Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity.

Increased levels of the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) have been repeatedly reported in several human solid tumors, especially in endocrine-related tumors such as pituitary adenomas. Securin PTTG has a critical role in pituitary tumorigenesis. However, the cause of upregulation has not been found yet, despite analyses made at the gene, promoter and mRNA level that show that no mutations, epigenetic modifications or other mechanisms that deregulate its expression may explain its overexpression and action as an oncogene. We describe that high PTTG protein levels are induced by the RWD-containing sumoylation enhancer (RWDD3 or RSUME), a protein originally identified in the same pituitary tumor cell line in which PTTG was also cloned. We demonstrate that PTTG and RSUME have a positive expression correlation in human pituitary adenomas. RSUME increases PTTG protein in pituitary tumor cell lines, prolongs the half-life of PTTG protein and regulates the PTTG induction by estradiol. As a consequence, RSUME enhances PTTG transcription factor and securin activities. PTTG hyperactivity on the cell cycle resulted in recurrent and unequal divisions without cytokinesis, and the consequential appearance of aneuploidies and multinucleated cells in the tumor. RSUME knockdown diminishes securin PTTG and reduces its tumorigenic potential in a xenograft mouse model. Taken together, our findings show that PTTG high protein steady state levels account for PTTG tumor abundance and demonstrate a critical role of RSUME in this process in pituitary tumor cells.

Epidemiology of hip fracture in Tucuman, Argentina.

UNLABELLED: The incidence of osteoporotic hip fracture was studied previously in a central area of Argentina. Studying Tucuman (north area) was very useful to compare results of the different areas and detect a similar incidence in women and a slightly higher incidence in men compared with previous data for the central region. INTRODUCTION/METHODS: Epidemiology of hip fracture was studied over a 1-year period in the city of San Miguel de Tucumán (SMT) and in the whole province of Tucumán, located in the northeast of Argentina (latitudes 26° and 28° south). The results were compared with previous studies performed in the central region of Argentina. RESULTS: Two hundred and eighty-three patients (208 women and 75 men) aged 50 years or over in SMT suffered a hip fracture. The incidence in females and males was 334.9 and 163.8 hip fractures per 100,000 inhabitants per year, respectively (female/male ratio 2.0). A total of 498 hip fractures were recorded in Tucuman province (367 in women and 131 in men). The results in females and males were 276.5 and 114.7 hip fractures per 100,000 inhabitants per year, respectively. Average age of the female and male population was 78±9 and 77±9 years, respectively. CONCLUSIONS: These results showed that the incidence of hip fracture in female and male populations in SMT was similar to previous studies performed in the central area of the country. Further studies on the south area of Argentina should be conducted to complete the information on a large country extending from latitudes 22° to 55°S.

Effects of the gp130 cytokines ciliary neurotropic factor (CNTF) and interleukin-11 on pituitary cells: CNTF receptors on human pituitary adenomas and stimulation of prolactin and GH secretion in normal rat anterior pituitary aggregate cultures.

Two of the most potent cytokines regulating anterior pituitary cell function are leukemia inhibitory factor (LIF) and interleukin (IL)-6, which belong to the cytokine family using the common gp130 signal transducer. Recently, the expression and action of two other members of this family, IL-11 and ciliary neurotrophic factor (CNTF), on different cell lines has also been demonstrated. We studied the expression of the specific receptor subunits for CNTF in mammotropic, non-functioning and somatotropic tumors and the action of CNTF and IL-11 in the regulation of hormone secretion in these and normal pituitary cells. The mRNA for the alpha chain specific for the CNTF receptor was detected by Northern blot in tumors secreting prolactin (PRL) and GH and in non-functioning tumors. We found that both IL-11 and CNTF exerted a similar stimulatory effect on GH mRNA expression in somatotropic monolayer cell cultures from acromegalic tumors, but these cytokines had no significant influence on GH secretion. CNTF stimulates prolactin secretion in lactotropic monolayer cell cultures from patients with prolactinoma. In monolayer cell cultures from normal rat anterior pituitary, IL-11 and CNTF had no significant effect on the release of either GH or PRL, or on GH mRNA. However, when the cells were cultured in aggregate cultures, in which the three-dimensional structure of the cells is reconstituted, both cytokines, in doses at which they had no effect on monolayer cultures, significantly stimulated both PRL and GH secretion. These data show that IL-11 and CNTF may act as regulatory factors in anterior pituitary cells, in which the three-dimensional structure of the gland is of critical importance.

