Putting cells in motion: Advantages of endogenous boosting of BDNF production

Motor exercise, such as sport or musical activities, helps with a plethora of diseases by modulating brain functions in neocortical and subcortical regions, resulting in behavioural changes related to mood regulation, well-being, memory, and even cognitive preservation in aging and neurodegenerative diseases. Although evidence is accumulating on the systemic neural mechanisms mediating these brain effects, the specific mechanisms by which exercise acts upon the cellular level are still under investigation. This is particularly the case for music training, a much less studied instance of motor exercise than sport. With regards to sport, consistent neurobiological research has focused on the brain-derived neurotrophic factor (BDNF), an essential player in the central nervous system. BDNF stimulates the growth and differentiation of neurons and synapses. It thrives in the hippocampus, the cortex, and the basal forebrain, which are the areas vital for memory, learning, and higher cognitive functions. Animal models and neurocognitive experiments on human athletes converge in demonstrating that physical exercise reliably boosts BDNF levels. In this review, we highlight comparable early findings obtained with animal models and elderly humans exposed to musical stimulation, showing how perceptual exposure to music might affect BDNF release, similar to what has been observed for sport. We subsequently propose a novel hypothesis that relates the neuroplastic changes in the human brains after musical training to genetically-and exercise-driven BDNF levels

LASER-VISUAL-INERTIAL ODOMETRY BASED SOLUTION FOR 3D HERITAGE MODELING: THE SANCTUARY OF THE BLESSED VIRGIN OF TROMPONE

Abstract. The advent of new mobile mapping systems that integrate different sensors has made it easier to acquire multiple 3D information with high speed. Today, technological development has allowed the creation of portable systems particularly suitable for indoor surveys, which mainly integrating LiDAR devices, chambers and inertial platforms, make it possible to create in a fast and easy way, full 3D model of the environment. However, the performance of these instruments differs depending on the acquisition context (indoor and outdoor), the characteristics of the scene (for example lighting, the presence of objects and people, reflecting surfaces, textures) and, above all, the mapping and localization algorithms implemented in devices. The purpose of this study is to analyse the results, and their accuracy, deriving from a survey conducted with the KAARTA Stencil 2 handheld system. This instrument, composed of a 3D LiDAR Velodyne VLP-16, a MEMS inertial platform and a feature tracker camera, it is able to realize the temporal 3D map of the environment. Specifically, the acquisition tests were carried out in a context of metrical documentation of an architectural heritage, in order extract architectural detail for the future reconstruction of virtual and augmented reality environments and for Historical Building Information Modeling purposes. The achieved results were analysed and the discrepancies from some reference LiDAR data are computed for a final evaluation. The system was tested in the church and cloister of the Sanctuary of the Beata Vergine del Trompone in Moncrivello (VC) (Italy).</p

Does the term 'trophic' actually mean anti-amyloidogenic? The case of NGF.

The term trophic is widely used to indicate a general pro-survival action exerted on target cells by different classes of extracellular messengers, including neurotrophins (NTs), a family of low-molecular-weight proteins whose archetypal member is the nerve growth factor (NGF). The pro-survival action exerted by NTs results from a coordinated activation of multiple metabolic pathways, some of which have only recently come to light. NGF has been shown to exert a number of different, experimentally distinguishable effects on neurons, such as survival, differentiation of target neurons, growth of nerve fibers and their guidance (tropism) toward the source of its production. We have proposed a more complete definition of the NGF trophic action that should also include its newly discovered property of inhibiting the amyloidogenic processing of amyloid precursor protein (APP), which is among the first hypothesized primary trigger of Alzheimer's disease (AD) pathogenesis. This inhibitory action appears to be mediated by a complex series of molecular events and by interactions among NGF receptors (TrkA and p75), APP processing and tau metabolic fate and fun

Thyroid cancers: From surgery to current and future systemic therapies through their molecular identities

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor

MicroRNA expression profiling of RAS-mutant thyroid tumors with follicular architecture: microRNA signatures to discriminate benign from malignant lesions

