Through Predictive Personalized Medicine

Neuroblastoma (NBM) is a deadly form of solid tumor mostly observed in the pediatric age. Although survival rates largely differ depending on host factors and tumor-related features, treatment for clinically aggressive forms of NBM remains challenging. Scientific advances are paving the way to improved and safer therapeutic protocols, and immunotherapy is quickly rising as a promising treatment that is potentially safer and complementary to traditionally adopted surgical procedures, chemotherapy and radiotherapy. Improving therapeutic outcomes requires new approaches to be explored and validated. In-silico predictive models based on analysis of a plethora of data have been proposed by Lombardo et al. as an innovative tool for more efficacious immunotherapy against NBM. In particular, knowledge gained on intracellular signaling pathways linked to the development of NBM was used to predict how the different phenotypes could be modulated to respond to anti-programmed cell death-ligand-1 (PD-L1)/programmed cell death-1 (PD-1) immunotherapy. Prediction or forecasting are important targets of artificial intelligence and machine learning. Hopefully, similar systems could provide a reliable opportunity for a more targeted approach in the near future

Being in the Past and Perform the Future in a Virtual World: VR Applications to Assess and Enhance Episodic and Prospective Memory in Normal and Pathological Aging

The process of aging commonly features a gradual deterioration in cognitive performance and, in particular, the decline of memory. Despite the increased longevity of the world's population, the prevalence of neurodegenerative conditions, such as dementia, continues to be a major burden on public health, and consequently, the latest research has been focused on memory and aging. Currently, the failure of episodic and Prospective memory (PM) is one of the main complaints in the elderly, considered among the early symptoms of dementia. It is therefore increasingly important to define more clearly the boundaries between normal and pathological aging. Recently, researchers have begun to build and apply Virtual Environments (VE) to the explicit purpose of better understanding the performance of episodic and PM in complex and realistic contexts, with the perspective of further developing effective training procedures that depend on reliable cognitive assessment methods. Virtual technology offers higher levels of realism than "pen and paper" testing and at the same time more experimental control than naturalistic settings. In this mini-review article, we examine the outcomes of recently available studies on virtual reality technology applications developed for the assessment and improvement of episodic and/or PM. To consider the latest technology, we selected 29 articles that have been published in the last 10 years. These documents show that VR-based technologies can provide a valid basis for screening and treatment and, through increased sensory stimulation and enriched environments reproducing the scenarios of everyday life, could represent effective stimulating experiences even in pathological aging

Neuronal nitric oxide synthase is involved in CB/TRPV1 signalling: Focus on control of hippocampal hyperexcitability

Cannabinoids (CB), transient receptors potential vanilloid type 1 (TRPV1) and nitric oxide (NO) were found to be interlinked in regulating some neuronal functions such as membrane excitability and synaptic transmission. TRPV1 play a fundamental role since it represents a synaptic target for CB that triggers several downstream cellular pathways. In this regard, recent evidence report that TRPV1 could influence NO production by modulating neuronal NO synthase (nNOS) activity. In the present research, we pointed to manipulate nNOS function to assess its role on TRPV1 signalling in hyperexcitability conditions elicited in the dentate gyrus of hippocampal formation. The activation of TRPV1 receptors is achieved by administering capsaicin (CAP), the main TRPV1 agonist exerting a widely reported proepileptic effects. In order to focus on nNOS activity, we used 7-nitroindazole (7NI), nNOS inhibitor, or L-Arginine (ARG), NO precursor, before CAP. Then, the effects of each of these co-administration protocols were tested in presence of WIN 55,212, a CB agonist. The study was conducted in rats using an electrically-induced acute model of temporal lobe hyperexcitability, the Maximal Dentate Activation (MDA), considering different indicators of paroxysmal activity such as: percentage of responses to electrical stimulation, MDA discharge parameters and threshold current intensity for MDA. Data showed that the excitatory effects of CAP were reduced by 7NI and enhanced by ARG pretreatments, respectively. In addition, the co-treatment with WIN counteracted CAP effect, substantially resulting in an inhibitory effect. Finally, the CAP-WIN functional interaction appeared to be modulated by interfering with NO signalling since 7NI increased the inhibitory effect induced by the co-treatment with CAP and WIN, whereas ARG reduced it. These findings suggest that nNOS function could be involved in the CB/TRPV1 signalling and shed light on a new putative cannabinoid-related control of neuronal hyperexcitability in the hippocampu

Nitric oxide-active compounds modulate the intensity of glutamate-evoked responses in the globus pallidus of the rat

Aim The effects of local applied NO-active compounds on glutamate (GLU)-evoked responses were investigated in globus pallidus (GP) neurons. Main methods Extracellularly recorded single units from anesthetized rats were treated with GLU before and during the microiontophoretic application of S-nitrosoglutathione (SNOG), a NO donor, and Nω-nitro-l-arginine methyl ester (L-NAME), a NOS inhibitor. Key findings Most GP cells were excited by SNOG whereas administration of L-NAME induced decrease of GP neurons activity. Nearly all neurons responding to SNOG and/or L-NAME showed significant modulation of their excitatory responses to the administration of iontophoretic GLU. In these cells, the changes induced by NO-active drugs in the magnitude of GLU-evoked responses were used as indicators of NO modulation. In fact, when a NO-active drug was co-iontophoresed with GLU, significant changes in GLU-induced responses were observed: generally, increased magnitudes of GLU-evoked responses were observed during SNOG ejection, whereas the administration of L-NAME decreased responses to GLU. Significance The results suggest that the NO-active drugs modulate the response of GP neurons to glutamatergic transmission. Nitrergic modulation of glutamatergic transmission could play an important role in the control of GP bioelectric activity, considered a fundamental key in the BG function

Pregnenolone sulphate improves memory processing in early-handled female rats

Early life experiences lead to sex-specific behavioural and neurochemical changes in adulthood. Indeed, early handling enhances learning and memory in male rats (Cannizzaro et al., 2005), whereas it impairs learning performance in female adult rats, a finding that has been correlated to decreased nitric oxide (NO) production in the hippocampus (Noschang et al., 2010). Pregnenolone sulfate (PREGS) is considered as one of the most potent memory-enhancing neurosteroids, since its activity as a potent positive modulator of N-methyl-d-aspartate receptors (NMDARs) and a negative modulator of gamma-aminobutyric acid(A) receptors (GABA(A)Rs) (Vallée et al., 2001). Given these premises, this study aims at characterizing the effect of PREGS on cognitive processes in adult female rats, subject to early handling protocol, by using an object-place association learning task, the ''Can test'', a motivated, non-aversive, spatial/object discrimination test (Popovic´ et al., 2001). Female Wistar rats underwent daily, brief, maternal separation from postnatal day 2 until 21. Once in adulthood, the effect of PREGS administration (10 mg/kg, s.c.) on correct responses, reference memory and working memory was assessed. Results show that PREGS was able to significantly increase the number of correct responses, and consistently, to decrease reference and working memory errors, compared with vehicle. No statistically significant effect of PREGS administration was observed in non-handled, control group. These findings sustain the impact of neurosteroids in learning and memory processing, and suggest a particular role for PREGS in reversing conditions of altered functionality, likely due to the modulation of the glutamate-NO-cGMP pathway (Cauli et al., 2011), and thus neurobiological mechanisms underlying learning and memory. As a consequence, PREGS may represent an important therapeutic tool as memory-enhancer, in order to tackle cognitive deficit caused by stress in early lif

Reducing Visuospatial Pseudoneglect in Healthy Subjects by Active Video Gaming

Pseudoneglect phenomenon refers to a condition in which healthy subjects tend to perceive the left side of exactly bisected lines as being slightly longer than the right one. However, behavioural data showed that athletes practising an open-skill sport display less pseudoneglect than the general population. Given the fact that so-called exergames (also known as active video games) are platforms designed to fully mimic sport activity, this work intends to investigate whether and how a one-week training period of exergame open-skill sport can determine a similar decrease in pseudoneglect. Fifteen healthy participants (non-athletes) responded to a visuospatial attention task and a control memory task in basal conditions (t0: Pre-game) and after a short period (one week, one hour/day) of tennis exergaming (t1: Post-game). In the Post-game condition, subjects from this experimental group (ExerGame group: EG) reduced leftward space overestimation and made significantly fewer leftward errors compared to the Pre-game condition. Additionally, two other experimental groups were employed: one evaluated within the same conditions of the main experiment but using a non-exergame (Non-Exergame groups: NEG) and the other one without any video game stimulus (Sedentary group: SE). Our findings suggest that daily training of a tennis exergame seems to be able to improve visuospatial attention isotropy by reducing leftward space overestimation, whereas outcomes from non-exergaming and sedentary activity do not modify subjects’ performance