High levels of matrix metalloproteinases regulate proliferation and hormone secretion in pituitary cells.

Beside the digestion of the extracellular matrix during tumor invasion and metastasis, more recently, new functions for matrix metalloproteinases (MMPs) have been proposed. We studied the expression and function of these enzymes in pituitary cells. We observed the activities of MMP-2 and MMP-9 together with expression of membrane-type MMP and tissue inhibitor of metalloproteinase-1 in all types of human pituitary adenomas. We found surprisingly high levels of MMP activity and low levels of tissue inhibitor of metalloproteinases, indicating a high level of extracellular matrix-degrading activity in pituitary adenomas. To examine the function of metalloproteinase activity in pituitary cells we used the synthetic MMP inhibitor batimastat. These studies demonstrate that MMPs secreted by pituitary cells can release growth factors anchored to the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. These results define a new additional mechanism for the control of pituitary hormone secretion and indicate new potential therapeutic targets for pituitary adenomas.

Endoscopic harvesting of the greater saphenous vein for aortocoronary bypass grafting.

We conducted an observational study to evaluate the effectiveness of an endoscopic technique for harvesting the greater saphenous vein for aortocoronary bypass grafting. We hypothesized that the endoscopic technique would minimize the risk of postoperative wound complications. From May 1997 to July 1998, we used an endoscopic technique to harvest the greater saphenous vein in 50 patients who underwent aortocoronary artery bypass grafting. Twenty-five of the patients had an increased risk for wound complications due to preexisting diabetes, obesity, peripheral vascular disease, or lymphedema. The average duration of the procedure was 39 minutes (range, 11 to 70 minutes). The average length of the harvested vein was 58 cm (range, 25 to 85 cm). We made an average of 2.5 incisions per patient (range, 1 to 5 incisions), and the average incision length was 7 cm (range, 3 to 10 cm). Two patients (4%) required conversion to an open technique using 5 small incisions. Postoperative complications included 1 wound infection (2%) and 1 small hematoma (2%). Two patients (4%) had minor erythema at the incision site, and 5 patients (10%) had postoperative lymphedema. The most common problem, ecchymosis, was seen in 6 patients (12%). None required repeat hospitalization or reoperation for wound complications. In our study, the endoscopic approach yielded superior cosmetic results, and reduced wound complications and discomfort, compared with traditional methods of vein harvesting. After gaining expertise with this minimally invasive method of vein harvesting, a surgeon can safely remove the saphenous vein in 20 to 30 minutes.

Interleukin-2 (IL-2) and IL-6 regulate c-fos protooncogene expression in human pituitary adenoma explants.

We have previously shown that interleukin-2 (IL-2) and IL-6, which are expressed in the anterior pituitary, affect anterior pituitary cell proliferation in normal rats and cell lines. Here we examined their effects on the c-fos expression by human anterior pituitary adenomas. Adenoma cells in culture do not express c-fos mRNA. In adenoma explants, however, c-fos expression was detected and was regulated by IL-2 or IL-6. In different tumors (ACTH-, PRL-, GH-secreting and non functioning adenomas), these interleukins had inhibitory or stimulatory effects but the kind of response does not seem to be associated to tumor type or size. Using blocking antibodies, we observed that intrinsic IL-2 and IL-6 regulate c-fos expression in the same way. Our data suggest that IL-2 and IL-6 are not only involved in the regulation of pituitary adenoma function but may also, given the role of c-fos in cell proliferation, be implicated in the development of human pituitary adenomas.