Dipyridamole Ameliorates Memory Impairment and Increases Hippocampal Calbindin Expression in Niemann Pick C1 Mice.

Niemann Pick type C1 (NPC1) is a rare, fatal disorder characterized by endosomal lipid accumulation that leads to damage of both peripheral organs and central nervous system (cerebellum and hippocampus are especially affected). Currently, miglustat is the only approved drug for NPC1, thus the identification of new treatments is mandatory. We have previously demonstrated that the drug dipyridamole (DIP), an enhancer of adenosine signaling, can reduce the pathological phenotype in patient-derived fibroblasts.

Functional Interaction between Adenosine A and mGlu Receptors Mediates STEP Phosphatase Activation and Promotes STEP/mGluR Binding in Mouse Hippocampus and Neuroblastoma Cell Line.

(1) Background: Recently, we found that adenosine A receptor (AR) stimulation results in an increase in STEP phosphatase activity. In order to delve into the mechanism through which AR stimulation induced STEP activation, we investigated the involvement of mGluR since it is well documented that AR and mGluR physically and functionally interact in several brain areas. (2) Methods: In a neuroblastoma cell line (SH-SY5Y) and in mouse hippocampal slices, we evaluated the enzymatic activity of STEP by using a para-nitrophenyl phosphate colorimetric assay.

Relative effectiveness of a 2nd booster dose of COVID-19 mRNA vaccine up to four months post administration in individuals aged 80 years or more in Italy: A retrospective matched cohort study.

Several countries started a 2nd booster COVID-19 vaccination campaign targeting the elderly population, but evidence around its effectiveness is still scarce. This study aims to estimate the relative effectiveness of a 2nd booster dose of COVID-19 mRNA vaccine in the population aged ≥ 80 years in Italy, during predominant circulation of the Omicron BA.2 and BA.

Effectiveness of BNT162b2 vaccine against SARS-CoV-2 infection and severe COVID-19 in children aged 5-11 years in Italy: a retrospective analysis of January-April, 2022.

Background: By April 13, 2022, more than 4 months after the approval of BNT162b2 (Pfizer-BioNTech) for children, less than 40% of 5-11-year-olds in Italy had been vaccinated against COVID-19. Estimating how effective vaccination is in 5-11-year-olds in the current epidemiological context dominated by the omicron variant (B.1.

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study.

Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC.

Effectiveness of an mRNA vaccine booster dose against SARS-CoV-2 infection and severe COVID-19 in persons aged ≥60 years and other high-risk groups during predominant circulation of the delta variant in Italy, 19 July to 12 December 2021.

Background: Consolidated information on the effectiveness of COVID-19 booster vaccination in Europe are scarce.

Research Design And Methods: We assessed the effectiveness of a booster dose of an mRNA vaccine against any SARS-CoV-2 infection (symptomatic or asymptomatic) and severe COVID-19 (hospitalization or death) after over two months from administration among priority target groups (n = 18,524,568) during predominant circulation of the Delta variant in Italy (July-December 2021).

Results: Vaccine effectiveness (VE) against SARS-CoV-2 infection and, to a lesser extent, against severe COVID-19, among people ≥60 years and other high-risk groups (i.

[Unmet clinical need and new therapeutic options.].

The debate around unmet clinical need (UCN) is still very much alive. How do we define UCN? How does it influence the definition of clinically relevant outcomes in a therapeutic area? Who defines UCN? What are the consequences of recognizing different grading of UCN? In this paper we will address these questions and finally formulate proposals for the Italian context. The paper is based on a discussion within a panel of experts.

Effectiveness of mRNA vaccines and waning of protection against SARS-CoV-2 infection and severe covid-19 during predominant circulation of the delta variant in Italy: retrospective cohort study.

Objectives: To estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different time after vaccination.

Design: Retrospective cohort study.

Setting: Italy, 27 December 2020 to 7 November 2021.

[The regulatory evaluation of tumor-agnostic drugs.].

The transition from the traditional to the mutational model in oncology represents a crucial change, not only from the nosological point of view, since - unlike the traditional one - the new approach is no longer strictly linked to anatomical localization and histology, but also from the point of view of adaptation of the health and regulatory systems to the new paradigm. Agnostic oncology therefore represents a challenge for the evolution of the entire path of the drug, not only for its clinical development, but also concerning the diagnostic-therapeutic and regulatory approach to be followed for the authorization and evaluation of these drugs.

Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Convalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia.

Objective: To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia.

Design, Setting, And Participants: This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy.

Myelin Defects in Niemann-Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives.

Niemann-Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, and , coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane.

