Biomedical subjects
Publications and source records attributed to T N Moyana.
Myristoylation refers to the co-translational addition of a myristoyl group to an amino-terminal glycine residue of a protein by an ubiquitously distributed enzyme myristoyl-CoA:protein N-myristoyltransferase (NMT, EC 2.3.1.97). This review describes the basic enzymology, molecular cloning and regulation of NMT activity in various pathophysiological processes such as colon cancer and diabetes.
CONTEXT: The advent of panneuroendocrine markers has helped to better depict the heterogeneity of gastrointestinal carcinoids. Consequently, it has been proposed that these tumors constitute a histologic spectrum that includes well-, moderately, and poorly differentiated carcinoids. However, the reproducibility of this grading system and its prognostic importance have sometimes been called into question. OBJECTIVE: To investigate the potential utility of cell proliferation and oncoprotein markers in augmenting the histologic classification. DESIGN AND SETTING: Retrospective study; tertiary care teaching hospital. METHODS: Fifty-eight patients with 41 well-differentiated, 12 moderately differentiated and 5 poorly differentiated carcinoids from various topographic sites of the gastrointestinal tract were selected and immunostained for panneuroendocrine markers, MIB-1, p53, and bcl-2. MAIN OUTCOME MEASURES: Degree of association between histologic grading, MIB-1, p53, and bcl-2 immunoreactivity and carcinoid metastatic behavior. RESULTS: The group comprised 30 males and 28 females whose mean age was 52.7 years (range, 14-81). Mean follow-up time was 85.8 months. All 58 patients tested positive for chromogranin A and/or synaptophysin. The group was divided into nonmetastatic (42/58, or 72.4%) and metastatic (16/58, or 27.6%) cases. Histologic grading tended to be associated with metastatic spread, but this occurrence of metastases did not attain statistical significance (P =.08). Positivity for MIB-1 (P =.004) and p53 (P =.04) was significantly associated with metastatic behavior, whereas bcl-2 was not (P = 0. 63). CONCLUSIONS: Although an organoid pattern and neuroendocrine immunophenotype help to define the spectrum of gastrotestinal carcinoids, this study suggests that the histologic grading of these tumors has some limitations with respect to predicting metastatic behavior. However, MIB-1 and p53 can compliment histologic grading as prognostic indicators in this regard while bcl-2 appears to be less useful.
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Endometrial calcifications occur sporadically and are associated with infertility. Previous uterine trauma during instrumentation and/or uterine infection are likely involved in their pathogenesis. The association between endometrial calcifications and recurrent pregnancy loss has been very infrequently reported. A 28-year-old woman with a history of two consecutive first trimester pregnancy losses presented with ultrasonographic hyperechoic endometrial areas associated with histologic endometrial calcification foci. A third pregnancy conceived before starting micronized oral progesterone supplementation also spontaneously aborted at eight weeks. During the fourth pregnancy, progesterone supplementation was taken for the initial 12 weeks. The endometrial lesions were no longer detectable and the pregnancy progressed to term without complications. Endometrial calcifications, related to intrauterine bone tissue, have been previously treated with curettage or with endoscopic surgery, and to the best of our knowledge, have not been reported to disappear spontaneously. In this case, regression of the endometrial calcifications and a favorable pregnancy outcome occurred in concert with oral micronized progesterone supplementation. A combination of transvaginal ultrasonography and endometrial biopsy appears to be an effective method for diagnosing and monitoring of this rare condition.
A 19-year-old postpartum patient with a previous history of asthma and eosinophilic myocarditis is described. Eosinophilic myocarditis is thought to be caused by exacerbation of the idiopathic hypereosinophilic syndrome by pregnancy. The diagnosis was made by a right ventricular endomyocardial biopsy, which showed an eosinophilic infiltrate with a few scattered foci of myonecrosis, but no fibrosis, vasculitis or granulomas. The patient's myocardial function continued to decline over a two-year follow-up period, despite normal levels of eosinophils. She developed echocardiographic evidence of diastolic and systolic dysfunction.
