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The mammalian Target of Rapamycin (mTOR) is a molecular complex equipped with kinase activity which controls cell viability being key in the PI3K/PTEN/Akt pathway. mTOR acts by integrating a number of environmental stimuli to regulate cell growth, proliferation, autophagy, and protein synthesis. These effects are based on the modulation of different metabolic pathways. Upregulation of mTOR associates with various pathological conditions, such as obesity, neurodegeneration, and brain tumors. This is the case of high-grade gliomas with a high propensity to proliferation and tissue invasion. Glioblastoma Multiforme (GBM) is a WHO grade IV malignant, aggressive, and lethal glioma. To date, a few treatments are available although the outcome of GBM patients remains poor. Experimental and pathological findings suggest that mTOR upregulation plays a major role in determining an aggressive phenotype, thus determining relapse and chemoresistance. Among several activities, mTOR-induced autophagy suppression is key in GBM malignancy. In this article, we discuss recent evidence about mTOR signaling and its role in normal brain development and pathological conditions, with a special emphasis on its role in GBM.

The date of birth of Realdo Colombo is still uncertain. However, 1516 is conventionally credited as the year where he was born in Cremona. Colombo’s life can be divided into three periods, according to the cities where he worked: Padua, Pisa and Rome. A talented anatomist, in Padua Colombo became assistant of Andreas Vesalius in 1541. In 1545 he moved to Pisa at the behest of the Grand Duke Cosimo I de’ Medici. Finally, he was invited in Rome by Pope Paul III and became the physician of many important patients, including Michelangelo Buonarroti. He also performed the autopsy on the body of Saint Ignatius of Loyola. In his unique masterpiece, De re anatomica, consisting of 15 books, Colombo reported original observations. He hoped to have a text illustrated by Michelangelo that would have competed with the fabrica of Vesalius, but that purpose did not realize. Indeed, the unique engraving of the volume, published posthumously in 1559, is the frontispiece. The most important anatomical discovery attributed to Colombo is the original description of the pulmonary circulation, based on hundreds of dissections and vivisections. The Galen’s long-standing doctrine of the blood circulation from the right ventricle to the left ventricle through invisible pores of the interventricular septum was definitively rejected. Although two other figures had already described the pulmonary circulation – the thirteenth century Arabic physician Ibn al-Nafis, in the Commentary on Anatomy in Avicenna’s Canon, and the Spanish philosopher Michael Servetus, in the theological book Christianismi restitutio – Colombo seems to have arrived at his conclusions independently. He also understood the function of the cardiac valves. Colombo’s book had a profound effect on William Harvey, when he prepared his lectures on anatomy for the College of Physicians of London, and was determinant for the publication of his description of the blood circulation in De motu cordis (1628). Other anatomical observations are attributed to Colombo. He corrected previous misconceptions, demonstrating that the right kidney is lower than the left, and showing that the lens is in the anterior chamber of the eye. He recognized anatomical variants, such as the presence of palmaris longus muscle, and described congenital malformations, such as the horseshoe kidney. He also seems to have coined the term “placenta” and claimed to have been the first to describe the clitoris and its function., Italian Journal of Anatomy and Embryology, Vol. 121, No. 1 (Supplement) 2016

A number of plastic events were described in the spinal cord in the course of amyotrophic lateral sclerosis (ALS). These consist of various morphological effects, involving neurons, glia, and inflammatory cells, as well. Among plastic changes, an increase in neuronal progenitor cells (NPC) occurs within ependymal cells layer of lamina X. This stem cell-like activity is known to be weak in baseline conditions but it is known to increase significantly during spinal cord disorders, when it preferentially generates glial cells, due to the strong gliogenic effect of the spinal cord “milieu”. In the present work, we used immunohistochemistry and electron microscopy to analyze cell number within lamina X at the end stage of disease in the G93A mouse model of ALS in baseline conditions and following chronic lithium administration. These cells were identified by using GFAP, bIII-tubulin, NeuN, and calbindin- D28K immunostaining. In the absence of lithium we observed an increase of lamina X cells in ALS mice with a glial phenotype, while in G93A mice treated with lithium these cells differentiate towards neuronal-like phenotype. These effects of lithium are concomitant with slowed disease progression and are reminiscent of the neurogenetic effects described in the sub-ependymal ventricular zone of the hippocampus. The present data confirm the scarce NPC activity in the intact spinal cord which is enhanced by disease conditions; in the presence of chronic lithium, such increased NPCs differentiate towards a neuron-like rather than a glial phenotype., Italian Journal of Anatomy and Embryology, Vol 119, No 1 (Supplement) 2014

