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D C Aron

Publications and source records attributed to D C Aron.

At least 73 records · Page 4Linked to original sources
PubMed1986

Nonsomatostatin secretory peptide(s) derived from prosomatostatin's amino terminus in a rat medullary thyroid carcinoma cell line.

We have established a system, the CA77 rat medullary thyroid carcinoma cell line, for studying the products of somatostatin (SS) gene expression. Based on the amino acid sequence of proSS, we developed a RIA for the amino terminus of proSS (proSS-NTP) and demonstrated in acidic cell extracts two major proSS-NTP-containing species of 8000 and 4000 daltons. Studies were then performed on species secreted into culture medium. Serial dilutions of culture medium showed tracer displacement curves parallel to serial dilutions of synthetic proSS-NTP standard. Analysis by gel filtration chromatography of 24-h culture medium showed the major proSS-NTP-containing species to have an estimated mol wt of 8000 daltons. No 4000-dalton species was observed. The acute effects of calcium and glucagon, known secretagogues of SS, on secretion of immunoreactive (i) proSS-NTP were investigated in 3-h experiments. Basal (0.5 mM calcium) secretory rates (mean +/- SE) of iproSS-NTP and iSS were 1.29 +/- 0.36 and 7.38 +/- 1.51 ng/mg acid-extractable protein, respectively. High calcium (3 mM) stimulated iproSS-NTP and iSS secretion 302 +/- 100% and 363 +/- 105%, respectively. High calcium plus 10(-6) M glucagon also stimulated secretion of iproSS-NTP and iSS in a coordinate fashion. Analyses by gel filtration chromatography of 3-h culture medium revealed that high calcium markedly increased the 8000-dalton proSS-NTP-containing species. No 4000-dalton species was observed. The absence of 4000-dalton proSS-NTP species in 24-h culture medium, the lack of degradation of 4000-dalton proSS-NTP (recovered from CA77 cell extracts) added to tissue culture medium, and the selective secretion of the 8000-dalton proSS-NTP species under both basal and stimulated conditions coordinate with the secretion of SS indicate that the 4000-dalton proSS-NTP-containing species is not secreted.

Animals↗
PubMed1986

Elaboration of nonsomatostatin peptides containing the amino-terminal portion of prosomatostatin in a somatostatin-secreting human medullary thyroid carcinoma cell line.

We identified a system, the TT human medullary thyroid carcinoma cell line which contained 74.5 +/- 26.0 ng (mean +/- SD) immunoreactive SRIH/mg protein, for studying the products of SRIH gene expression. The close homology between man and rat for the entire proSRIH and complete homology for a portion of the amino terminus (proSRIH-NTP) permitted the application of a RIA directed toward the amino terminus of rat proSRIH. Immunohistochemical studies of the human TT cell line showed that SRIH and proSRIH-NTP immunoreactivities were present in the same cells. RIA of gel filtration fractions showed that the major cellular proSRIH-NTP-containing species lack SRIH and had an apparent mol wt of 8000. A 10,000-dalton SRIH-containing species coeluting with proSRIH-NTP immunoreactivity, putative proSRIH, also was found. Similar species were found in culture medium. The major cellular and secreted form of SRIH immunoreactivity had a mol wt of 1600 (SRIH). High pressure liquid chromatography revealed that both cellular and secreted 8000-dalton proSRIH-NTP-containing material consisted of a major and several minor species. None of the species contained SRIH. The precise structure of these proSRIH-NTP-containing species and their physiological roles are not known. The fact that proSRIH-NTP-containing species are secreted suggests that they may be functional. Since the processing of proSRIH and consequently the final products appear to be tissue specific, alterations in the relative presence of different forms might reflect specific pathological processes.

Carcinoma↗
PubMed1986

An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing's syndrome.

