No abstract

Molecular analysis for a panel of mutations has significant diagnostic value for all categories of indeterminate cytology and can be helpful for more effective clinical management of these patients.

Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which causes the common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since the identification of the peptide in 1982 and the cloning of the cDNA in 1987, it has become clear that PTHrP is a prohormone that is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only in cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalcemia of malignancy in which PTHrP plays the role of a classical "endocrine" hormone, under normal circumstances PTHrP plays predominantly paracrine and/or autocrine roles. These apparent physiological functions are also complex and appear to include 1) regulation of smooth muscle (vascular, intestinal, uterine, bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct, mammary gland) calcium transport, and 3) regulation of tissue and organ development, differentiation, and proliferation. In this review, the discovery of PTHrP, the structure of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.

Types 1 and 2 diabetes affect some 380 million people worldwide. Both result ultimately from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with peak beta cell labeling indices achieving approximately 2% in first year of life1-4. In embryonic life and after early childhood, beta cell replication rates are very low. While beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts1-8. Hence, there remains an urgent need for diabetes therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, we report the results of a high-throughput small molecule screen (HTS) revealing a novel class of human beta cell mitogenic compounds, analogues of the small molecule, harmine. We also define dual specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine, and the Nuclear Factors of activated T-cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation as well as beta cell differentiation. These observations suggest that harmine analogues (“harmalogs”) may have unique therapeutic promise for human diabetes therapy. Enhancing potency and beta cell specificity are important future challenges.

In 50 consecutive patients with cancer-associated hypercalcemia, we measured nephrogenous cyclic AMP, tubular phosphorus threshold, fasting calcium excretion, plasma 1,25-dihydroxyvitamin D, and immunoreactive parathyroid hormone as determined by four region-specific antiserums. Nephrogenous cyclic AMP excretion was elevated in 41 patients and suppressed in nine (means, 5.85 vs. 0.51 nmol per 100 ml of glomerular filtrate). There was no overlap between these groups. When compared with 15 patients with primary hyperparathyroidism, the group with increased cyclic AMP excretion had similar reductions in tubular phosphorus threshold; higher fasting calcium excretion (means, 0.66 vs. 0.25 mg per 100 ml of glomerular filtrate, P < 0.01); marked reductions in 1,25-dihydroxyvitamin D (means, 20 vs. 83 pg per milliliter, P < 0.001); and lower levels of immunoreactive parathyroid hormone in all four assays. The data suggest that elevated excretion of nephrogenous cyclic AMP may be a useful marker of humorally mediated cancer-associated hypercalcemia, that this type of hypercalcemia is common, that the humoral factor responsible for this syndrome is not native 1-84 parathyroid hormone, and that the various subtypes of cancer-associated hypercalcemia are biochemically distinguishable from primary hyperparathyroidism.