Glioblastoma Multiforme (GBM), a WHO grade IV malignant glioma, is the most common, aggressive and lethal primary brain tumor [1]. GBM poses a unique challenge due to its propensity for proliferation and tissue invasion. Multiple experimental and pathological findings suggest that, at molecular level, the up-regulation of the molecular complex mTOR plays a pivotal role in determining cell growth, stem cell proliferation, infiltration, relapse and resistance to standard treatments [2]. When activated, mTOR controls and modulates, directly or indirectly, several cellular events and biochemical pathways [3,4]; in particular, mTOR acts as a negative modulator of autophagy, resulting in a defective autophagy in GBM. In the present study we analyzed the ultrastructural correlates of autophagy inhibition in GBM cells and we reverted various alterations by administering the mTOR inhibitor rapamycin. Rapamycin effects were both dose- and time-dependent and consisted in reducing cell proliferation and inducing cell differentiation. In particular, rapamycin was able to restore autophagy vacuoles and it increased specific markers of neuronal differentiation while it inhibited stem cell-like phenotype. The present data lend substance to mTOR and autophagy as critical determinant in astrocytomas and provide the first ultrastructural evidence of autophagy modulation in these brain tumors., Italian Journal of Anatomy and Embryology, Vol 119, No 1 (Supplement) 2014

Recent data suggests that catecholamine systems might have a trophic role in the spinal cord. These data are based on the clinical evidence that beta-2 agonists produce a relief in spinal motor neuron disorders. Therefore, in the present study we isolated ventral spinal cord cell cultures and we administered either the beta-2 agonist salbutamol alone or in combination with the beta-2 antagonist butoxamine. These experiments were carried out both in baseline conditions and in the presence of a non-NMDA glutamate shock. In fact, increased extracellular glutamate concentration can be toxic for neuronal cells. Glutamate- mediated excitotoxicity relies on the stimulation of both NMDA and non- NMDA receptors although naturally occurring motor neuron loss is thought to depend on an excess of stimulation of non-NMDA receptors. Therefore, primary cell cultures obtained from the ventral spinal cord of 14-days-old mice embryos were preadministered MK-801, a non-competitive antagonist of NMDA receptors, immediately before the non-NMDA (both kainate and AMPA) receptor agonist kainic acid (KA, 50 and 100 μM for 15 min) either in baseline conditions or in combination with salbutamol (10 μM) and butoxamine (50 μM) administered 30 min before KA. We found that the beta-2 antagonist butoxamine did not produce any effect either alone or in combination with kainate. Although butoxamine prevented the effects induced by the beta-2 agonist salbutamol. In particular, salbutamol prevented non-NMDA-induced motor neuron loss and this effect was abolished by the concomitant administration of butoxamine. When salbutamol was administered alone we detected morphological changes at motor neuron level. We also analysed whether salbutamol administration increased the expression of survival motor neuron protein (SMN, an endogenous molecule which provides protective effect for motor neurons) as a possible mechanism of neuroprotection. Unexpectedly, the protective effects induced by salbutamol were accompanied by a reduction of the SMN, while KA induced an increase in SMN levels. These results lend substance that catecholamine receptors subtype beta-2 protect motor neurons in the short term following glutamate excitotoxicity. It is likely that the paradoxical effects observed for SMN level might be due to the need of a compensatory mechanism (following NMDA) or the reduced level of neuronal stress (following salbutamol). Further studies are in progress to unravel the mechanisms responsible for neuroprotection induced at motor neuron level by catecholamine and beta-2 receptors., Italian Journal of Anatomy and Embryology, Vol 117, No 2 (Supplement) 2012