Modification of proteins by myristoylation has been proposed as a chemotherapeutic target against colon cancer because it is important in the function of various signal transduction proteins. Recently we reported that the enzyme that catalyzes this modification, N-myristoyltransferase (NMT), is elevated in colorectal adenocarcinomas [Magnuson, B. A., Raju, R. V. S., Moyana, T. N., and Sharma, R. K. (1995) J. Natl. Cancer. Inst. 87, 1630-1635]. The purpose of the present study was to investigate whether the elevated activity of NMT in colorectal adenocarcinomas is due to an increase in the production of NMT or a change in the structure of the preexisting enzyme. The expression of NMT in normal colonic mucosa and adenocarcinomas from human colorectal surgical specimens was studied by immunoblotting, and its localization was confirmed by immunohistochemistry. The molecular weight of NMT was determined by fast protein liquid chromatography. In both normal mucosa and colorectal adenocarcinomas, NMT with a molecular mass of 48.5 kDa was identified with anti-human NMT and anti-peptide antibody. However, the expression of NMT was found to be higher in the colorectal tumors. This finding was further confirmed by immunohistochemical studies which showed stronger cytoplasmic staining in the tumors. These findings represent the first description of NMT overexpression in colorectal adenocarcinomas. This has implications with regard to (i) the design of chemotherapeutic drugs and (ii) prognosis, for instance, in monitoring colorectal cancer recurrence or metastases.
Ampullary tumours are uncommon. They may occur with familial polyposis syndromes or neurofibromatosis. It can be difficult to distinguish them from their periampullary counterparts on clinical, radiologic or histologic grounds. Because most ampullary and periampullary tumours are malignant, they tend to be treated by radical surgery. A 67-year-old man was seen with a sporadic ampullary hamartoma that simulated cancer. It was successfully treated by local excision through a transverse duodenotomy.
The incidence of systemic candidiasis appears to be on the rise, and unusual or hitherto undocumented clinicopathologic features of invasive candidiasis continue to be described. This report adds further to this spectrum by describing granulomatous appendicitis due to invasive candidiasis. The patient was a 23-year-old woman with acute promyelocytic leukemia. Her other risk factors included the use of aggressive chemotherapy, immunosuppressives, broadspectrum antibiotics, and invasive instrumentation. In view of the acquired immunodeficiency syndrome epidemic, as well as the improved survival of patients with prolonged neutropenia owing to better intensive care units, there is reason to believe that other as yet undocumented clinicopathologic manifestations of invasive candidiasis or other opportunistic infections may come to light.
BACKGROUND: Colorectal cancer is one of the leading causes of cancer death in North America. Since treatment of colonic cancer remains difficult because of the lack of effective chemotherapeutic agents, it is important to continue to search for cellular functions that can be disrupted by chemotherapeutic drugs and inhibit the development or progression of this disease. Modification of proteins by myristoylation has been recognized as important in the function of various viral, oncogenic, and signal-transduction proteins and thus has been proposed as a target for chemotherapeutic drug design. However, the activity of the enzyme that catalyzes this modification, N-myristoyltransferase, has not been investigated in cancer relative to normal tissue. PURPOSE: The purpose of this study was twofold: 1) to investigate the activity of N-myristoyltransferase in azoxymethane-induced rat colonic cancer tissue compared with normal and normal-appearing rat colonic tissue and 2) to determine if similar differences would be observed in a small sample of human colonic tumors. METHODS: N-Myristoyltransferase activity was determined in 45 colonic tissue specimens from Sprague-Dawley rats--10 given injections of the colon carcinogen, azoxymethane, and three untreated. Tissue specimens included 35 colonic tumors of varying pathologic stages, seven specimens of normal-appearing adjacent mucosa, and three specimens of normal colonic mucosa. Colectomy specimens from five patients were assayed for N-myristoyltransferase activity. Subcellular distribution of N-myristoyltransferase activity was determined. Synthetic peptides of known myristoylated proteins--pp60src and cyclic adenosine monophosphate-dependent protein kinase--were used in kinetic analyses of N-myristoyltransferase in colonic cancer and normal-appearing colonic tissue. All P values are two-tailed. RESULTS: N-Myristoyltransferase activity was increased in rat colonic tumors compared with normal-appearing adjacent mucosa and normal mucosa (P = .0002). Elevation of N-myristoyltransferase activity was present in all tumors, including colonic polyps. Increased N-myristoyltransferase activity was also observed in human colonic tumors and was predominantly cytosolic. N-Myristoyltransferase of colonic cancer tissues had a similar Michaelis constant but an approximate twofold higher maximum velocity for both the pp60src- and cyclic adenosine monophosphate-dependent protein kinase-derived peptides compared with N-myristoyltransferase of normal-appearing tissue. CONCLUSIONS: This study demonstrates for the first time that N-myristoyltransferase activity is higher in colonic epithelial neoplasms than in normal-appearing colonic tissue and that an increase in N-myristoyltransferase activity appears at an early stage in colonic carcinogenesis.
BACKGROUND: Gastrointestinal neoplastic epithelium of glandular origin commonly produces N-linked and O-linked glycoproteins such as carcinoembryonic antigen (CEA) and tumor-associated polymorphic epithelial mucin (PEM). Antibodies to these glycoproteins increasingly are being used in immunodiagnosis and/or immunotherapy. Although GI carcinoid tumors have a neuroendocrine immunophenotype and generally have an indolent clinical course compared with their adenocarcinomatous counterparts, they also arise from undifferentiated crypt epithelium. The purpose of this study was to determine whether GI carcinoids similarly expressed epitopes for CEA and PEM. METHODS: Thirty-nine GI carcinoid tumors from various topographic sites were analyzed by immunohistochemistry using the murine monoclonal antibodies B72.3, ACT19, and T84. The former two antibodies recognize epitopes in PEM, whereas the latter is an anti-CEA antibody, which was confirmed using enzyme-linked immunosorbent assays. RESULTS: The majority of carcinoid tumors (74%), particularly jejunoileal carcinoids, reacted for ACT19 antibody, whereas considerably fewer reacted for B72.3 (31%) and T84 (26%). The extent of staining was also greatest with ACT19. The GI mucosa adjacent to or overlying the carcinoid tumors also stained for the various antibodies. CONCLUSIONS: The extent and degree of positivity of carcinoid tumors for ACT19 raises the possibility that this antibody may be used in the future for the radioimmunodiagnosis and/or immunotherapy of these tumors, particularly in cases that are multicentric, unresectable, or with metastatic disease.
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The purpose of this study was to better establish the morphologic basis of the early mucosal lesions of experimental inflammatory bowel disease because understanding the development of these lesions has important pathogenetic implications. Sprague-Dawley rats were given 1.5% hydrolyzed lambda-carrageenan orally for 30 days. This produced small intestinal lesions which were then evaluated. Light microscopy showed an increased amount of inflammatory cells in the gut wall with prominent Peyer's patches, microgranulomas, crypt abscesses, pin-point ulcerations, and a repair reaction. Scanning electron microscopy revealed pin-point ulcerations in relation to Peyer's patches. Transmission electron microscopy, in addition to the above findings, showed disruptions of enterocyte microvilli and terminal webs. Follicle-associated epithelium appeared to be a predictive site for the development of crypt abscesses and pin-point ulcerations. Enzyme-linked immunoadsorbent assays indicated that orally administered carrageenan elicited a systemic antibody response. Our results suggest that damage to enterocyte microvilli and terminal webs may be important early events in the morphogenesis of the lesions.
Gastrointestinal endocrine cells are situated both in the epithelium as well as in the subepithelium, especially in relation to enteric nerves. This has complicated efforts at delineating the histogenesis of gastrointestinal carcinoids. However, gastrointestinal carcinoids themselves are a heterogeneous group made up of various subsets, and as such may have different modes of origin. The present study investigated the histogenesis of rectal carcinoids because this has not been adequately addressed. Nine rectal carcinoids together with sex- and age-matched controls were stained with silver stains and various immunoreagents. The number of intraepithelial endocrine cells per unit length of mucosa in the carcinoid group was compared with the controls using the Student t test. Our results showed that there was no evidence of diffuse intraepithelial endocrine cell hyperplasia associated with these carcinoids. In six of the cases, however, there were focal areas where the carcinoids abutted onto the mucosal epithelium, and in another two cases there were focal areas depicting crypt cell proliferative micronests. These findings suggest that most conventional rectal carcinoids arise from localized areas of crypt cell proliferation rather than from diffuse areas of intraepithelial endocrine cell hyperplasia. Furthermore, rectal carcinoids appear to be constituted of a heterogenous population of endocrine cells rather than a monoclonal population of cells with each cell expressing a multiplicity of hormones.
