, retrospective studies can be done. This application should find usefulness in a wide variety of experimental research settings, particularly cancer research.
9,10-Dimethyl-1,2-benzanthracene↗
Keratinocyte transglutaminase in human skin and oral mucosa: cytoplasmic localization and uncoupling of differentiation markers.
Expression of keratinocyte transglutaminase, a specific differentiation marker, has been examined by immunogold-silver cytochemistry in human epidermis and oral epithelium, and in oral mucosal hyperplasia and neoplasia. Two major findings have been obtained. First, considerable immunoreactivity was evident not only at the plasma membrane (the site of cross-linked envelope formation) but also in the cytoplasm of spinous cells, suggesting a cytoplasmic function for this transglutaminase. Staining at the cell border was seen principally in the granular layer of orthokeratinized epithelium (epidermis, hard palate), the outer spinous cells of ortho- and parakeratinized epithelium and in the suprabasal cells showing squamous differentiation in benign and malignant neoplasms. By contrast, diffuse cytoplasmic staining was observed in the upper spinous layer of the normal epithelium and benign lesions. The cytoplasmic immunoreactivity, which extended nearly to the basal layer in hyperkeratosis of the oral mucosa, was evident in two of three verrucous carcinomas examined. In keeping with their undifferentiated character, invasive nests of squamous cell carcinoma and basaloid epithelium in benign and neoplastic lesions were immunonegative for transglutaminase. The second major finding was that lesions of severe oral epithelial dysplasia, immunonegative for transglutaminase, were capable of expressing involucrin immunoreactivity, indicating an uncoupling of keratinocyte programming. These results suggest that immunogold-silver staining for transglutaminase may be useful in evaluating the degree of differentiation in benign and malignant oral epithelial proliferation.
Cell Differentiation↗
Production of transforming growth factor alpha by hamster eosinophils.
Previously it was demonstrated that malignant transformation of the Syrian hamster cheek pouch mucosa is associated with the expression of TGF-alpha. Therefore in situ hybridization and immunohistochemistry was used to investigate the cellular sources of TGF-alpha production in this model system. Surprisingly one cell type in the inflammatory infiltrate present in the connective tissue adjacent to the transformed epithelium represented a major source of TGF-alpha mRNA. Detailed analysis of these cells revealed that they were eosinophils. In addition to TGF-alpha mRNA, about 40% of the eosinophils associated with the oral tumors exhibited TGF-alpha product reactive with a monoclonal antibody against the C terminus of the mature TGF-alpha peptide. Normal hamster bone marrow eosinophils also exhibited TGF-alpha mRNA and product by in situ hybridization and immunohistochemistry. These results suggest that the eosinophil represents a biologically significant source of TGF-alpha.
9,10-Dimethyl-1,2-benzanthracene↗
A rapid method to determine proliferation patterns of normal and malignant tissues by H3 mRNA in situ hybridization.
A general method applicable for the determination of any mammalian tissue's proliferative pattern is described. This method determines the cellular mRNA level of a proliferation-dependent gene, histone H3, by in situ hybridization. The cell-cycle S-phase-specific expression of this highly conserved ubiquitous cellular gene, and the lack of it in resting cells, permits the unambiguous identification of cycling cells in any tissues, normal or diseased. This method can be conveniently coupled with routine biopsy and could be streamlined for a central laboratory with results obtainable in 2 days. Furthermore, this procedure works successfully on formalin-fixed paraffin-embedded sections, thus allowing retrospective studies of biopsies or autopsy materials.
Cell Cycle↗
Detection of transforming growth factor-alpha messenger RNA in normal and chemically transformed hamster oral epithelium by in situ hybridization.
We have recently demonstrated the consistent detection of transforming growth factor alpha (TGF-alpha) in chemically transformed hamster oral tumors. By Northern blot analysis, no TGF-alpha mRNA can be detected in normal cheek pouch mucosa. The consistent expression of TGF-alpha associated with the malignant transformation in the well-defined hamster oral cancer model prompted us to hypothesize that the aberrant expression of this important cellular gene could be related to a specific stage of epithelial alteration. In situ hybridization was used to test this hypothesis. We now report that by in situ hybridization we can detect TGF-alpha mRNA in normal hamster oral epithelium and also at all stages of transformation. In all epithelium, labeling of TGF-alpha mRNA in the basal layer is more pronounced than that observed in the spinous and squamous layers. There is a significant increase of TGF-alpha mRNA labeling early in 7,12-dimethylbenz(a)anathracene-induced oral carcinogenesis. This increase is associated with morphological changes of epithelial hyperplasia or dysplasia. Although lesions exhibiting full-thickness epithelial dysplasia (carcinoma in situ) showed more labeling of TGF-alpha mRNA than do areas of lesser dysplasia, the transition to full-fledged papillary or invasive squamous cell carcinoma is not associated with further elevations of TGF-alpha expression.
9,10-Dimethyl-1,2-benzanthracene↗
TGF-alpha and EGF-receptor mRNAs in human oral cancers.
Transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) have been shown to be present in most squamous cell carcinomas. Using the Syrian hamster oral cancer model, we have recently demonstrated the consistent presence of TGF-alpha and EGFR mRNAs in chemically transformed hamster oral keratinocytes. We now present evidence that in human oral cancer (in vivo and in vitro), TGF-alpha and EGFR mRNAs can also be consistently detected. No TGF-alpha mRNA can be detected in normal human oral epithelium by Northern blot analysis. These findings reinforce the use of the hamster cheek pouch as an experimental model for the study of oral cancer development, at least in reference to the possible participation of TGF-alpha in the malignant transformation process.
Animals↗