We have developed a high-dose dexamethasone suppression test that can be administered overnight with a single 8-mg dose and used the new procedure in the differential diagnosis of 83 patients with Cushing's syndrome. In 76 patients with surgically or pathologically proven cause--60 with Cushing's disease, 7 with the ectopic adrenocorticotrophic hormone syndrome, and 9 with adrenal tumors--suppression of plasma cortisol levels to less than 50% of baseline indicated a diagnosis of Cushing's disease. The test had a sensitivity of 92%, a specificity of 100%, and a diagnostic accuracy of 93%. These values equal or exceed those of the standard 2-day test whether based on suppression of urinary 17-hydroxycorticosteroids or plasma cortisol. We conclude that this overnight, high-dose dexamethasone suppression test is practical and reliable in the differential diagnosis of Cushing's syndrome.

17-Hydroxycorticosteroids↗
PubMed1984

Identification of cellular prosomatostatin and nonsomatostatin peptides derived from its amino terminus.

Rat prosomatostatin was isolated from a somatostatin-producing cell line and was partially microsequenced. This indicated the amino terminal structure of cellular prosomatostatin and implied a 92-amino acid sequence for the somatostatin precursor. Based on the structure for cellular prosomatostatin, a peptide was synthesized and used to develop a radioimmunoassay directed toward the amino terminal portion of prosomatostatin. This assay has revealed two peptides containing the amino-terminal portion of prosomatostatin in a somatostatin-secreting CA-77 rat medullary thyroid carcinoma cell line. These two peptides - MW 4000 and 8000 daltons - lack somatostatin immunoreactivity. Thus, processing of prosomatostatin occurs both at the amino and carboxyl regions. These results open the way for elucidation of the structure, function and metabolism of non-somatostatin peptides derived from the amino terminus of prosomatostatin.

Amino Acid Sequence↗
PubMed1983

Cloning and characterization of a mRNA-encoding rat preprosomatostatin.

An undecanucleotide extended hybridization probe has been used to screen a rat medullary thyroid carcinoma cDNA library for clones which contain preprosomatostatin sequences. The nucleotide sequence encoding rat preprosomatostatin is reported. The sequence of cDNA contains 67 nucleotides in the 3'-noncoding region, 84 nucleotides in the 5'-untranslated region, and 458 bases corresponding to the coding region. The mRNA codes for a somatostatin precursor 116 amino acids in length (Mr = 12,773). The preprosomatostatin has a sequence of hydrophobic amino acids at the NH2 terminus, followed by a peptide of approximately 78 residues, which precedes somatostatin-14. The amino acid sequences of rat and human preprosomatostatin (Shen, L. P., Pictet, R. L., and Rutter, W. J. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 4575-4579) differ by only 4 amino acid residues. Translation of rat poly(A) RNA in a rabbit reticulocyte cell-free system followed by immunoprecipitation with antisera directed against somatostatin-14 demonstrated the synthesis of a single protein having a molecular weight of 15,000. Two proteins having molecular weights of 14,000 and 15,000 are immunoprecipitated from a wheat germ cell-free translation mixture. Northern analysis of the somatostatin mRNA indicated that it is approximately 850 nucleotides in length. Analysis of several medullary thyroid carcinomas demonstrated that one tumor, designated WF, had immunoreactive somatostatin-14 in concentrations of 350 ng of somatostatin-14/mg of protein and somatostatin mRNA that represented 10% of the cellular poly(A) RNA. Cell lines derived from this tumor may provide an attractive system to investigate the regulation of somatostatin gene expression.

Amino Acid Sequence↗
PubMed1983

Rat pre-prosomatostatin. Structure and processing by microsomal membranes.

The tetradecapeptide hormone somatostatin arises from proteolytic processing of a large precursor, pre-prosomatostatin. Studies of other hormone precursors predict that the NH2 terminus of pre-prosomatostatin comprises a leader, or signal, region which is cleaved during its translation. Such co-translational cleavage would generate prosomatostatin. In these studies, we present the complete sequence of rat pre-prosomatostatin, deduced from the nucleotide sequence of cDNAs derived from a somatostatin-rich medullary thyroid carcinoma. These findings indicate that rat pre-prosomatostatin contains 116 amino acids (12,737 daltons). Cell-free translations of medullary thyroid carcinoma mRNA with dog pancreas microsomal membranes were performed to identify the cleavage point of the leader region from prosomatostatin. Partial microsequencing data indicates that the cleavage occurs between the glycine and alanine at positions 24 and 25 of pre-prosomatostatin. Thus, rat prosomatostatin contains 92 amino acids (10,388 daltons). Comparison of the amino acid sequences of the rat and human pre-prosomatostatins reveals only four amino acid substitutions. In view of the high degree of homology between rat and human pre-prosomatostatin, we expect a similar cleavage site and NH2-terminal structure for human prosomatostatin. The high level of conservation between rodents and humans of the entire pre-prosomatostatin molecule further suggests the possibility of biologic functions of the NH2-terminal portions of prosomatostatin.

