Latest PUBLICATIONS

  • Regulating levels of the neuromodulator d-serine in human brain: structural insight into pLG72 and d-amino acid oxidase interaction.
    Publication Date: 01/09/2016, on The FEBS journal
    by Birolo L, Sacchi S, Smaldone G, Molla G, Leo G, Caldinelli L, Pirone L, Eliometri P, Di Gaetano S, Orefice I, Pedone E, Pucci P, Pollegioni L
    DOI: 10.1111/febs.13809

    The human flavoenzyme d-amino acid oxidase (hDAAO) degrades the NMDA-receptor modulator d-serine in the brain. Although hDAAO has been extensively characterized, little is known about its main modulator pLG72, a small protein encoded by the primate-specific gene G72 that has been associated with schizophrenia susceptibility. pLG72 interacts with neosynthesized hDAAO, promoting its inactivation and degradation. In this work, we used low-resolution techniques to characterize the surface topology of the hDAAO-pLG72 complex. By using limited proteolysis coupled to mass spectrometry, we could map the exposed regions in the two proteins after complex formation and highlighted an increased sensitivity to proteolysis of hDAAO in complex with pLG72. Cross-linking experiments by using bis(sulfosuccinimidyl)suberate identified the single covalent bond between T182 in hDAAO and K62 in pLG72. In order to validate the designed mode of interaction, three pLG72 variants incrementally truncated at the C terminus, in addition to a form lacking the 71 N-terminal residues, were produced. All variants were dimeric, folded, and interacted with hDAAO. The strongest decrease in affinity for hDAAO (as well as for the hydrophobic drug chlorpromazine) was apparent for the N-terminally deleted pLG72(72-153) form, which lacked K62. On the other hand, eliminating the disordered C-terminal tail yielded a more stable pLG72 protein, improved the binding to hDAAO, although giving lower enzyme inhibition. Elucidation of the mode of hDAAO-pLG72 interaction now makes it possible to design novel molecules that, by targeting the protein complex, can be therapeutically advantageous for diseases related to impairment in d-serine metabolism.

  • Dilated perivascular spaces and fatigue: is there a link? Magnetic resonance retrospective 3Tesla study.
    Publication Date: 01/09/2016, on Neuroradiology
    by Conforti R, Cirillo M, Sardaro A, Caiazzo G, Negro A, Paccone A, Sacco R, Sparaco M, Gallo A, Lavorgna L, Tedeschi G, Cirillo S
    DOI: 10.1007/s00234-016-1711-0

    Fatigue (F) is a common, inexplicable, and disabling symptom in multiple sclerosis (MS) patients. The purpose of this study was to evaluate a possible correlation between fatigue and morpho-volumetric features and site of dilated perivascular spaces (dPS), visible on 3T magnetic resonance (MR) in fatigued multiple sclerosis patients (FMS).

  • Rituximab in the treatment of Neuromyelitis optica: a multicentre Italian observational study.
    Publication Date: 01/09/2016, on Journal of neurology
    by Annovazzi P, Capobianco M, Moiola L, Patti F, Frau J, Uccelli A, Centonze D, Perini P, Tortorella C, Prosperini L, Lus G, Fuiani A, Falcini M, Martinelli V, Comi G, Ghezzi A
    DOI: 10.1007/s00415-016-8188-y

    Rituximab (RTX) efficacy in NMO is suggested by several case series. No consensus exists on optimal dosing strategies. At present the treatment schedules more frequently used are 375 mg/m2/week iv for 4 weeks (RTX-A) and 1000 mg iv twice, 2 weeks apart (RTX-B). Aim of this study is to confirm RTX efficacy and safety in the treatment of NMO and to evaluate whether a most favourable dosage regimen exists. Data on RTX-treated NMO patients were collected from 13 Italian Hospitals. 73 patients (64 F), were enlisted. RTX-A was administered in 42/73 patients, RTX-B in 31/73. Median follow-up was 27 months (range 7-106). Mean relapse rate in the previous year before RTX start was 2.2 ± 1.3 for RTX-A and 2.3 ± 1.2 for RTX-B. ARR in the first year of treatment was 0.8 ± 0.9 for RTX-A and 0.2 ± 0.4 for RTX-B, in the second year of treatment was 0.9 ± 1.5 for RTX-A and 0.4 ± 0.8 for RTX-B patients (p = 0.001 for the first year, ns (0.09) for the second year). RTX-B was more effective in delaying the occurrence of a relapse (HR 2.2 (95 % IC 1.08-4.53) p = 0.02). Adverse events were described in 19/73 patients (mainly urinary tract and respiratory infections, and infusion reactions). Two deaths were reported in severely disabled patients. Though with the limitations of an observational study, our data support RTX efficacy in NMO and suggest that high dose pulses might be more effective than a more fractioned dose.

  • Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.
    Publication Date: 01/09/2016, on Journal of neurology, neurosurgery, and psychiatry
    by Patti F, Messina S, Solaro C, Amato MP, Bergamaschi R, Bonavita S, Bruno Bossio R, Brescia Morra V, Costantino GF, Cavalla P, Centonze D, Comi G, Cottone S, Danni M, Francia A, Gajofatto A, Gasperini C, Ghezzi A, Iudice A, Lus G, Maniscalco GT, Marrosu MG, Matta M, Mirabella M, Montanari E, Pozzilli C, Rovaris M, Sessa E, Spitaleri D, Trojano M, Valentino P, Zappia M,
    DOI: 10.1136/jnnp-2015-312591

    The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.

  • Identification of major Toxoneuron nigriceps venom proteins using an integrated transcriptomic/proteomic approach.
    Publication Date: 01/09/2016, on Insect biochemistry and molecular biology
    by Laurino S, Grossi G, Pucci P, Flagiello A, Bufo SA, Bianco G, Salvia R, Vinson SB, Vogel H, Falabella P
    DOI: 10.1016/j.ibmb.2016.07.001

    Endoparasitoids in the order Hymenoptera are natural enemies of several herbivorous insect pest species. During oviposition they inject a mixture of factors, which include venom, into the host, ensuring the successful parasitism and the development of their progeny. Although these parasitoid factors are known to be responsible for host manipulation, such as immune system suppression, little is known about both identity and function of the majority of their venom components. To identify the major proteins of Toxoneuron nigriceps (Hymenoptera: Braconidae) venom, we used an integrated transcriptomic and proteomic approach. The tandem-mass spectrometric (LC-MS/MS) data combined with T. nigriceps venom gland transcriptome used as a reference database resulted in the identification of a total of thirty one different proteins. While some of the identified proteins have been described in venom from several parasitoids, others were identified for the first time. Among the identified proteins, hydrolases constituted the most abundant family followed by transferases, oxidoreductases, ligases, lyases and isomerases. The hydrolases identified in the T. nigriceps venom glands included proteases, peptidases and glycosidases, reported as common components of venom from several parasitoid species. Taken together, the identified proteins included factors that could potentially inhibit the host immune system, manipulate host physiological processes and host development, as well as provide nutrients to the parasitoid progeny, degrading host tissues by specific hydrolytic enzymes. The venom decoding provides us with information about the identity of candidate venom factors which could contribute to the success of parasitism, together with other maternal and embryonic factors.

  • A challenging diagnosis of late-onset tumefactive multiple sclerosis associated to cervicodorsal syringomyelia: doubtful CT, MRI, and bioptic findings: Case report and literature review.
    Publication Date: 01/09/2016, on Medicine
    by Conforti R, Capasso R, Galasso R, Cirillo M, Taglialatela G, Galasso L
    DOI: 10.1097/MD.0000000000004585

    Tumefactive multiple sclerosis (MS) is an unusual variant of demyelinating disease characterized by lesions with pseudotumoral appearance on radiological imaging mimicking other space-occupying lesions, such as neoplasms, infections, and infarction. Especially when the patient's medical history is incompatible with MS, the differential diagnosis between these lesions constitutes a diagnostic challenge often requiring histological investigation. An older age at onset makes distinguishing tumefactive demyelinating lesion (TDL) from tumors even more challenging.

  • The relationships between apathy and executive dysfunction in multiple sclerosis.
    Publication Date: 01/09/2016, on Neuropsychology
    by Raimo S, Trojano L, Spitaleri D, Petretta V, Grossi D, Santangelo G
    DOI: 10.1037/neu0000279

    Neuropsychiatric symptoms are common in multiple sclerosis (MS). Among these, apathy is relatively frequent but its relationships with cognitive dysfunctions have been poorly investigated.

