Armen H. Tashjian

Thyrotropin releasing hormone: Direct evidence for stimulation of prolactin production by pituitary cells in culture

Abstract Addition of thyrotropin releasing hormone (TRH) to the medium of 2 clonal strains of functional rat pituitary cells stimulated the production of prolactin and inhibited growth hormone production. There was no effect on cell growth. Stimulation of prolactin production by TRH was detected within 4 hr, it reached a maximum level (2–5 times control) at 24–48 hr and persisted for at least 20 days in the continued presence of TRH. Stimulation was observed with a concentration of TRH as low as 0.10 ng/ml.

C-Cell Hyperplasia Preceding Medullary Thyroid Carcinoma

Abstract Two sisters at risk for hereditary medullary carcinoma and having small but progressive increases of serum calcitonin in response to calcium infusion underwent thyroidectomy. The thyroid g...

Prostaglandin-stimulated bone resorption by rheumatoid synovia. A possible mechanism for bone destruction in rheumatoid arthritis.

Synovial tissue from patients with rheumatoid arthritis was maintained in organ culture for 3-14 days. Conditioned media from these synovial cultures contained bone resorption-stimulating activity, measured in vitro by using calcium release from mouse calvaria as the assay system. The synovial cultures also produce prostaglandin E2 (PGE2) as measured by serologic methods. The production of both the bone resorption-stimulating activity and PGE2 was inhibited by more than 90% by treatment of the synovial cultures with indomethacin (5 mug/ml). In contrast, treatment of the synovial cultures with colchicine (0.1 mug/ml) caused a marked and parallel increase in the concentration of both bone resorption-stimulating activity and PGE2 in the conditioned media. The bone resorption-stimulating activity was quantitatively extracted into diethyl ether. Within the limits of experimental error, all of the bone resorption-stimulating activity in medium was accounted for by its content of PGE2, itself a potent osteolytic factor. We conclude that the bone resorption-stimulating activity produced by rheumatoid synovia in culture is PGE2.

Immunoassay of Human Calcitonin

Abstract A radioimmunoassay using 131I-labeled synthetic human calcitonin and antiserum to human calcitonin revealed normal basal levels of the peptide in serum of 0.02 to 0.4 ng per milliliter. Calcium infusion produced a twofold to threefold rise in serum calcitonin in most control subjects. Chronic hypercalcemia was not regularly associated with elevated serum calcitonin, and calcitonin levels were normal in six patients with chronic hypocalcemia. In medullary carcinoma of the thyroid gland basal serum calcitonin was 1 to 540 ng per milliliter. Calcitonin levels correlated with the extent of disease. In patients with medullary carcinoma, serum calcitonin responses to calcium and glucagon infusions tended to be greater than in control subjects. Results of family studies suggest that the immunoassay may prove useful in the early diagnosis of this tumor among high-risk persons. We conclude that calcitonin normally circulates in human serum, that its concentration may not always correlate directly with ser...

Early Diagnosis of Medullary Carcinoma of the Thyroid Gland by Means of Calcitonin Assay

Abstract Medullary thyroid carcinoma was predicted correctly by means of radioimmunoassay of serum and urine calcitonin in 11 members of one family. An increased concentration of calcitonin in seru...

Establishment of Four Functional, Clonal Strains of Animal Cells in Culture

The single-cell plating technique was used to develop four clonal cell lines that perform organ-specific functions after being serially cultured for prolonged periods. These strains include steroid-secreting Leydig cells, melanomacells that form pigment, and two strains from a hormone-secreting rat pituitary tumor. One of the cell lines from the pituitary tumor secretes growt hormone, while another line derived from the same tumor secretes a substance similar to adrenocorticotropic hormone.

Hypercalcemia and tumor-prostaglandins: The VX2 carcinoma model in the rabbit☆☆☆

The VX2 carcinoma produces profound hypercalcemia (17-22 mg/100 ml) in the rabbit about 3-4 wk after transplantation. A bone resorption-stimulation factor (assayed in vitro with mouse calvaria in culture) has been extracted with diethyl ether from the tumor tissue and from the medium of a clonal strain of VX2 cells grown in culture. Serologic methods reveal that the tumors contain 294 plus or minus 51 ng/g fresh weight (mean plus or minus SE, 25 tumors) of prostaglandin E2 (PGE2), a potent bone resorption-stimulating agent. VX2 cells in culture produce 0.5-3.0 mug PGE2 per mg cell protein per 24 hr. The production of bone resorption-stimulating activity and PGE2 by VX2 cells in culture were both inhibited by indomethacin (100 ng/ml). Tumors from normocalcemic, indomethacin-treated rabbits (10-40 mg/rabbit/24 hr) contained little or no bone resorption-stimulating activity nor PGE2. Tumor-bearing rabbits receiving indomethacin continuously did not develop hypercalcemia, however, following cessation of indomethacin administration, hypercalcemia developed rapidly and was again reversed by reinstitution of indomethacin feeding. In untreated, hypercalcemic, tumor-bearing rabbits, initiation of indomethacin treatment was followed by a rapid return of the plasma calcium to the normal range. Systemic venous plasma from hypercalcemic tumor-bearing plasma contained higher concentrations of PGE2 than plasma from normocalcemic control rabbits. Venous drainage of the tumor contained even higher plasma PGE2 concentrations than systemic venous plasma in hypercalcemic animals; plasma PGE2 concentrations locally and in systemic plasma were unmeasurable (less than 70 pg/ml) in normocalcemic, indomethacin-treated, tumor-bearing rabbits. We conclude that PGE2 is a bone resorption-stimulating factor produced by VX2 tumor cells, and that secretion of PGE2 by the tumor in vivo may well be responsible for the hypercalcemia observed in tumor-bearing rabbits.

Natural history of familial medullary thyroid carcinoma: effect of a program for early diagnosis.

To detect familial medullary thyroid carcinoma in a premetastatic stage, we administered tests provocative of calcitonin secretion (infusion of calcium or pentagastrin or both) each year for seven years to members of a pedigree now numbering 107. Since 1970, 21 patients converted from normal to abnormal secretory responses (two separate tests in which calcitonin levels exceeded 0.58 ng per milliliter). Twenty of 21 glands removed showed C-cell hyperplasia, and eight of the 20 also showed foci of carcinoma. As compared to the 12 patients with tumors detected during the first year of screening, all of whom had bilateral carcinoma (seven of 12 with local metastases), later carcinomas were smaller (mean diameter of 0.2 vs. 0.8 cm), were unilateral (in all but two cases) and occurred in younger patients (mean age of 14.9 vs. 36.4 years), and none had detectable metastases.

Prostaglandin production by mouse fibrosarcoma cells in culture: Inhibition by indomethacin and aspirin

Abstract Five clonal strains of mouse tumor cells (HSDM1) synthesize and secrete large quantities (0.70-2.0 μg/mg cell protein/24 hr) of prostaglandin E2. Five lines of control cells did not synthesize significant amounts of prostaglandins. HSDM1 cells produce prostaglandin E2 during both the logarithmic and stationary phases of the cell growth cycle. Prostaglandin production was inhibited by aspirin-like drugs; for example, 50% inhibition was obtained with as little as 3 × 10−9 M indomethacin. We conclude that the HSDM1 cell system will serve as a useful model system to study prostaglandin synthesis and secretion.

Medullary carcinoma of the thyroid gland. Studies of thyrocalcitonin in plasma and tumor extracts.

Abstract In two patients with medullary carcinoma of the thyroid gland tumor extracts contained 1000 to 2000 times more hypocalcemic activity than normal human thyroid tissue. Activity was detected by bioassay in plasma of both patients. One had severe hypocalcemia and hypophosphatemia. Hypocalcemic activity rose in response to calcium infusion and closely paralleled changes in plasma calcium. Several lines of evidence supported the conclusion that the hypocalcemic material in tumors and plasma was thyrocalcitonin. Parallel log dose-response lines were obtained in bioassays of tumor extracts, plasma and porcine thyrocalcitonin. The hypocalcemic activity was lost during incubation with purified thyrocalcitonin-inactivating factor and hydrogen peroxide. Like authentic thyrocalcitonin, the activity did not sediment in the ultracentrifuge. Net synthesis of thyrocalcitonin was shown by culture of tumor cells in vitro. Human tumor thyrocalcitonin did not cross-react significantly in the radioimmunoassay for por...