A Fractional Epidemiological Model for Bone Remodeling Process

This article focuses on modeling bone formation process using a fractional differential approach, named bones remodeling process. The first goal of the work is to investigate existence and uniqueness of the proposed fractional differential model. The next goal is to investigate how similar is the proposed approach to the method based on system classical differential equations. The dynamical system of equations used is built upon three main parameters. These are chemical substances, namely, calcitonin secretion, osteoclastic and osteoblastic, which are involved in the bone’s formation process. We implement some numerical simulations to graphically show the impact of an arbitrary fractional order of derivative. We finally obtained that modeling bone formation process using fractional differential equations yielded comparable results with those obtained through a system of classical differential equations. Flexibility in the choice of the fractional order of derivative is an advantage as it helps in selecting the best fractional order of derivative.

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10–100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or <two-fold response to stimulation. The measurement of calcitonin in fine-needle aspirate washout (FNA-CT) and calcitonin immunocytochemical staining from thyroid nodules are ancillary methods that may significantly improve MTC diagnosis. The present review examines the gray areas in the interpretation of calcitonin measurement in order to provide a tool to clarify the origin of calcitonin secretion and differentiate the behavior of the two-faced Janus of neuroendocrinology: intra-thyroid (MTC) and extra-th9yroid NENs.

Efficacy of a novel second-generation somatostatin-dopamine chimera (TBR-065) in human medullary thyroid cancer: a preclinical study

Introduction: Somatostatin and dopamine receptors have a pivotal role in control of hormone secretion and cell proliferation in different neuroendocrine neoplasms, including medullary thyroid cancer (MTC). In the present preclinical study, we evaluated the antitumor activity of TBR-065 (formerly BIM-23B065), a second-generation somatostatin-dopamine chimera, in two human MTC cell lines. Methods: the effects of lanreotide (LAN) and TBR-065 on the cell growth proliferation, calcitonin secretion, cell cycle, apoptosis, cell migration and tumor-induced angiogenesis have been evaluated through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, ECLIA assay, wound-healing assay and zebrafish platform, respectively. Results: TBR-065 exerted a more prominent antitumor activity compared to LAN in both MTC cell lines, as shown by inhibition of cell proliferation (maximal inhibition in TT: -50.3% and -37.6%, respectively; in MZ-CRC-1: -58.8% and -27%, respectively) and migration (in TT: -42.7% and -22.9%, respectively; in MZ-CRC-1: -75.5% and -58.2%, respectively). Only the new chimera decreased significantly the fraction of cells in S phase (TT: -33.8%, MZ-CRC-1: -18.8%), and increased cells in G2/M phase (TT: +13%, MZ-CRC-1: +30.5%). In addition, TBR-065 exerted a more prominent pro-apoptotic effect compared to LAN in TT cells. A concomitant decrease of calcitonin secretion was observed after 2 days of incubation with both drugs, with a more relevant effect of TBR-065. However, neither LAN nor TBR-065 showed any effect on tumor-induced angiogenesis, as evaluated using a zebrafish/tumor xenograft model. Discussion/Conclusion: In MTC cell lines a second generation somatostatin-dopamine analogue, TBR-065, exerts a more relevant anti-tumor activity, as compared with LAN, through modulation of cell cycle, induction of apoptosis and reduction in migration. Further studies are required to establish whether TBR-065 has comparable potent inhibitory effects on tumor growth in vivo.