  • Homostachydrine (pipecolic acid betaine) as authentication marker of roasted blends of Coffea arabica and Coffea canephora (Robusta) beans.
    Publication Date: 15/08/2016, on Food chemistry
    by Servillo L, Giovane A, Casale R, Cautela D, D'Onofrio N, Balestrieri ML, Castaldo D
    DOI: 10.1016/j.foodchem.2016.02.154

    The occurrence of pipecolic acid betaine (homostachydrine) and its biosynthetic precursor N-methylpipecolic acid was detected for the first time in green coffee beans of Robusta and Arabica species. The analyses were conducted by HPLC-ESI tandem mass spectrometry and the metabolites identified by product ion spectra and comparison with authentic standards. N-methylpipecolic acid was found at similar levels in green coffee beans of Robusta and Arabica, whereas a noticeable difference of homostachydrine content was observed between the two green coffee bean species. Interestingly, homostachydrine content was found to be unaffected by coffee bean roasting treatment because of a noticeable heat stability, a feature that makes this compound a candidate marker to determine the content of Robusta and Arabica species in roasted coffee blends. To this end, a number of certified pure Arabica and Robusta green beans were analyzed for their homostachydrine content. Results showed that homostachydrine content was 1.5±0.5mg/kg in Arabica beans and 31.0±10.0mg/kg in Robusta beans. Finally, to further support the suitability of homostachydrine as quality marker of roasted blends of Arabica and Robusta coffee beans, commercial samples of roasted ground coffee blends were analyzed and the correspondence between the derived percentages of Arabica and Robusta beans with those declared on packages by manufacturers was verified.

  • Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial.
    Publication Date: 13/08/2016, on Lancet (London, England)
    by Bennett J, Wellman J, Marshall KA, McCague S, Ashtari M, DiStefano-Pappas J, Elci OU, Chung DC, Sun J, Wright JF, Cross DR, Aravand P, Cyckowski LL, Bennicelli JL, Mingozzi F, Auricchio A, Pierce EA, Ruggiero J, Leroy BP, Simonelli F, High KA, Maguire AM
    DOI: 10.1016/S0140-6736(16)30371-3

    Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study.

  • Morphological and Functional Retinal Assessment in Epiretinal Membrane Surgery.
    Publication Date: 10/08/2016, on Seminars in ophthalmology
    by Donati S, Caprani SM, Semeraro F, Vinciguerra R, Virgili G, Testa F, Simonelli F, Azzolini C
    DOI: 10.1080/08820538.2016.1177097

    To analyze functional and morphological findings after surgery for idiopathic epiretinal macular membrane (IEMM).

  • Transcriptomic analysis of the autophagy machinery in crustaceans.
    Publication Date: 09/08/2016, on BMC genomics
    by Suwansa-Ard S, Kankuan W, Thongbuakaew T, Saetan J, Kornthong N, Kruangkum T, Khornchatri K, Cummins SF, Isidoro C, Sobhon P
    DOI: 10.1186/s12864-016-2996-4

    The giant freshwater prawn, Macrobrachium rosenbergii, is a decapod crustacean that is commercially important as a food source. Farming of commercial crustaceans requires an efficient management strategy because the animals are easily subjected to stress and diseases during the culture. Autophagy, a stress response process, is well-documented and conserved in most animals, yet it is poorly studied in crustaceans.

  • Mulibrey nanism: Two novel mutations in a child identified by Array CGH and DNA sequencing.
    Publication Date: 01/08/2016, on American journal of medical genetics. Part A
    by Mozzillo E, Cozzolino C, Genesio R, Melis D, Frisso G, Orrico A, Lombardo B, Fattorusso V, Discepolo V, Della Casa R, Simonelli F, Nitsch L, Salvatore F, Franzese A
    DOI: 10.1002/ajmg.a.37770

    In childhood, several rare genetic diseases have overlapping symptoms and signs, including those regarding growth alterations, thus the differential diagnosis is sometimes difficult. The proband, aged 3 years, was suspected to have Silver-Russel syndrome because of intrauterine growth retardation, postnatal growth retardation, typical facial dysmorphic features, macrocephaly, body asymmetry, and bilateral fifth finger clinodactyly. Other features were left atrial and ventricular enlargement and patent foramen ovale. Total X-ray skeleton showed hypoplasia of the twelfth rib bilaterally and of the coccyx, slender long bones with thick cortex, and narrow medullary channels. The genetic investigation did not confirm Silver-Russel syndrome. At the age of 5 the patient developed an additional sign: hepatomegaly. Array CGH revealed a 147 kb deletion (involving TRIM 37 and SKA2 genes) on one allele of chromosome 17, inherited from his mother. These results suggested Mulibrey nanism. The clinical features were found to fit this hypothesis. Sequencing of the TRIM 37 gene showed a single base change at a splicing locus, inherited from his father that provoked a truncated protein. The combined use of Array CGH and DNA sequencing confirmed diagnosis of Mulibrey nanism. The large deletion involving the SKA2 gene, along with the increased frequency of malignant tumours in mulibrey patients, suggests closed monitoring for cancer of our patient and his mother. Array CGH should be performed as first tier test in all infants with multiple anomalies. The clinician should reconsider the clinical features when the genetics suggests this. © 2016 Wiley Periodicals, Inc.

