Showing papers by "Anna Spada published in 2019"

Cytoskeleton actin-binding proteins in clinical behavior of pituitary tumors.

Abstract: Although generally benign, pituitary tumors are frequently locally invasive, with reduced success of neurosurgery and unresponsive to pharmacological treatment with somatostatin or dopamine analogues. The molecular basis of the different biological behavior of pituitary tumors are still poorly identified, but a body of work now suggests that the activity of specific cytoskeleton proteins is a key factor regulating both the invasiveness and drug resistance of these tumors. This review recapitulates the experimental evidence supporting a role for the actin-binding protein filamin A (FLNA) in the regulation of somatostatin and dopamine receptors expression and signaling in pituitary tumors, thus in determining the responsiveness to currently used drugs, somatostatin analogues and dopamine receptor type 2 agonists. Regarding the regulation of invasive behavior of pituitary tumoral cells, we bring evidence to the role of the actin-severing protein cofilin, whose activation status may be modulated by dopaminergic and somatostatinergic drugs, through FLNA involvement. Molecular mechanisms involved in the regulation of FLNA expression and function in pituitary tumors will also be discussed.

Trabecular Bone Score (TBS) and Bone Metabolism in Patients Affected with Type 1 Neurofibromatosis (NF1).

Abstract: In patients with neurofibromatosis type 1 (NF1), decreased bone mineral density (BMD) and low levels of 25-hydroxy vitamin D3 (25OHD) have been reported. Recently, the trabecular bone score (TBS) measurement has been proposed as index of bone microarchitecture and fracture risk. In 74 NF1 patients (48 females, 26 males, age 41 ± 12), we measured TBS and investigated clinical stage, lifestyle, vitamin D, serum bone turnover markers, vertebral and femoral BMD. A homogenous cohort of 61 healthy subjects was used as control group. TBS was lower in NF1 patients (1.266 ± 0.113 vs. 1.346 ± 0.105) without differences between sexes. No correlations with 25OHD, low exercise, low calcium intake, reduced sun exposure, and number of skin neurofibromas were observed. As expected, hypovitaminosis D was common (98.6%), as well as BMD reduction in hip and spine sites: In NF1 patients, bone texture evaluated by TBS was low in both sexes without any correlation with clinical or metabolic parameters, suggesting a direct role of the fibromin mutation.

Stem Cells in Pituitary Tumors: Experimental Evidence Supporting Their Existence and Their Role in Tumor Clinical Behavior.

Abstract: Although generally benign, pituitary tumors frequently show local invasiveness and resistance to pharmacological therapy. After the demonstration of the existence of pituitary gland stem cells, over the past decade, the presence of a stem cell subpopulation in pituitary tumors has been investigated, analogous to the cancer stem cell model developed for malignant tumors. This review recapitulates the experimental evidence supporting the existence of a population of stem-like cells in pituitary tumors, focusing on their potential role in tumor initiation, progression, recurrence and resistance to pharmacological therapy.

Bone involvement and mineral metabolism in Williams’ syndrome

Abstract: The previous studies suggested a possible increased risk of hypercalcaemia and reduced bone mineral density (BMD) in Williams’ syndrome (WS) However, an extensive study regarding bone metabolism has never been performed To investigate bone health in young adults with WS Cross-sectional study Endocrinology and Metabolic Diseases and Medical Genetic Units 29 WS young adults and 29 age- and sex-matched controls In all subjects, calcium, phosphorus, bone alkaline phosphatase (bALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHVitD), osteocalcin (OC), carboxyterminal cross-linking telopeptide of type I collagen (CTX), 24-h urinary calcium and phosphorus, femoral-neck (FN) and lumbar-spine (LS) BMD and vertebral fractures (VFx) were assessed In 19 patients, serum fibroblast growth factor-23 (FGF23) levels were measured WS patients showed lower phosphorus (31 ± 07 vs 38 ± 05 mg/dL, p = 00001) and TmP/GFR (081 ± 032 vs 106 ± 025 mmol/L, p = 0001), and an increased prevalence (p = 0005) of hypophosphoremia (345 vs 34%) and reduced TmP/GFR (379 vs 34%) Moreover, bALP (263 ± 85 vs 350 ± 80 U/L), PTH (245 ± 126 vs 337 ± 108 pg/mL), OC (194 ± 53 vs 245 ± 87 ng/mL), and FN-BMD (− 051 ± 032 vs 036 ± 032) were significantly lower (p < 005), while CTX significantly higher (4012 ± 1693 vs 3223 ± 1224 pg/mL, p < 005) Serum and urinary calcium and 25OHVitD levels, LS-BMD and VFx prevalence were comparable No cases of hypercalcemia and suppressed FGF23 were documented Patients with low vs normal phosphorus and low vs normal TmP/GFR showed comparable FGF23 levels FGF23 did not correlate with phosphorus and TmP/GFR values Adult WS patients have reduced TmP/GFR, inappropriately normal FGF23 levels and an uncoupled bone turnover with low femoral BMD

Cofilin is a mediator of RET-promoted medullary thyroid carcinoma cell migration, invasion and proliferation

Abstract: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that originates from parafollicular thyroid C cells and accounts for 5% of thyroid cancers. In inherited cases of MTC, and in about 40% of sporadic cases, activating mutations of the receptor tyrosine kinase proto-oncogene RET are found. Constitutively active RET triggers signaling pathways involved in cell proliferation, survival and motility, but the mechanisms underlying malignant transformation of C-cells have been only partially elucidated. Cofilin is a key regulator of actin cytoskeleton dynamics. A crucial role of cofilin in tumor development, progression, invasion and metastasis has been demonstrated in different human cancers, but no data are available in MTC. Interestingly, RET activation upregulates cofilin gene expression. The aim of this study was to investigate cofilin contribution in invasiveness and growth of MTC cells, and its relevance in the context of mutant RET signaling. We found that cofilin transfection in human MTC cell line TT significantly increased migration (178 ± 44%, p The inhibition of constitutively active RET in TT cells by both the RET pharmacological inhibitor RPI-1 and the transfection of dominant negative RET mutant (RETΔTK) resulted in a reduction of cofilin expression (−37 ± 8%, p In conclusion, these data indicate that an unbalanced cofilin expression, induced by oncogenic RET, contributes to promote MTC invasiveness and growth, suggesting the possibility of targeting cofilin pathway for more effective treatment of MTC.