BACKGROUND: The purpose of this study was to determine the histogenesis of jejunoileal and appendiceal carcinoids and to ascertain whether this could be useful in further explaining the pathology of these neoplasms. METHODS: Eight cases each of multiple jejunoileal carcinoids and appendiceal carcinoids together with their respective age-matched and sex-matched controls were stained with silver stains, chromogranin A, serotonin, and S-100. Histomorphometric evaluations of the endocrine cells in the mucosa adjacent to the carcinoids were carried out and compared with the respective controls using the Student's t test. RESULTS: All the carcinoids from both groups stained for argyrophilia, argentaffinity, chromogranin A, and serotonin. Histomorphometric evaluations showed intraepithelial endocrine cell hyperplasia (IECH) in the jejunoileal carcinoid group (P = 0.007, chromogranin; P = 0.004, serotonin) but not in the appendiceal carcinoid group. On the other hand, subepithelial endocrine cell aggregates that were separate from the main tumor were seen in two cases of appendiceal carcinoids. With S-100, all appendiceal carcinoids showed intrinsic tumor positivity whereas the jejunoileal carcinoids did not. CONCLUSIONS: The finding of IECH with multiple jejunoileal carcinoids suggests that these carcinoids arise from a field effect. The absence of IECH with appendiceal carcinoids as well as their association with subepithelial endocrine cell aggregates and their intimate relationship with Schwann cell processes suggests that appendiceal carcinoids arise from a more discrete unit, the subepithelial neuroendocrine complex.
Colorectal leiomyosarcoma (CLM) is an uncommon tumour. Reports of its occurrence have been published mostly as single cases or small series. This study documents 12 cases of CLM that were seen over a 28-year period in Saskatchewan. The annual incidence of CLM was 0.45 per million people and constituted 0.12% of all colorectal malignant tumours seen during the study period. CLMs had a predilection for the rectum and sigmoid and commonly were associated with rectal bleeding or abdominal pain. More than half the tumours were detected by sigmoidoscopy. A correct preoperative or intraoperative histologic diagnosis of leiomyosarcoma was made in only two out of six cases. A potentially curative surgical procedure was done in 10 of the 12 patients. The mean follow-up was 6.9 years. Eight patients had tumour recurrence or metastasis, or both. From the findings of this study the authors recommend wide excision of colorectal smooth-muscle tumours whenever there is a suggestion of malignancy.
Untreated celiac disease is characterized by gastrointestinal endocrine cell hyperplasia (ECH). This study investigated the constitutive nature of the ECH. Ten duodenal biopsies showing villous atrophy from adult celiacs were evaluated against ten sex- and age-matched controls. The mean number of endocrine cells per unit length of mucosa in the celiacs was compared with the control group using the Student t test. These values, respectively, were as follows: Churukian-Schenk method, 52.4 versus 29.6 (P = 0.001); Fontana-Masson, 32.5 versus 18.4 (P = 0.016); chromogranin, 33.4 versus 23.6 (P = 0.017); serotonin, 44.7 versus 26.7 (P = 0.006); somatostatin, 5.0 versus 5.4 (P = 0.631); and gastrin, 0.37 versus 0.37 (P = 1.000). There was thus ECH as shown by the first four stains with, in some areas, the endocrine cells continuously abutting against each other to form linear profiles. With respect to specific hormonal products, only serotonin showed ECH. These results suggest that the ECH in celiac disease is not a haphazard process but, instead, a selective proliferation of certain endocrine cell types.
Smooth-muscle tumors are an interesting group of tumors that show considerable site specificity in their pathobiology. Recent work has also shown that some previously so-called smooth-muscle tumors were not, in fact, truly leiomyogenic, hence the origin of the more embracing term stromal tumors. The purpose of this retrospective study was to delineate the tumor subsets constituting colorectal stromal tumors, and to determine the histopathologic correlates for biologic aggressiveness for these tumors. The cohort was constituted of 12 patients; the mean follow-up was 6.6 years with a median of 5.0 years. Immunohistochemical evaluations showed tumoral positivity for muscle-specific actin (12 of 12), vimentin (11 of 12), desmin (two of 12), and S100 protein (zero of 12). Electron microscopic examinations corroborated this leiomyogenicity profile (five of five). Semiquantitative histomorphometric analysis showed that tumor size, cellularity, mitoses, and necrosis, in that order, correlated with biologic aggressiveness. The immunohistochemistry results for this cohort of colorectal stromal tumors vindicated the traditional histochemical evaluations in that all tumors showed features of leiomyogenicity. For colorectal smooth-muscle tumors, tumor size appears to be the best predictor for biologic aggressiveness. This study reinforces the concept of site-specificity for smooth-muscle tumors.
This paper presents two cases of adenosquamous carcinoma of the colon and brings to 39 the total number documented in medical literature. The concurrent glandular and squamous differentiation of the tumor cells was demonstrated by immunocytochemistry and electron microscopy. Evaluation of the biologic characteristics of all the reported cases suggests that malignant squamous elements in colonic carcinomas behave more aggressively than their glandular counterparts. In contradistinction from the pure squamous-cell carcinoma of the colon, adenosquamous carcinoma does not show the same predilection for the right colon.