  • Epigenetic regulation of TGF-β1 signalling in dilative aortopathy of the thoracic ascending aorta.
    Publication Date: 01/08/2016, on Clinical science (London, England : 1979)
    by Forte A, Galderisi U, Cipollaro M, De Feo M, Della Corte A
    DOI: 10.1042/CS20160222

    The term 'epigenetics' refers to heritable, reversible DNA or histone modifications that affect gene expression without modifying the DNA sequence. Epigenetic modulation of gene expression also includes the RNA interference mechanism. Epigenetic regulation of gene expression is fundamental during development and throughout life, also playing a central role in disease progression. The transforming growth factor β1 (TGF-β1) and its downstream effectors are key players in tissue repair and fibrosis, extracellular matrix remodelling, inflammation, cell proliferation and migration. TGF-β1 can also induce cell switch in epithelial-to-mesenchymal transition, leading to myofibroblast transdifferentiation. Cellular pathways triggered by TGF-β1 in thoracic ascending aorta dilatation have relevant roles to play in remodelling of the vascular wall by virtue of their association with monogenic syndromes that implicate an aortic aneurysm, including Loeys-Dietz and Marfan's syndromes. Several studies and reviews have focused on the progression of aneurysms in the abdominal aorta, but research efforts are now increasingly being focused on pathogenic mechanisms of thoracic ascending aorta dilatation. The present review summarizes the most recent findings concerning the epigenetic regulation of effectors of TGF-β1 pathways, triggered by sporadic dilative aortopathy of the thoracic ascending aorta in the presence of a tricuspid or bicuspid aortic valve, a congenital malformation occurring in 0.5-2% of the general population. A more in-depth comprehension of the epigenetic alterations associated with TGF-β1 canonical and non-canonical pathways in dilatation of the ascending aorta could be helpful to clarify its pathogenesis, identify early potential biomarkers of disease, and, possibly, develop preventive and therapeutic strategies.

  • Neuropsychological correlates of Pisa syndrome in patients with Parkinson's disease.
    Publication Date: 01/08/2016, on Acta neurologica Scandinavica
    by Vitale C, Falco F, Trojano L, Erro R, Moccia M, Allocca R, Agosti V, Santangelo F, Barone P, Santangelo G
    DOI: 10.1111/ane.12514

    A complex relationship exists between postural control and cognition in the elderly. Namely, neural mechanisms that are required for the regulation of posture have been variably associated with cognitive dysfunctions. Parkinson's disease (PD) is the second most common neurodegenerative disease among the elderly, and it has been associated with both cognitive and postural abnormalities such as Pisa syndrome (PS). Although its onset has been considered to be multifactorial, the pathophysiological mechanisms underpinning PS are still not fully explained. Until now, no study investigated the possible contribution of cognitive dysfunction to occurrence of PS in PD.

  • Energetics of ligand-receptor binding affinity on endothelial cells: An in vitro model.
    Publication Date: 01/08/2016, on Colloids and surfaces. B, Biointerfaces
    by Fotticchia I, Guarnieri D, Fotticchia T, Falanga AP, Vecchione R, Giancola C, Netti PA
    DOI: 10.1016/j.colsurfb.2016.04.018

    Targeted therapies represent a challenge in modern medicine. In this contest, we propose a rapid and reliable methodology based on Isothermal Titration Calorimetry (ITC) coupled with confluent cell layers cultured around biocompatible templating microparticles to quantify the number of overexpressing receptors on cell membrane and study the energetics of receptor-ligand binding in near-physiological conditions. In the in vitro model here proposed we used the bEnd3 cell line as brain endothelial cells to mimic the blood brain barrier (BBB) cultured on dextran microbeads ranging from 67μm to 80μm in size (Cytodex) and the primary human umbilical vein cells (HUVEC) for comparison. The revealed affinity between transferrin (Tf) and transferrin receptor (TfR) in both systems is very high, Kd values are in the order of nM. Conversely, the value of TfRs/cell reveals a 100-fold increase in the number of TfRs per bEnd3 cells compared to HUVEC cells. The presented methodology can represent a novel and helpful strategy to identify targets, to address drug design and selectively deliver therapeutics that can cross biological barriers such as the blood brain barrier.