Genetic Variants in Genes Correlated to the PI3K/AKT Pathway: The Role of ARAP3, CDH5, KIF11 and RELN in Primary Lymphedema.

Genetic anomalies affecting lymphatic development and function can lead to lymphatic dysfunction, which could manifest as lymphedema. Understanding the signaling pathways governing lymphatics function is crucial for developing targeted diagnostic and therapeutic interventions. This study aims to characterize genetic variants in genes involved in the PI3K/AKT signaling pathway, which plays a critical role in lymphangiogenesis. 408 patients diagnosed with primary lymphedema were sequenced using a next-generation sequencing (NGS) gene panel composed of 28 diagnostic genes and 71 candidate genes. The analysis revealed six variants in genes RELN, ARAP3, CDH5, and KIF11. Five of these variants have never been reported in the literature. All these genes have been correlated to lymphatic activity and are involved in the PI3K/ AKT pathway. As the PI3K/AKT signaling pathway plays an essential role in lymphangiogenesis and lymphatic function, genetic variants in genes correlated to this pathway could lead to lymphedema. Our findings underscore the potential of the PI3K/AKT pathway in lymphedema pathogenesis, supporting the role of RELN, ARAP3, CDH5,, and KIF11 as diagnostic and therapeutic targets.

Plasma calcitonin and tumors.

Plasma levels of calcium, phosphorus, immunoreactive calcitonin (iCT), immunoreactive parathyroid hormone (iPTH), and carcinoembryonic antigen (CEA) were measured in patients affected by tumors of various organs: 22 breast, 41 lung, 23 kidney, 16 gastrointestinal tract, and 8 other types, iCT plasma level was elevated in 53.6% of patients with bronchogenic cancer, in 31.8% with breast cancer, in 65.3% with renal cancer, in 31.2% with gastrointestinal cancer, and in 62.5% with other tumors. Blood calcium level was increased in 6 patients suffering from lung cancer; iCT plasma level was increased in all but one of these subjects. iPTH plasma level, measured in 35 patients, was elevated only in one case, in which normo-calcemia was present. Our results demonstrate that plasma iCT is increased in a high percentage of cancer patients and that it is probably a good tumor marker. The simultaneous measurement of CEA increases the diagnostic probability of the individual marker. The incidence of laboratory findings suggestive of primary or ectopic hyperparathyroidism was very low in our series of patients.

Effects of age on the urinary excretion of total and non-dialyzable hydroxyproline.

This study was carried out in order to investigate the effects of age on the urinary excretion of total and non-dialyzable hydroxyproline (OHPr) in normal subjects. We found that total urinary OHPr was negatively correlated with age but, by means of partial regression analysis, no correlation was found after correction for changes in creatinine clearance; on the contrary, non-dialyzable OHPr showed a statistically significant negative correlation with age (r = -0.56) even when creatinine clearance was held constant (p less than 0.05). A highly significant direct correlation was found between total and non-dialyzable OHPr in the whole group (r = 0.54) and when only premenopausal women and men under 60 years of age were considered (r = 0.51). No correlation was found when postmenopausal women and men more than 60-year-old were taken into account. Our data appear to indicate that also the decrease in osteogenetic activity is responsible for the physiological late involutional bone loss; they also show the importance of hormonal changes in inducing an uncoupling between bone formation and resorption.

Pathophysiological studies in hypercalciuric and normocalciuric stone formers.

This study has been carried out in order to investigate the effects of a standard oral calcium load in 18 hypercalciuric and 18 normocalciuric recurrent stone formers. Following oral loading there was not a significant difference in the two groups studied, as far as serum calcium increment was concerned; however, urinary calcium excretion was significantly greater in hypercalciuric stone formers. The results obtained, although they do not exclude the presence of intestinal calcium hyperabsorption, seem to demonstrate the existence of a diminution of renal tubular calcium reabsorption in patients with idiopathic hypercalciuria.

Acute effects of removal of parathyroid adenoma on plasma and urinary hydroxyproline levels.

This study was carried out to investigate early effects of parathyroidectomy (PTx) on bone matrix collagen metabolism. Eleven patients suffering from primary hyperparathyroidism were studied by measuring urinary excretion of hydroxyproline (OHPr) and cAMP in samples collected before PTx and, on the day of surgery, at intervals of 1-3 h for the first 10 h and then at longer intervals. In six patients nondialyzable urinary OHPr and free plasma aminoacid levels were also assayed. We found that the average period required for OHPr/Cr ratio and plasma OHPr to reach normal values was longer than the mean time required for cAMP/Cr ratio to reach normal limits. In all patients the total amount of nondialyzable OHPr decreased in the first 24 h after PTx but thereafter a daily increase in the urinary excretion of nondialyzable component was seen, so that the fractional amount of nondialyzable OHPr in the fourth postoperative day (26.8 +/- 5.2 SE) was significantly higher than that of preoperative one (6.1 +/- 1.0; p less than 0.02). Our results confirm that PTx induces a reduction in the rate of bone collagen resorption and indicate that changes of OHPr/Cr ratio and free plasma OHPr values may be considered useful indices of successful parathyroid surgery, even though they lag behind those of cAMP. The different behavior of total and nondialyzable OHPr after surgery indicates that acute deficiency of parathyroid hormone induces a positive uncoupling of the two processes of bone remodeling, thus supporting the view that the acute direct effect of the hormone on bone formation is an inhibition of this process.