Publications by authors named "Stefano Marini"

89 Publications

Comparative Performance of a New SARS-CoV-2 Rapid Detection System.

Microbiol Spectr 2021 Oct 13:e0020521. Epub 2021 Oct 13.

Department of Medical Biotechnologies, University of Sienagrid.9024.f, Siena, Italy.

The extraordinary global demand for reagents and diagnostic instruments needed for timely detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly affected their availability. In order to meet diagnostic needs, it has been necessary to develop new diagnostic procedures. To date, molecular diagnostic tools have represented the gold standard for diagnosis of SARS-CoV-2 infection, and thus an alternative and real-time PCR system was required. To this aim, a molecular rapid test which works with direct real-time RT-PCR may be a relevant aid. In the present work, the accuracy, sensitivity, and specificity of the bKIT Virus Finder COVID-19 rapid molecular test by Hyris Ltd. was evaluated. Moreover, the influence of a different swab storage medium composition was examined relative to that of a routinely used comparator assay. The Hyris Ltd. assay showed an overall agreement of 100% with the comparator based on a panel consisting of 74 retrospective positive nasopharyngeal swabs (NPSs), collected either in universal transport medium (UTM) or using ESwab. No false-positive result was achieved on samples that previously tested negative. Cross-reactivity screening on microorganisms that commonly colonize the human upper respiratory tract was not detected, excluding the risk of false-positive results. Simultaneously, drugs frequently administered to cure respiratory diseases did not interfere with the analytical performance of the assay. Our results showed that the Hyris Ltd. bKIT Virus Finder COVID-19 is a reliable assay for rapid qualitative detection of SARS-CoV-2, providing the advantage of less complex and unambiguous interpretation of results. Indeed, skilled technicians are not required, and thus the Hyris system is suitable as a rapid and easy system for SARS-CoV-2 diagnosis. In order to overcome the increased demand for diagnostic tools for the timely detection of SARS-CoV-2 infection, we tested the bKIT Virus Finder COVID-19 molecular rapid test by Hyris Ltd. The new system was confirmed as a reliable assay for rapid SARS-CoV-2 detection, since sensitivity and specificity parameters were fully satisfied. Moreover, the bKIT Virus Finder COVID-19 provides the advantage of easy results interpretation, since skilled technicians are not required, and thus the Hyris system is a valuable SARS-CoV-2 rapid diagnosis system.
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http://dx.doi.org/10.1128/Spectrum.00205-21DOI Listing
October 2021

At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention.

Cancers (Basel) 2021 Sep 28;13(19). Epub 2021 Sep 28.

Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.

Immunoproteasome is a noncanonical form of proteasome with enzymological properties optimized for the generation of antigenic peptides presented in complex with class I MHC molecules. This enzymatic property makes the modulation of its activity a promising area of research. Nevertheless, immunotherapy has emerged as a front-line treatment of advanced/metastatic tumors providing outstanding improvement of life expectancy, even though not all patients achieve a long-lasting clinical benefit. To enhance the efficacy of the currently available immunotherapies and enable the development of new strategies, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is needed. Therefore, a better understanding of the role of immunoproteasome in antigen processing and of the therapeutic implication of its modulation is mandatory. Studies on the potential crosstalk between proteasome modulators and immune checkpoint inhibitors could provide novel perspectives and an unexplored treatment option for a variety of cancers.
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http://dx.doi.org/10.3390/cancers13194852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507813PMC
September 2021

Effects of Extracellular Osteoanabolic Agents on the Endogenous Response of Osteoblastic Cells.

Cells 2021 Sep 10;10(9). Epub 2021 Sep 10.

Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

The complex multidimensional skeletal organization can adapt its structure in accordance with external contexts, demonstrating excellent self-renewal capacity. Thus, optimal extracellular environmental properties are critical for bone regeneration and inextricably linked to the mechanical and biological states of bone. It is interesting to note that the microstructure of bone depends not only on genetic determinants (which control the bone remodeling loop through autocrine and paracrine signals) but also, more importantly, on the continuous response of cells to external mechanical cues. In particular, bone cells sense mechanical signals such as shear, tensile, loading and vibration, and once activated, they react by regulating bone anabolism. Although several specific surrounding conditions needed for osteoblast cells to specifically augment bone formation have been empirically discovered, most of the underlying biomechanical cellular processes underneath remain largely unknown. Nevertheless, exogenous stimuli of endogenous osteogenesis can be applied to promote the mineral apposition rate, bone formation, bone mass and bone strength, as well as expediting fracture repair and bone regeneration. The following review summarizes the latest studies related to the proliferation and differentiation of osteoblastic cells, enhanced by mechanical forces or supplemental signaling factors (such as trace metals, nutraceuticals, vitamins and exosomes), providing a thorough overview of the exogenous osteogenic agents which can be exploited to modulate and influence the mechanically induced anabolism of bone. Furthermore, this review aims to discuss the emerging role of extracellular stimuli in skeletal metabolism as well as their potential roles and provide new perspectives for the treatment of bone disorders.
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http://dx.doi.org/10.3390/cells10092383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471159PMC
September 2021

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations.

