PubMed · 6026327
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G J Clunie, A Gunn, J S Robson. 1967. Hyperparathyroid crisis.. https://doi.org/10.1002/bjs.1800540609
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The high mobility group As (HMGAs) belong to a family of nonhistone nuclear proteins that orchestrate the assembly of nucleoprotein complexes. Through a complex network of protein-DNA and protein-protein interaction, they play important roles in gene transcription, recombination, and chromatin structure. This protein family is involved, through different mechanisms, in both benign and malignant neoplasias. We have recently reported that transgenic mice carrying the Hmga1 or Hmga2 genes under transcriptional control of the cytomegalovirus promoter develop pituitary adenomas secreting prolactin and growth hormone. We have shown that the mechanism of the HMGA2-induced pituitary adenoma is based on the increased E2F1 activity. The expression profile of mouse normal pituitary glands and adenomas induced in HMGA transgenic mice revealed an increased expression of the ccnb2 gene, coding for the cyclin B2 protein, in the neoplastic tissues compared with the normal pituitary gland. Here, we show, by electrophoretic mobility shift assay and chromatin immunoprecipitation, a direct binding of HMGA proteins to the promoter of ccnb2 gene, whereas luciferase assays showed that HMGAs are able to up-regulate ccnb2 promoter activity. Finally, we report an increased CCNB2 expression in human pituitary adenomas of different histotypes that is directly correlated with HMGA1 and HMGA2 expression. Because cyclin B2 is involved in the regulation of the cell cycle, these results taken together indicate that HMGA-induced cyclin B2 overexpression gives an important contribution to experimental and human pituitary tumorigenesis.
The nonadenomatous parathyroid glands associated with parathyroid adenoma in patients with primary hyperparathyroidism (pHPT) are assumed to exhibit suppressed secretion of parathyroid hormone (PTH). Because the function of these glands is of clinical importance for calcium homeostasis after surgery for pHPT, we studied the decrease of serum levels associated with intact PTH (i-PTH) and amino-terminal PTH (N-PTH) after excision of a parathyroid adenoma. Blood samples were obtained from the cubital vein and the inferior thyroid vein in six patients with pHPT. The results show that the levels of both i-PTH and N-PTH decreased after removal of the parathyroid adenoma (p < 0.05 for both). Because the reduction was more pronounced for i-PTH than for N-PTH, the N/i ratio increased from 0.54 +/- 0.33 to 3.76 +/- 1.62 (p < 0.05). Furthermore, the levels of i-PTH and N-PTH were higher centrally than peripherally both before and after adenoma excision (p < 0.05). The results therefore suggest that the secretion of i-PTH and N-PTH in the remaining normal-size parathyroid glands is not completely suppressed. Furthermore, in these parathyroid glands the secretion of amino-terminal PTH fragments is relatively predominant when compared to the release of the intact PTH. The findings underscore the importance of the N-terminal PTH fragment for maintaining calcium homeostasis during the early postoperative period after surgery for pHPT and may explain the rarity of prolonged hypocalcemia after parathyroidectomy.
Although tobacco has been clearly implicated as a cause of a number of cancers, earlier studies had not generally found cigarette smokers to be at higher risk for cancers of the large bowel. Unlike the earlier studies, more recent studies have tended to find cigarette smokers to be at higher risk of colorectal cancer. In addition, cigarette smoking has been consistently associated with a higher risk of colorectal adenomas, precursors of cancers. We hypothesize that smoking is an initiator of colorectal carcinogenesis. The consistent finding of a positive association between smoking and risk of adenomas may reflect the presumably shorter induction period for these lesions. Recent studies indicate that an increased risk for large-bowel cancer emerges only after about four decades after one begins smoking, perhaps accounting for the null studies that were conducted earlier during the smoking epidemic. Most studies had not taken into account an induction period between timing of smoking and risk for cancer. The increasing male-to-female mortality ratio from colorectal cancer over the latter half of this century in the United States may have been a result of tobacco use by men earlier in the century. If the associations observed with colorectal adenomas and cancers in recent studies are causal, approximately 20% of the large-bowel cancers in men would be attributable to smoking. On the basis of the strength of the available evidence, intensified effort to prevent smoking among young people is warranted.