Waiting for the emperor. Italian princes, the pope and Charles V

In the 1540s, Italian princes, lords and cardinals wrote to each other using a secret, highly imaginative language. They were waiting for Emperor Charles V to descend on Italy to cut the papacy and Papal States down to size once and for all. Their letters, which have never before been used by historians, were not literary fantasies; behind the fictitious names, metaphors and the ferocious satire against Pope Paul III, there were weapons, money and power. For years, against the background of the battle between the two giants – the pope and the emperor – the courts of Mantua, Florence, Milan and Ferrara pursued a grand plan of containing the pope’s power by allying with men of Charles V. This history of Italy differs greatly from the one we are usually taught. The epoch-making conflict between the ‘Italy of the Emperor’ and the ‘Italy of the Pope’ was not merely political: it was mixed with religious problems, it developed in the sphere of communication, and it left traces in Italian cultural life, on the frescoed walls of palaces and in the pages of books. But the daring project drawn up by the Italian princes in the shade of the imperial eagle failed, and failed forever

Genetic Predisposition to Familial Nonmedullary Thyroid Cancer: An Update of Molecular Findings and State-of-the-Art Studies

Familial thyroid cancer has become a well-recognized entity in patients with thyroid cancer originating from follicular cells, that is, nonmedullary thyroid carcinoma. The diagnosis of familial thyroid cancer provides an opportunity for early detection and possible prevention in family members. Understanding the syndromes associated with familial thyroid cancer allows clinicians to evaluate and treat patients for coexisting pathologic conditions. About five percents of patients with well-differentiated thyroid carcinoma have a familial disease. Patients with familial non-medullalry thyroid cancer have more aggressive tumors with increased rates of extrathyroid extension, lymph node metastases, and frequently show the phenomenon of “anticipation” (earlier age at disease onset and increased severity in successive generations). So far, four predisposition loci have been identified in relatively rare extended pedigrees, and association studies have identified multiple predisposing variants for differentiated thyroid cancer. This suggests that there is a high degree of genetic heterogeneity and that the development of this type of tumor is a multifactorial and complex process in which predisposing genetic variants interact with a number of incompletely understood environmental risk factors. Thus, the search for the causative variants is still open and will surely benefit from the new technological approaches that have been developed in recent years

Comment to the Description of a Novel Cohesinopathy in Chronic Intestinal Pseudo Obstruction

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The mitochondrial permeability transition pore is a dispensable element for mitochondrial calcium efflux

AbstractThe mitochondrial permeability transition pore (mPTP) has long been known to have a role in mitochondrial calcium (Ca2+) homeostasis under pathological conditions as a mediator of the mitochondrial permeability transition and the activation of the consequent cell death mechanism. However, its role in the context of mitochondrial Ca2+ homeostasis is not yet clear. Several studies that were based on PPIF inhibition or knock out suggested that mPTP is involved in the Ca2+ efflux mechanism, while other observations have revealed the opposite result.The c subunit of the mitochondrial F1/FO ATP synthase has been recently found to be a fundamental component of the mPTP. In this work, we focused on the contribution of the mPTP in the Ca2+ efflux mechanism by modulating the expression of the c subunit. We observed that forcing mPTP opening or closing did not impair mitochondrial Ca2+ efflux. Therefore, our results strongly suggest that the mPTP does not participate in mitochondrial Ca2+ homeostasis in a physiological context in HeLa cells

Mutant MYO1F alters the mitochondrial network and induces tumor proliferation in thyroid cancer

Familial aggregation is a significant risk factor for the development of thyroid cancer and Familial Non-Medullary Thyroid Cancer (FNMTC) accounts for 5-7% of all NMTC. Whole Exome Sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.400G>A, NM_012335; p.Gly134Ser) in exon 5 of MYO1F, mapping to the linkage locus. In the thyroid FRTL-5 cell model stably expressing the mutant MYO1F p.Gly134Ser protein we observed an altered mitochondrial network, with increased mitochondrial mass and a significant increase of both intracellular and extracellular Reactive Oxygen Species, compared to cells expressing the wild-type protein or carrying the empty vector. The mutation conferred a significant advantage in colony formation, invasion and anchorage independent growth. These data were corroborated by in vivo studies in zebrafish, since we demonstrated that the mutant MYO1F p.Gly134Ser, when overexpressed, can induce proliferation in whole vertebrate embryos, compared to the wild-type one. MYO1F screening in additional 192 FNMTC families identified another variant in exon 7, which leads to exon skipping, and is predicted to alter the ATP-binding domain in MYO1F. Our study identified for the first time a role for MYO1F in NMTC. This article is protected by copyright. All rights reserved

Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility

The enteric nervous system (ENS) is the third division of the autonomic autonomic nervous system and the largest collection of neurons outside the central nervous system (CNS). The ENS has been referred to as "the brain in the gut" or "the second brain of the human body" because of its highly integrated neural circuits controlling a vast repertoire of gut functions, including absorption/secretion, splanchnic blood vessels, some immunological aspects, intestinal epithelial barrier, and gastrointestinal (GI) motility. The latter function is the result of the ENS fine-tuning over smooth musculature, along with the contribution of other key cells, such as enteric glia (astrocyte like cells supporting and contributing to neuronal activity), interstitial cells of Cajal (the pacemaker cells of the GI tract involved in neuromuscular transmission), and enteroendocrine cells (releasing bioactive substances, which affect gut physiology). Any noxa insult perturbing the ENS complexity may determine a neuropathy with variable degree of neuro-muscular dysfunction. In this review, we aim to cover the most recent update on genetic mechanisms leading to enteric neuropathies ranging from Hirschsprung's disease (characterized by lack of any enteric neurons in the gut wall) up to more generalized form of dysmotility such as chronic intestinal pseudo-obstruction (CIPO) with a significant reduction of enteric neurons. In this line, we will discuss the role of the RAD21 mutation, which we have demonstrated in a family whose affected members exhibited severe gut dysmotility. Other genes contributing to gut motility abnormalities will also be presented. In conclusion, the knowledge on the molecular mechanisms involved in enteric neuropathy may unveil strategies to better manage patients with neurogenic gut dysmotility and pave the way to targeted therapies