Biochim Biophys Acta Mol Basis Dis 2020 07 8;1866(7):165793. Epub 2020 Apr 8.

Dept of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis.
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http://dx.doi.org/10.1016/j.bbadis.2020.165793DOI Listing
July 2020

Effects of oral administration of common antioxidant supplements on the energy metabolism of red blood cells. Attenuation of oxidative stress-induced changes in Rett syndrome erythrocytes by CoQ10.

Mol Cell Biochem 2020 Jan 8;463(1-2):101-113. Epub 2019 Oct 8.

Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.

Nutritional supplements are traditionally employed for overall health and for managing some health conditions, although controversies are found concerning the role of antioxidants-mediated benefits in vivo. Consistently with its critical role in systemic redox buffering, red blood cell (RBC) is recognized as a biologically relevant target to investigate the effects of oxidative stress. In RBC, reduction of the ATP levels and adenylate energy charge brings to disturbance in intracellular redox status. In the present work, several popular antioxidant supplements were orally administrated to healthy adults and examined for their ability to induce changes on the energy metabolism and oxidative status in RBC. Fifteen volunteers (3 per group) were treated for 30 days per os with epigallocatechin gallate (EGCG) (1 g green tea extract containing 50% EGCG), resveratrol (325 mg), coenzyme Q10 (CoQ10) (300 mg), vitamin C (1 g), and vitamin E (400 U.I.). Changes in the cellular levels of high-energy compounds (i.e., ATP and its catabolites, NAD and GTP), GSH, GSSG, and malondialdehyde (MDA) were simultaneously analyzed by ion-pairing HPLC. Response to oxidative stress was further investigated through the oxygen radical absorptive capacity (ORAC) assay. According to our experimental approach, (i) CoQ10 appeared to be the most effective antioxidant inducing a high increase in ATP/ADP, ATP/AMP, GSH/GSSG ratio and ORAC value and, in turn, a reduction of NAD concentration, (ii) EGCG modestly modulated the intracellular energy charge potential, while (iii) Vitamin E, vitamin C, and resveratrol exhibited very weak effects. Given that, the antioxidant potential of CoQ10 was additionally assessed in a pilot study which considered individuals suffering from Rett syndrome (RTT), a severe X-linked neuro-developmental disorder in which RBC oxidative damages provide biological markers for redox imbalance and chronic hypoxemia. RTT patients (n = 11), with the typical clinical form, were supplemented for 12 months with CoQ10 (300 mg, once daily). Level of lipid peroxidation (MDA production) and energy state of RBCs were analyzed at 2 and 12 months. Our data suggest that CoQ10 may significantly attenuate the oxidative stress-induced damage in RTT erythrocytes.
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http://dx.doi.org/10.1007/s11010-019-03633-5DOI Listing
January 2020

On the Horizon: Targeting Next-Generation Immune Checkpoints for Cancer Treatment.

Chemotherapy 2019 6;64(2):62-80. Epub 2019 Aug 6.

Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.

Background: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy.

Summary: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.
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http://dx.doi.org/10.1159/000500902DOI Listing
November 2019

Embolization of iliac metastasis during lenvatinib treatment in patient with advanced Hürthle cell thyroid carcinoma.

Future Oncol 2019 Aug 6;15(24s):35-40. Epub 2019 Aug 6.

Department of Medical Sciences & Public Health, Postgraduate School of Endocrinology & Metabolic Diseases, University of Cagliari, Cagliari, Italy.

Lenvatinib is a tyrosine kinase inhibitor (TKI) with antiproliferative and antiangiogenic effects indicated for the treatment of progressive, locally advanced or metastatic progressive thyroid carcinoma, refractory to radioactive iodine therapy. Antiangiogenic therapies induce ischemic necrosis of tumor tissue, with increased risk of hemorrhagic complications. The management of hemorrhagic risk is based on precautionary measures and for any surgical procedure, it is advised to interrupt the treatment in order to avoid complications. 'Flare-up' of tumor activity may follow TKI interruption. However, it is not known if continuing TKIs during minimally invasive interventions is safe. We report here the first case in which an embolization of metastasis is performed without interrupting lenvatinib treatment. The procedure was successful and free of complications.
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http://dx.doi.org/10.2217/fon-2019-0184DOI Listing
August 2019

Screening of asymptomatic rheumatic heart disease among refugee/migrant children and youths in Italy.

Pediatr Rheumatol Online J 2019 Apr 2;17(1):12. Epub 2019 Apr 2.

Médecins Sans Frontières-Operational Centre Brussels, Italy Mission, Rome, Italy.