Purpose: RAS mutations represent common driver alterations in thyroid cancer. They can be found in benign, low-risk and malignant thyroid tumors with follicular architecture, which are often diagnosed as indeterminate nodules on preoperative cytology. Therefore, the detection of RAS mutations in preoperative setting has a suboptimal predictive value for malignancy. In this study, we investigated differentially expressed microRNA (miRNA) in benign and malignant thyroid tumors with follicular architecture carrying mutations in RAS genes. Methods: Total RNA was purified from 60 RAS-mutant follicular-patterned thyroid tumors, including follicular adenoma (FA), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), papillary and follicular thyroid carcinoma cases (PTC, FTC); 22 RAS-negative FAs were used as controls. The expression analysis of 798 miRNAs was performed by digital counting (nCounter nanoString platform). Results: Comparing RAS-mutant and RAS-negative FAs, 12 miRNAs showed significant deregulation, which was likely related to the oncogenic effects of RAS mutations. Twenty-two miRNAs were differentially expressed in RAS-mutant benign versus malignant tumors. Considering the tumor type, 24 miRNAs were deregulated in PTC, 19 in NIFTP, and seven in FTC and compared to FA group; among these, miR-146b-5p, miR-144-3p, and miR-451a showed consistent deregulation in all the comparisons with the highest fold change. Conclusions: The miRNA expression analysis of follicular-patterned thyroid tumors demonstrated that RAS mutations influences miRNA profile in benign tumors. In addition, several miRNAs showed a histotype-specific deregulation and could discriminate between RAS-mutant benign and RAS-mutant malignant thyroid lesions, thus deserving further investigation as potential diagnostic markers

Targeted therapy against chemoresistant colorectal cancers: Inhibition of p38α modulates the effect of cisplatin in vitro and in vivo through the tumor suppressor FoxO3A

Chemoresistance is a major obstacle to effective therapy against colorectal cancer (CRC) and may lead to deadly consequences. The metabolism of CRC cells depends highly on the p38 MAPK pathway, whose involvement in maintaining a chemoresistant behavior is currently being investigated. Our previous studies revealed that p38a is the main p38 isoform in CRC cells. Here we show that p38a pharmacolog- ical inhibition combined with cisplatin administration decreases colony formation and viability of cancer cells and strongly increases Bax-dependent apoptotic cell death by activating the tumor suppressor pro- tein FoxO3A. Our results indicate that FoxO3A activation up-regulates transcription of its target genes (p21, PTEN, Bim and GADD45), which forces both chemosensitive and chemoresistant CRC cells to undergo apoptosis. Additionally, we found that FoxO3A is required for apoptotic cell death induction, as confirmed by RNA interference experiments. In animal models xenografted with chemoresistant HT29 cells, we further confirmed that the p38-targeted dual therapy strategy produced an increase in apoptosis in cancer tissue leading to tumor regression. Our study uncovers a major role for the p38- FoxO3A axis in chemoresistance, thereby suggesting a new therapeutic approach for CRC treatment; moreover, our results indicate that Bax status may be used as a predictive biomarker

Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance.

Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly (APP(YG/YG) mice). This mutation alters the processing of APP and TrkA signaling and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APP(YG/YG) mice. Here, we show that APP(YG/YG) mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone, and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APP(YG/YG) mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APP(YG/YG) are a valuable mouse model to study APP functions in physiological and pathological processes

The Molecular Signature More Than the Site of Localization Defines the Origin of the Malignancy

The diagnosis of the primary origin of metastases to the thyroid gland is not easy, in particular in case of concomitant lung adenocarcinoma which shares several immunophenotypical features. Although rare, these tumors should be completely characterized in order to set up specific therapies. This is the case of a 64-years-old woman referred to our institution for a very advanced neoplastic disease diagnosed both as poorly differentiated/anaplastic thyroid cancer (PDTC/ATC) for the huge involvement of the neck and concomitant lung adenocarcinoma (LA). Neither the clinical features and the imaging evaluation nor the tumor markers allowed a well-defined diagnosis. Moreover, the histologic features of the thyroid and lung biopsies confirmed the synchronous occurrence of two different tumors. The molecular analysis showed a c.34G&gt;T (p.G12C) mutation in the codon 12 of K-RAS gene, in both tissues. Since, this mutation is highly prevalent in LA and virtually absent in PDTC/ATC the lung origin of the malignancy was assumed, and the patient was addressed to the correct therapeutic strategy

Vulnerability to low-dose combination of irinotecan and niraparib in ATM-mutated colorectal cancer

Background: Despite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes. Methods: We tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence. Results: We showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence. Conclusions: This work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials