PubMed · 13947151
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J de GENNES. 1963-07-01. [Toxic thyroid adenomas].. https://pubmed.ncbi.nlm.nih.gov/13947151/
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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.
Application of case-cohort design to multi-state disease progression in epidemiological studies has been barely addressed. To estimate multi-state disease natural history, we proposed non-homogeneous exponential regression stochastic model to accommodate the data requiring a non-standard case-cohort design. We allowed transition rates to vary with time by modelling the time of transitions between two states with Weibull distribution. The exponential regression model was used to assess the effect of patient-specific covariates on multi-state disease progressions. This method was successfully applied to two epidemiological applications. The first application was to elucidate the effect of betel quids, smoking and alcohol on three-state disease progression, from normal, through leukoplakia and finally to oral cancer. The second application was to extend the three-state to a five-state model to estimate transition rates from normal to diminutive adenoma to small adenoma to large adenoma and finally to invasive carcinoma of the colon and rectum. Finally, an index for assessing the treatment efficacy for pre-cancerous lesion was developed by comparing transition probabilities derived from the proposed model with the probabilities of malignant transformation after a medical regime.
Tumor galanin content was measured in extracts from human pituitary adenomas using a specific RIA method for monitoring human galanin. Twenty-two out of twenty-four tumors contained galanin with notably high levels in corticotroph adenomas, varying levels in clinically inactive tumors, and low levels in GH secreting adenomas. Tumor galanin and ACTH contents were closely correlated in all tumors. In four young patients with microadenomas and highly active Mb Cushing tumor galanin was inversely related to tumor volume. The molecular form of tumor galanin, studied with reverse-phase HPLC, was homogeneous with the majority of tumor galanin coeluting with standard human galanin. In the tumors analysed with in situ hybridization there was a good correlation between galanin peptide levels and galanin mRNA expression. In some tumors galanin mRNA and POMC levels coexisted, in others they were essentially in different cell populations. Levels of plasma galanin-LI were not related to tumor galanin concentration, and galanin levels were in the same range in sinus petrosus close to the pituitary venous drainage as in peripheral blood. Corticotrophin releasing hormone injections in two patients caused ACTH, but no detectable galanin release into sinus petrosus. Our results demonstrate that corticotroph, but not GH adenomas, express high levels of galanin, in addition to ACTH, and that in some tumors both polypeptides are synthesised in the same cell population. However, galanin levels in plasma were not influenced by the tumor galanin content.