Background: Rheumatic heart disease (RHD) is a chronic condition responsible of congestive heart failure, stroke and arrhythmia. Almost eradicated in high-income countries (HIC), it persists in low- and middle-income countries. The purpose of the study was to assess the feasibility and meaningfulness of ultrasound-based RHD screening among the population of unaccompanied foreign minors in Italy and determine the burden of asymptomatic RHD among this discrete population.

Methods: From February 2016 to January 2018, Médecins Sans Frontières conducted a weekly mobile screening by echocardiography in reception centers and family houses for unaccompanied foreign minors in Rome, followed by fix echocardiographic retesting for those resulting positive at screening. 'Definite' and 'borderline' cases were defined according to the World Hearth Federation criteria.

Results: Six hundred fifty-three individuals (13-26 years old) were screened; 95.6% were below 18 years old (624/653). Six 'definite RHD' were identified at screening, yielding a detection rate of 9.2‰ (95% CI 4.1-20.3‰), while 285 (436.4‰) were defined as 'borderline' (95% CI 398.8-474.9‰). Out of 172 "non-negative borderline" cases available for being retested (113 "non-negative borderline" lost in follow-up), additional 11 were categorized as 'definite RHD', for a total of 17 'definite RHD', yielding a final prevalence of 26.0‰ (95% CI 16.2-41.5‰) (17/653), and 122 (122/653) were confirmed as 'borderline' (final prevalence of 186.8‰, 95% CI 158.7-218.7). In multivariate logistic regression analysis the presence of systolic murmur was a strong predictor for both 'borderline' (OR 4.3 [2.8-6.5]) and 'definite RHD' (OR 5.2 [1.7-15.2]), while no specific country/geographic area of origin was statistically associated with an increased risk of latent, asymptomatic RHD.

Conclusions: Screening for RHD among the unaccompanied migrant minors in Italy proved to be feasible. The burden of 'definite RHD' was similar to that identified in resource-poor settings, while the prevalence of 'borderline' cases was higher than reported in other studies. In view of these findings, the health system of high-income countries, hosting migrants and asylum seekers, are urged to adopt screening for RHD in particular among the silent and marginalized population of refugee and migrant children.
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http://dx.doi.org/10.1186/s12969-019-0314-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444853PMC
April 2019

The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S.

Cell Mol Life Sci 2018 Sep 28;75(18):3441-3456. Epub 2018 Mar 28.

Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.

The interaction of insulin-degrading enzyme (IDE) with the main intracellular proteasome assemblies (i.e, 30S, 26S and 20S) was analyzed by enzymatic activity, mass spectrometry and native gel electrophoresis. IDE was mainly detected in association with assemblies with at least one free 20S end and biochemical investigations suggest that IDE competes with the 19S in vitro. IDE directly binds the 20S and affects its proteolytic activities in a bimodal fashion, very similar in human and yeast 20S, inhibiting at (IDE) ≤ 30 nM and activating at (IDE) ≥ 30 nM. Only an activating effect is observed in a yeast mutant locked in the "open" conformation (i.e., the α-3ΔN 20S), envisaging a possible role of IDE as modulator of the 20S "open"-"closed" allosteric equilibrium. Protein-protein docking in silico proposes that the interaction between IDE and the 20S could involve the C-term helix of the 20S α-3 subunit which regulates the gate opening of the 20S.
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http://dx.doi.org/10.1007/s00018-018-2807-yDOI Listing
September 2018

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages.

ChemMedChem 2018 03 14;13(5):422-430. Epub 2018 Feb 14.

European Research Centre for Drug Discovery and Development - NatSynDrugs - and Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, via Aldo Moro 1, 53100, Siena, Italy.

The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.
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http://dx.doi.org/10.1002/cmdc.201700759DOI Listing
March 2018

Retention of Mitochondria in Mature Human Red Blood Cells as the Result of Autophagy Impairment in Rett Syndrome.

Sci Rep 2017 09 26;7(1):12297. Epub 2017 Sep 26.

Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.

Rett Syndrome (RTT), which affects approximately 1:10.000 live births, is a X-linked pervasive neuro-developmental disorder which is caused, in the vast majority of cases, by a sporadic mutation in the Methyl-CpG-binding protein-2 (MeCP2) gene. This is a transcriptional activator/repressor with presumed pleiotropic activities. The broad tissue expression of MeCP2 suggests that it may be involved in several metabolic pathways, but the molecular mechanisms which provoke the onset and progression of the syndrome are largely unknown. In this paper, we report that primary fibroblasts that have been isolated from RTT patients display a defective formation of autophagosomes under conditions of nutrient starvation and that the mature Red Blood Cells of some RTT patients retain mitochondria. Moreover, we provide evidence regarding the accumulation of the p62/SQSTM1 protein and ubiquitin-aggregated structures in the cerebellum of Mecp2 knockout mouse model (Mecp2 ) during transition from the non-symptomatic to the symptomatic stage of the disease. Hence, we propose that a defective autophagy could be involved in the RTT clinical phenotype, which introduces new molecular perspectives in the pathogenesis of the syndrome.
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http://dx.doi.org/10.1038/s41598-017-12069-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614985PMC
September 2017

A prospective non-randomized controlled, multicenter trial comparing Appendectomy and Conservative Treatment for Patients with Uncomplicated Acute Appendicitis (the ACTUAA study).

Int J Colorectal Dis 2017 Nov 15;32(11):1649-1660. Epub 2017 Aug 15.

General Surgery Unit, Santissima Trinità Hospital, Cagliari, Italy.

Purpose: Acute appendicitis (AA) is among the most common causes of lower abdominal pain and admissions to the emergency department. Over the past 20 years, there has been a renewed interest in the conservative management of uncomplicated AA, and several studies demonstrated that an antibiotic-first strategy is a viable treatment option for uncomplicated AA. The aim of this prospective non-randomized controlled, multicenter trial is to compare antibiotic therapy and emergency appendectomy as treatment for patients with uncomplicated AA confirmed by US and/or CT or MRI scan.

Methods: All adult patients in the age range 18 to 65 years with suspected AA, consecutively admitted to the Surgical Department of the 13 participating Italian Hospitals, will be invited to take part in the study. A multicenter prospective collected registry developed by surgeons, radiologists, and pathologists with expertise in the diagnosis and treatment of uncomplicated acute appendicitis represents the best research method to assess the long-term role of antibiotics in the management of the disease. Comparison will be made between surgical and antibiotic-first approaches to uncomplicated AA through the analysis of the primary outcome measure of complication-free treatment success rate based on 1-year follow-up. Quality of life, length of hospital stay, pain evaluation, and time to return to normal activity will be evaluated as secondary outcome measures.

Trial Registration: Clinicaltrials.gov ID: NCT03080103.
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http://dx.doi.org/10.1007/s00384-017-2878-5DOI Listing
November 2017

Creativity and psychiatric illness: A functional perspective beyond chaos.

Prog Neuropsychopharmacol Biol Psychiatry 2018 Jan 5;80(Pt B):91-100. Epub 2017 Jul 5.

Department of Neurosciences Clinical Imaging, Chair of Psychiatry, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy.

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http://dx.doi.org/10.1016/j.pnpbp.2017.06.038DOI Listing
January 2018

Multiple functions of insulin-degrading enzyme: a metabolic crosslight?

Crit Rev Biochem Mol Biol 2017 10 21;52(5):554-582. Epub 2017 Jun 21.

a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.

Insulin-degrading enzyme (IDE) is a ubiquitous zinc peptidase of the inverzincin family, which has been initially discovered as the enzyme responsible for insulin catabolism; therefore, its involvement in the onset of diabetes has been largely investigated. However, further studies on IDE unraveled its ability to degrade several other polypeptides, such as β-amyloid, amylin, and glucagon, envisaging the possible implication of IDE dys-regulation in the "aggregopathies" and, in particular, in neurodegenerative diseases. Over the last decade, a novel scenario on IDE biology has emerged, pointing out a multi-functional role of this enzyme in several basic cellular processes. In particular, latest advances indicate that IDE behaves as a heat shock protein and modulates the ubiquitin-proteasome system, suggesting a major implication in proteins turnover and cell homeostasis. In addition, recent observations have highlighted that the regulation of glucose metabolism by IDE is not merely based on its largely proposed role in the degradation of insulin in vivo. There is increasing evidence that improper IDE function, regulation, or trafficking might contribute to the etiology of metabolic diseases. In addition, the enzymatic activity of IDE is affected by metals levels, thus suggesting a role also in the metal homeostasis (metallostasis), which is thought to be tightly linked to the malfunction of the "quality control" machinery of the cell. Focusing on the physiological role of IDE, we will address a comprehensive vision of the very complex scenario in which IDE takes part, outlining its crucial role in interconnecting several relevant cellular processes.
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http://dx.doi.org/10.1080/10409238.2017.1337707DOI Listing
October 2017

Transcranial Direct Current Stimulation in Substance Use Disorders: A Systematic Review of Scientific Literature.

J ECT 2017 Sep;33(3):203-209

From the Department of Neuroscience, Imaging and Clinical Sciences, University "G. D'Annunzio", Chieti, Italy.

Introduction: New treatment options such as noninvasive brain stimulation have been recently explored in the field of substance use disorders (SUDs), including transcranial direct current stimulation (tDCS).

Objectives: In light of this, we have performed a review of the scientific literature to assess efficacy and technical and methodological issues resulting from applying tDCS to the field of SUDs.

Methods: Our analysis highlighted the following selection criteria: clinical studies on tDCS and SUDs (alcohol, caffeine, cannabis, cocaine, heroin, methamphetamine, and nicotine). Study selection, data analysis, and reporting were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Exclusion criteria were as follows: clinical studies about tDCS among behavioral addiction; review and didactic articles; physiopathological studies; and case reports.

Results: Eighteen scientific papers were selected out of 48 articles. Among these, 16 studied the efficacy of tDCS applied to the dorsolateral prefrontal cortex, and 8 suggested the efficacy of tDCS in reducing substance craving.

Conclusions: In light of these data, it is premature to conclude that tDCS over the dorsolateral prefrontal cortex is a very efficient technique in reducing craving. Small sample size, different stimulation protocols, and study duration were the main limitations. However, the efficacy of tDCS in treating SUDs requires further investigation.
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http://dx.doi.org/10.1097/YCT.0000000000000401DOI Listing
September 2017

The Role of Inhaled Loxapine in the Treatment of Acute Agitation in Patients with Psychiatric Disorders: A Clinical Review.

Int J Mol Sci 2017 Feb 8;18(2). Epub 2017 Feb 8.

Department of Neurosciences and Imaging, Chair of Psychiatry, University "G. D'Annunzio", 66013 Chieti, Italy.

Loxapine is a first generation antipsychotic, belonging to the dibenzoxazepine class. Recently, loxapine has been reformulated at a lower dose, producing an inhaled powder that can be directly administered to the lungs to treat the agitation associated with psychiatric disorders, such as schizophrenia and bipolar disorder. Thus, the aim of this narrative and clinical mini-review was to evaluate the efficacy and tolerability of inhaled loxapine in the treatment of acute agitation in patients with psychiatric disorders. The efficacy of inhaled loxapine has been evaluated in one Phase II trial on patients with schizophrenia, and in two Phase III trials in patients with schizophrenia and bipolar disorder. Moreover, there are two published case series on patients with borderline personality disorder and dual diagnosis patients. Inhaled loxapine has proven to be effective and generally well tolerated when administered to agitated patients with schizophrenia and bipolar disorder. Two case series have suggested that inhaled loxapine may also be useful to treat agitation in patients with borderline personality disorder and with dual diagnosis, but further studies are needed to clarify this point. However, the administration of inhaled loxapine requires at least some kind of patient collaboration, and is not recommended in the treatment of severe agitation in totally uncooperative patients. Moreover, the drug-related risk of bronchospasm must always be kept in mind when planning to use inhaled loxapine, leading to a careful patient assessment prior to, and after, administration. Also, the higher costs of inhaled loxapine, when compared to oral and intramuscular medications, should be taken into account when selecting it for the treatment of agitation.
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http://dx.doi.org/10.3390/ijms18020349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343884PMC
February 2017

Oxygen exchange and energy metabolism in erythrocytes of Rett syndrome and their relationships with respiratory alterations.

Mol Cell Biochem 2017 Feb 7;426(1-2):205-213. Epub 2017 Jan 7.

Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.

Rett syndrome (RTT) is a neurodevelopmental disorder, mainly affecting females, which is associated to a mutation on the methyl-CpG-binding protein 2 gene. In the pathogenesis and progression of classic RTT, red blood cell (RBC) morphology has been shown to be an important biosensor for redox imbalance and chronic hypoxemia. Here we have evaluated the impact of oxidation and redox imbalance on several functional properties of RTT erythrocytes. In particular, we report for the first time a stopped-flow measurement of the kinetics of oxygen release by RBCs and the analysis of the intrinsic affinity of the hemoglobin (Hb). According to our experimental approach, RBCs from RTT patients do not show any intrinsic difference with respect to those from healthy controls neither in Hb's oxygen-binding affinity nor in O exchange processes at 37 °C. Therefore, these factors do not contribute to the observed alteration of the respiratory function in RTT patients. Moreover, the energy metabolism of RBCs, from both RTT patients and controls, was evaluated by ion-pairing HPLC method and related to the level of malondialdehyde and to the oxidative radical scavenging capacity of red cells. Results have clearly confirmed significant alterations in antioxidant defense capability, adding important informations concerning the high-energy compound levels in RBCs of RTT subjects, underlying possible correlations with inflammatory tissue alterations.
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http://dx.doi.org/10.1007/s11010-016-2893-9DOI Listing
February 2017

Multiple allosteric sites are involved in the modulation of insulin-degrading-enzyme activity by somatostatin.

FEBS J 2016 10 29;283(20):3755-3770. Epub 2016 Sep 29.

Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Italy.

Somatostatin is a cyclic peptide, released in the gastrointestinal system and the central nervous system, where it is involved in the regulation of cognitive and sensory functions, motor activity and sleep. It is a substrate of insulin-degrading enzyme (IDE), as well as a modulator of its activity and expression. In the present study, we have investigated the modulatory role of somatostatin on IDE activity at 37 °C and pH 7.3 for various substrates [i.e. insulin, β-amyloid (Aβ) and bradykinin], aiming to quantitatively characterize the correlation between the specific features of the substrates and the regulatory mechanism. Functional data indicate that somatostatin, in addition to the catalytic site of IDE (being a substrate), is also able to bind to two additional exosites, which play different roles according to the size of the substrate and its binding mode to the IDE catalytic cleft. In particular, one exosite, which displays high affinity for somatostatin, regulates only the interaction of IDE with larger substrates (such as insulin and Aβ ) in a differing fashion according to their various modes of binding to the enzyme. A second exosite, which is involved in the regulation of enzymatic processing by IDE of all substrates investigated (including a 10-25 amino acid long amyloid-like peptide, bradykinin and somatostatin itself, which had been studied previously), probably acts through the alteration of an 'open-closed' equilibrium.
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http://dx.doi.org/10.1111/febs.13841DOI Listing
October 2016

Celecoxib Adjunctive Treatment to Antipsychotics in Schizophrenia: A Review of Randomized Clinical Add-On Trials.