Polybutylene succinate artificial scaffold for peripheral nerve regeneration

Regeneration and recovery of nerve tissues are a great challenge for medicine, and positively affect the quality of life of patients. The development of tissue engineering offers a new approach to the problem with the creation of multifunctional artificial scaffolds that act on various levels in the damaged tissue, providing physical and biochemical support for the growth of nerve cells. In this study, the effects of the use of a tubular scaffold made of polybutylene succinate (PBS), surgically positioned at the level of a sciatic nerve injured in rat, between the proximal stump and the distal one, was investigated. Scaffolds characterization was carried out by scanning electron microscopy and X-ray microcomputed tomography and magnetic resonance imaging, in vivo. The demonstration of the nerve regeneration was based on the evaluation of electroneurography, measuring the weight of gastrocnemius and tibialis anterior muscles, histological examination of regenerated nerves and observing the recovery of the locomotor activity of animals. The PBS tubular scaffold minimized iatrogenic trauma on the nerve, acting as a directional guide for the regenerating fibers by conveying them toward the distal stump. In this context, neurotrophic and neurotropic factors may accumulate and perform their functions, while invasion by macrophages and scar tissue is hampered

Modulation of Human Motor Cortical Excitability and Plasticity by Opuntia Ficus Indica Fruit Consumption: Evidence from a Preliminary Study through Non-Invasive Brain Stimulation

Indicaxanthin (IX) from Opuntia Ficus Indica (OFI) has been shown to exert numerous biological effects both in vitro and in vivo, such as antioxidant, anti-inflammatory, neuro-modulatory activity in rodent models. Our goal was to investigate the eventual neuro-active role of orally assumed fruits containing high levels of IX at nutritionally-relevant amounts in healthy subjects, exploring cortical excitability and plasticity in the human motor cortex (M1). To this purpose, we applied paired-pulse transcranial magnetic stimulation and anodal transcranial direct current stimulation (a-tDCS) in basal conditions and followed the consumption of yellow cactus pear fruits containing IX or white cactus pear fruits devoid of IX (placebo). Furthermore, resting state-functional MRI (rs-fMRI) preliminary acquisitions were performed before and after consumption of the same number of yellow fruits. Our data revealed that the consumption of IX-containing fruits could specifically activate intracortical excitatory circuits, differently from the placebo-controlled group. Furthermore, we found that following the ingestion of IX-containing fruits, elevated network activity of glutamatergic intracortical circuits can homeostatically be restored to baseline levels following a-tDCS stimulation. No significant differences were observed through rs-fMRI acquisitions. These outcomes suggest that IX from OFI increases intracortical excitability of M1 and leads to homeostatic cortical plasticity responses

“Golden” Tomato Consumption Ameliorates Metabolic Syndrome: A Focus on the Redox Balance in the High-Fat-Diet-Fed Rat

Tomato fruits defined as “golden” refer to a food product harvested at an incomplete ripening stage with respect to red tomatoes at full maturation. The aim of this study is to explore the putative influence of “golden tomato” (GT) on Metabolic Syndrome (MetS), especially focusing on the effects on redox homeostasis. Firstly, the differential chemical properties of the GT food matrix were characterized in terms of phytonutrient composition and antioxidant capacities with respect to red tomato (RT). Later, we assessed the biochemical, nutraceutical and eventually disease-modifying potential of GT in vivo in the high-fat-diet rat model of MetS. Our data revealed that GT oral supplementation is able to counterbalance MetS-induced biometric and metabolic modifications. Noteworthy is that this nutritional supplementation proved to reduce plasma oxidant status and improve the endogenous antioxidant barriers, assessed by strong systemic biomarkers. Furthermore, consistently with the reduction of hepatic reactive oxygen and nitrogen species (RONS) levels, treatment with GT markedly reduced the HFD-induced increase in hepatic lipid peroxidation and hepatic steatosis. This research elucidates the importance of food supplementation with GT in the prevention and management of MetS

NITRIC OXIDE AND BRAIN HYPEREXCITABILITY

Nitric oxide (NO) is a gaseous messenger involved in atypical forms of intercellular communications, able to exert a strong functional modulation of several neurotransmitter systems. In particular, NO heavily influences the excitatory neurotransmitter glutamate, mainly through NMDA receptors, and the inhibitory neurotransmitter GABA, mainly through GABA A receptors. Due to the involvement of glutamate and GABA in a delicate balance conditioning the functional status of the neural cells, this interaction suggests a role for NO in regulating neuronal excitability and its transition towards hyperexcitability phenomena. This article reviews the main knowledge about the relationships existing between the activity of the NO system and the experimental aspects of epilepsy, focusing on the somewhat antithetic findings about the proconvulsant or the anticonvulsant roles exerted by nitric oxide