Amino Acid Sequence↗
PubMed1982

Cushing's syndrome: problems in management.

CS comprises a group of disorders characterized by hypercortisolism. The variety of causes--pituitary-dependent CS (CD), adrenal tumor, and the ectopic ACTH syndrome--necessitates a variety of therapies--surgical, radiotherapeutic, and medical. Once a specific diagnosis is made, specific therapy can be instituted. Although some controversy persists regarding treatment, particularly that of CD, for most patients it is straightforward. However, in our experience with more than 60 patients, therapeutic dilemmas can arise in a number of circumstances, e.g. the patient with the radiologically normal sella or recurrent CD after adrenalectomy. In addition, the treatment of such conditions as the large ACTH-producing pituitary tumor, Nelson's syndrome, the malignant ectopic ACTH syndrome, and adrenal carcinoma is not entirely satisfactory. Our approach to these problems is illustrated by seven cases, and we emphasize that the proper management of CS requires both correct diagnosis and the logical application of all available therapies.

ACTH Syndrome, Ectopic↗
PubMed1981

Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's syndrome. Report of two cases and review of the literature.

Cushing's syndrome due to nodular adrenal hyperplasia comprises a clinically and biochemically heterogeneous group of disorders whose pathogenesis is unclear. We describe two patients with atypical steroid dynamics and large unilateral adrenal nodules who had pituitary ACTH-dependent disease. In the differential diagnosis of Cushing's syndrome, we recommend repeated ACTH measurement and selective venous sampling-particularly in those patients with impaired dexamethasone suppressibility and abnormal findings on computerized tomography.

Adrenal Gland Neoplasms↗
PubMed1981

Cushing's syndrome: problems in diagnosis.

Cushing's syndrome, an unusual group of disorders characterized by hypercortisolism, must be considered in the differential diagnosis of such common clinical problems as hirsutism, menstrual irregularity, hypertension, diabetes mellitus, and obesity. Its distinct forms--pituitary-dependent Cushing's syndrome (Cushing's disease), adrenal tumor and ectopic ACTH syndrome--must be identified correctly so that specific therapy can be administered. In the majority of cases, use of a relatively simple diagnostic sequence will provide accurate and rapid diagnosis. However, in our experience with more than 60 patients, diagnostic difficulties may arise from a variety of conditions (e.g., drug interference, alcohol ingestion, and depression). In addition, unusual circumstances, such as unexpected responses to dexamethasone, may complicate the diagnosis. Our approach to these problems is illustrated through a report of seven cases, and we emphasize that the proper management of Cushing's syndrome mandates a thorough marshalling of all the available data.

ACTH Syndrome, Ectopic↗
PubMed1981

Silent pituitary apoplexy: subclinical infarction of an adrenocorticotropin-producing pituitary adenoma.

A young woman developed intermittent headaches and progressive hyperpigmentation after bilateral adrenalectomy for Cushing's disease. Results of sellar polytomography were abnormal. Her plasma ACTH levels increased to 4750-7340 pg/ml and did not rise with insulin-induced hypoglycemia. Although she experienced no clinical features associated with spontaneous infarction of a pituitary tumor, plasma ACTH levels fell to 474-575 pg/ml, and hemorrhagic necrosis was found in a 5-mm chromophobe adenoma at transsphenoidal surgery. Postoperatively, ACTH levels returned to normal (51-88 pg/ml), with the rest of her anterior pituitary function remaining intact 4 yr later. Spontaneous infarction of pituitary microadenomas may be subclinical, resulting in improvement of pituitary hormone hypersecretion without impairment of other anterior pituitary hormone secretion.

Adenoma, Chromophobe↗