Mediators Inflamm 2016 25;2016:3476240. Epub 2016 Jul 25.

Department of Neurosciences Clinical Imaging, Chair of Psychiatry, "G. d'Annunzio" University, 65100 Chieti, Italy.

Schizophrenia is a severe, chronic and debilitating mental disorder. Past literature has reported various hypotheses about the psychopathology of schizophrenia. Recently, a growing literature has been trying to explain the role of inflammation in the etiopathogenesis of schizophrenia. In the past, numerous immune modulation and anti-inflammatory treatment options have been proposed for schizophrenia, but sometimes the results were inconsistent. Electronic search was carried out in November 2015. PubMed and Scopus databases have been used to find studies to introduce in this review. Only randomized-placebo-controlled add-on trials were taken into account. In this way, six articles were obtained for the discussion. Celecoxib showed beneficial effects mostly in early stages of schizophrenia. In chronic schizophrenia, the data are controversial, possibly in part for methodological reasons.
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http://dx.doi.org/10.1155/2016/3476240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976163PMC
June 2017

Celecoxib Adjunctive Treatment to Antipsychotics in Schizophrenia: A Review of Randomized Clinical Add-On Trials.

Mediators Inflamm 2016 25;2016:3476240. Epub 2016 Jul 25.

Department of Neurosciences Clinical Imaging, Chair of Psychiatry, "G. d'Annunzio" University, 65100 Chieti, Italy.

Schizophrenia is a severe, chronic and debilitating mental disorder. Past literature has reported various hypotheses about the psychopathology of schizophrenia. Recently, a growing literature has been trying to explain the role of inflammation in the etiopathogenesis of schizophrenia. In the past, numerous immune modulation and anti-inflammatory treatment options have been proposed for schizophrenia, but sometimes the results were inconsistent. Electronic search was carried out in November 2015. PubMed and Scopus databases have been used to find studies to introduce in this review. Only randomized-placebo-controlled add-on trials were taken into account. In this way, six articles were obtained for the discussion. Celecoxib showed beneficial effects mostly in early stages of schizophrenia. In chronic schizophrenia, the data are controversial, possibly in part for methodological reasons.
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http://dx.doi.org/10.1155/2016/3476240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976163PMC
June 2017

No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study).

Mult Scler 2016 08 14;22(9):1163-73. Epub 2015 Oct 14.

Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Italy.

Background: A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis.

Objectives: The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis.

Methods: This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months.

Results: A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months.

Conclusions: Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis.
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http://dx.doi.org/10.1177/1352458515611222DOI Listing
August 2016

The bridge between two worlds: psychoanalysis and fMRI.

Rev Neurosci 2016 Feb;27(2):219-29

In recent years, a connection between psychoanalysis and neuroscience has been sought. The meeting point between these two branches is represented by neuropsychoanalysis. The goal of the relationship between psychoanalysis and neuroscience is to test psychoanalytic hypotheses in the human brain, using a scientific method. A literature search was conducted on May 2015. PubMed and Scopus databases were used to find studies for the inclusion in the systematic review. Common results of the studies investigated are represented by a reduction, a modulation, or a normalization of the activation patterns found after the psychoanalytic therapy. New findings in the possible and useful relationship between psychoanalysis and neuroscience could change the modalities of relating to patients for psychoanalysts and the way in which neuroscientists plan their research. Researchers should keep in mind that in any scientific research that has to do with people, neuroscience and a scientific method cannot avoid subjective interpretation.
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http://dx.doi.org/10.1515/revneuro-2015-0031DOI Listing
February 2016

Proteasome Activity Is Affected by Fluctuations in Insulin-Degrading Enzyme Distribution.

PLoS One 2015 17;10(7):e0132455. Epub 2015 Jul 17.

Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, I-00133, Rome, Italy; Center for Space Biomedicine, University of Roma Tor Vergata, Via Montpellier 1, I-00133 Roma, Italy.

Insulin-Degrading-Enzyme (IDE) is a Zn2+-dependent peptidase highly conserved throughout evolution and ubiquitously distributed in mammalian tissues wherein it displays a prevalent cytosolic localization. We have recently demonstrated a novel Heat Shock Protein-like behaviour of IDE and its association with the 26S proteasome. In the present study, we examine the mechanistic and molecular features of IDE-26S proteasome interaction in a cell experimental model, extending the investigation also to the effect of IDE on the enzymatic activities of the 26S proteasome. Further, kinetic investigations indicate that the 26S proteasome activity undergoes a functional modulation by IDE through an extra-catalytic mechanism. The IDE-26S proteasome interaction was analyzed during the Heat Shock Response and we report novel findings on IDE intracellular distribution that might be of critical relevance for cell metabolism.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132455PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506093PMC
May 2016

Oral contraceptives combined with interferon β in multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2015 Aug 18;2(4):e120. Epub 2015 Jun 18.

Department of Neurology and Psychiatry (C.P., L.D.G., F.D.A., M.C.P., V.T., P.P.), Sapienza University of Rome, Italy; MS Center (C.P., L.D.G., V.T.B., F.M.), S. Andrea Hospital, Sapienza University of Rome, Italy; Centre for Primary Care and Public Health (V.G.), Queen Mary University of London, UK; TFS Trial Form Support S.L. (V.A.P., S.M.), Rome, Italy; Institute of Psychological Medicine and Clinical Neurosciences (V.T.), Cardiff University School of Medicine University Hospital of Wales (V.T.), Cardiff, UK; Santa Lucia Foundation (V.T.), Rome, Italy; and IRCCS Neuromed (P.P.), Pozzilli (IS), Italy.

Objective: To test the effect of oral contraceptives (OCs) in combination with interferon β (IFN-β) on disease activity in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: One hundred fifty women with RRMS were randomized in a 1:1:1 ratio to receive IFN-β-1a subcutaneously (SC) only (group 1), IFN-β-1a SC plus ethinylstradiol 20 μg and desogestrel 150 μg (group 2), or IFN-β-1a SC plus ethinylestradiol 40 μg and desogestrel 125 μg (group 3). The primary endpoint was the cumulative number of combined unique active (CUA) lesions on brain MRI at week 96. Secondary endpoints included MRI and clinical and safety measures.

Results: The estimated number of cumulative CUA lesions at week 96 was 0.98 (95% confidence interval [CI] 0.81-1.14) in group 1, 0.84 (95% CI 0.66-1.02) in group 2, and 0.72 (95% CI 0.53-0.91) in group 3, with a decrease of 14.1% (p = 0.24) and 26.5% (p = 0.04) when comparing group 1 with groups 2 and 3, respectively. The number of patients with no gadolinium-enhancing lesions was greater in group 3 than in group 1 (p = 0.03). No significant differences were detected in other secondary endpoints. IFN-β or OC discontinuations were equally distributed across groups.

Conclusions: Our results translate the observations derived from experimental models to patients, supporting the anti-inflammatory effects of OCs with high-dose estrogens, and suggest possible directions for future research.

Classification Of Evidence: This study provides Class II evidence that in women with RRMS, IFN-β plus ethinylstradiol and desogestrel decreases the cumulative number of active brain MRI lesions compared with IFN-β alone.
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http://dx.doi.org/10.1212/NXI.0000000000000120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476053PMC
August 2015

Targeting the Noradrenergic System in Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis of Prazosin Trials.

Curr Drug Targets 2015 ;16(10):1094-106

National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, "G. Mazzini" Hospital, p.zza Italia 1, 64100 Teramo (Italy).

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder that may develop after exposure to a life-threatening trauma. As veterans and armed forces may deal with diverse health problems compared with civilians, they have a greater risk for psychiatric disorders, including PTSD, than civilians, even if the disorder may be also frequent in the general population. PTSD is associated with significant comorbidity, especially with mood disorders and substance abuse. Moreover, the suicide risk is higher in PTSD patients than in the general population. Selective Serotonin Reuptake Inhibitors (SSRIs), atypical antipsychotics and benzodiazepines are commonly employed in the management of PTSD, but often these treatments fail or are discontinued due to adverse effects. It has been demonstrated that high noradrenergic activity may be associated with hyperarousal, trauma nightmares and sleep disturbances in PTSD subjects, probably through the stimulation of α -1 adrenergic receptors in the brain prefrontal cortex. The α -1 adrenoreceptor antagonist prazosin decreases noradrenaline effects at brain α-1 adrenoreceptors and may be a promising agent in the treatment of PTSD, as some studies have found it effective and well tolerated. Therefore, the present review is aimed to examine the role of noradrenergic system in the pathophysiology of PTSD. Moreover, we conducted a systematic review to evaluate the effectiveness and tolerability of prazosin in PTSD patients. Meta-analysis was used to combine data from multiple studies and better estimate the effect of prazosin on specific outcomes. We found prazosin to be significantly more efficacious than placebo in reducing distressing dreams in PTSD patients, even though our results should be interpreted with caution due to the small number of studies included in our quantitative synthesis.
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http://dx.doi.org/10.2174/1389450116666150506114108DOI Listing
July 2016

Targeting the Noradrenergic System in Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis of Prazosin Trials.

Curr Drug Targets 2015 ;16(10):1094-106

National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, "G. Mazzini" Hospital, p.zza Italia 1, 64100 Teramo (Italy).

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder that may develop after exposure to a life-threatening trauma. As veterans and armed forces may deal with diverse health problems compared with civilians, they have a greater risk for psychiatric disorders, including PTSD, than civilians, even if the disorder may be also frequent in the general population. PTSD is associated with significant comorbidity, especially with mood disorders and substance abuse. Moreover, the suicide risk is higher in PTSD patients than in the general population. Selective Serotonin Reuptake Inhibitors (SSRIs), atypical antipsychotics and benzodiazepines are commonly employed in the management of PTSD, but often these treatments fail or are discontinued due to adverse effects. It has been demonstrated that high noradrenergic activity may be associated with hyperarousal, trauma nightmares and sleep disturbances in PTSD subjects, probably through the stimulation of α -1 adrenergic receptors in the brain prefrontal cortex. The α -1 adrenoreceptor antagonist prazosin decreases noradrenaline effects at brain α-1 adrenoreceptors and may be a promising agent in the treatment of PTSD, as some studies have found it effective and well tolerated. Therefore, the present review is aimed to examine the role of noradrenergic system in the pathophysiology of PTSD. Moreover, we conducted a systematic review to evaluate the effectiveness and tolerability of prazosin in PTSD patients. Meta-analysis was used to combine data from multiple studies and better estimate the effect of prazosin on specific outcomes. We found prazosin to be significantly more efficacious than placebo in reducing distressing dreams in PTSD patients, even though our results should be interpreted with caution due to the small number of studies included in our quantitative synthesis.
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http://dx.doi.org/10.2174/1389450116666150506114108DOI Listing
July 2016

α-dystroglycan is a potential target of matrix metalloproteinase MMP-2.

Matrix Biol 2015 Jan 4;41:2-7. Epub 2014 Dec 4.

Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address:

Dystroglycan (DG) is a member of the glycoprotein complex associated to dystrophin and composed by two subunits, the β-DG, a transmembrane protein, and the α-DG, an extensively glycosylated extracellular protein. The β-DG ectodomain degradation by the matrix metallo-proteinases (i.e., MMP-2 and MMP-9) in both, pathological and physiological conditions, has been characterized in detail in previous publications. Since the amounts of α-DG and β-DG at the cell surface decrease when gelatinases are up-regulated, we investigated the degradation of α-DG subunit by MMP-2. Present data show, for the first time, that the proteolysis of α-DG indeed occurs on a native glycosylated molecule enriched from rabbit skeletal muscle. In order to characterize the α-DG portion, which is more prone to cleavage by MMP-2, we performed different degradations on tailored recombinant domains of α-DG spanning the whole subunit. The overall bulk of results casts light on a relevant susceptibility of the α-DG to MMP-2 degradation with particular reference to its C-terminal domain, thus opening a new scenario on the role of gelatinases (in particular of MMP-2) in the degradation of this glycoprotein complex, taking place in the course of pathological processes.
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http://dx.doi.org/10.1016/j.matbio.2014.11.007DOI Listing
January 2015

Novel Platinum(II) compounds modulate insulin-degrading enzyme activity and induce cell death in neuroblastoma cells.

J Biol Inorg Chem 2015 Jan 2;20(1):101-8. Epub 2014 Dec 2.

Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.

The properties of three novel Platinum(II) compounds toward the insulin-degrading enzyme (IDE) enzymatic activity have been investigated under physiological conditions. The rationale of this study resides on previous observations that these compounds, specifically designed and synthesized by some of us, induce apoptosis in various cancer cell lines, whereas IDE has been proposed as a putative oncogene involved in neuroblastoma onset and progression. Two of these compounds, namely [PtCl(O,O'-acac)(DMSO)] and [Pt(O,O'-acac)(γ-acac)(DMS)], display a modulatory behavior, wherefore activation or inhibition of IDE activity occurs over different concentration ranges (suggesting the existence of two binding sites on the enzyme). On the other hand, [Pt(O,O'-acac)(γ-acac)(DMSO)] shows a typical competitive inhibitory pattern, characterized by a meaningful affinity constant (K i  = 0.95 ± 0.21 μM). Although all three compounds induce cell death in neuroblastoma SHSY5Y cells at concentrations exceeding 2 μM, the two modulators facilitate cells' proliferation at concentrations ≤ 1.5 μM, whereas the competitive inhibitor [Pt(O,O'-acac)(γ-acac)(DMSO)] only shows a pro-apoptotic activity at all investigated concentrations. These features render the [Pt(O,O'-acac)(γ-acac)(DMSO)] a promising "lead compound" for the synthesis of IDE-specific inhibitors (not characterized yet) with therapeutic potentiality.
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http://dx.doi.org/10.1007/s00775-014-1217-3DOI Listing
January 2015
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