Fenretinide Beneficial Effects on Amyotrophic Lateral Sclerosis-associated SOD1 Mutant Protein Toxicity: In Vitro and In Vivo Evidences.

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease for which effective treatment options are still lacking. ALS occurs in sporadic and familial forms which are clinically indistinguishable; about 20% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene. Fenretinide (FEN), a cancer chemopreventive and antiproliferative agent currently used in several clinical trials, is a multi-target drug which also exhibits redox regulation activities.

Molecular tests and target therapies in oncology: recommendations from the Italian workshop.

Next-generation sequencing (NGS) and liquid biopsy are new technologies that can allow overall tumor profiling in a single analysis and play an important role in the implementation of precision oncology. However, the lack of guidelines in this setting has limited the development of precision oncology in Italy. This article summarizes recommendations for the appropriate use of NGS in tumor gene profiling, as well as access to tests and target drugs, that were prepared by a group of key opinion leaders and relevant stakeholders.

Insight into the Role of the STriatal-Enriched Protein Tyrosine Phosphatase (STEP) in A Receptor-Mediated Effects in the Central Nervous System.

The STriatal-Enriched protein tyrosine phosphatase STEP is a brain-specific tyrosine phosphatase that plays a pivotal role in the mechanisms of learning and memory, and it has been demonstrated to be involved in several neuropsychiatric diseases. Recently, we found a functional interaction between STEP and adenosine A receptor (AR), a subtype of the adenosine receptor family widely expressed in the central nervous system, where it regulates motor behavior and cognition, and plays a role in cell survival and neurodegeneration. Specifically, we demonstrated the involvement of STEP in AR-mediated cocaine effects in the striatum and, more recently, we found that in the rat striatum and hippocampus, as well as in a neuroblastoma cell line, the overexpression of the AR, or its stimulation, results in an increase in STEP activity.

P2X7 Receptor Agonist 2'(3')-O-(4-Benzoylbenzoyl)ATP Differently Modulates Cell Viability and Corticostriatal Synaptic Transmission in Experimental Models of Huntington's Disease.

Huntington's disease (HD) is a life-threatening neurodegenerative disorder. Altered levels and functions of the purinergic ionotropic P2X7 receptors (P2X7Rs) have been found in animal and cellular models of HD, suggesting their possible role in the pathogenesis of the disease; accordingly, the therapeutic potential of P2X7R antagonists in HD has been proposed. Here we further investigated the effects of P2X7R ligands in and HD experimental models.

Adenosine A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice.

In fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A receptors (ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking ARs might normalize the mGlu5R-mediated effects of FXS.

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial.

Background: Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients.

Methods: A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset.

TOCIVID-19 - A multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia. Study protocol.

Background: Pneumonia is the most frequent complication of COVID-19, due to an aberrant host immune response that is associated with an acute respiratory distress syndrome, and, in most critical patients, with a "cytokine storm". IL-6 might play a key role in the cytokine storm and might be a potential target to treat severe and critical COVID-19. Tocilizumab is a recombinant humanized monoclonal antibody, directed against IL-6 receptor.

The activity of the Striatal-enriched protein tyrosine phosphatase in neuronal cells is modulated by adenosine A receptor.

We recently demonstrated that a tonic activation of adenosine A receptors (A Rs) is required for cocaine-induced synaptic depression and increase in the activity of STriatal-Enriched protein tyrosine Phosphatase (STEP). In this study, we elaborated on the relationship between A R and STEP using genetic, pharmacological, and cellular tools. We found that the activities of protein tyrosine phosphatases (PTPs), and in particular of STEP, are significantly increased in the striatum and hippocampus of a transgenic rat strain over-expressing the neuronal A R (NSEA ) with respect to wild-type (WT) rats.

Adenosine A receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes.

Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A receptors (AR) restores cholesterol accumulation in late endosomes/lysosomes in human NPC fibroblasts and neural cell lines transiently transfected with NPC1 siRNA, suggesting that these receptors might be targeted to contrast the disease.

Adenosine A receptor as potential therapeutic target in neuropsychiatric disorders.

Adenosine A receptor (AR) is a G-protein coupled receptor that regulates several important functions in the central nervous system. Large amount of preclinical data suggests that the AR could represent a target for the development of new therapeutic strategies for different neuropsychiatric conditions. In this review we will recapitulate and discuss the most relevant studies on the role of ARs in neurodegenerative, neurodevelopmental and psychiatric diseases, which led to suggest a therapeutic use of AR agonists in certain diseases (Niemann-Pick disease, autism-spectrum disorders, schizophrenia) and AR antagonists in others (Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, fragile X syndrome, depression, anxiety).