Latest PUBLICATIONS

  • Tractography in amyotrophic lateral sclerosis using a novel probabilistic tool: a study with tract-based reconstruction compared to voxel-based approach.
    Publication Date: 15/03/2014, on Journal of neuroscience methods
    by Sarica A, Cerasa A, Vasta R, Perrotta P, Valentino P, Mangone G, Guzzi PH, Rocca F, Nonnis M, Cannataro M, Quattrone A
    DOI: 10.1016/j.jneumeth.2013.12.014

    Diffusion tensor imaging (DTI) is one of the most sensitive MRI tools for detecting subtle cerebral white matter abnormalities in amyotrophic lateral sclerosis (ALS). Nowadays a plethora of DTI tools have been proposed, but very few methods have been translated into clinical practice.

  • Affective theory of mind in patients with Parkinson's disease: comment.
    Publication Date: 01/03/2014, on Psychiatry and clinical neurosciences
    by Santangelo G, Vitale C, Errico D, Grossi D, Trojano L, Barone P
    DOI:

  • The genesis of closing-in in Alzheimer disease and vascular dementia: a comparative clinical and experimental study.
    Publication Date: 01/03/2014, on Neuropsychology
    by De Lucia N, Grossi D, Trojano L
    DOI: 10.1037/neu0000036

    Closing-in (CI) in visuo-constructional tasks occurs when a drawing is reproduced close to or superimposed on the original model. CI has been often observed in Alzheimer disease (AD) patients and only rarely investigated in patients with vascular dementia (VD). Recent studies suggested that CI in AD patients represents a default behavior released by frontal-executive impairments, but the cognitive mechanisms behind this phenomenon in VD patients have not been clarified. We aimed to ascertain whether the same mechanisms could determine CI in VD and in AD patients. For this purpose we explored whether CI is related to frontal-executive or visuospatial impairments in a prospective sample of AD and VD patients, and investigated whether CI can be induced by a secondary task in patients with either disease.

  • Subthreshold depression and subjective cognitive complaints in Parkinson's disease.
    Publication Date: 01/03/2014, on European journal of neurology
    by Santangelo G, Vitale C, Trojano L, Angrisano MG, Picillo M, Errico D, Agosti V, Grossi D, Barone P
    DOI: 10.1111/ene.12219

    Subthreshold depression (SubD) is characterized by clinically relevant depressive symptoms not meeting criteria for major depression. The possible association of SubD with subjective cognitive complaints and/or objective cognitive impairments was investigated in a sample of consecutive, non-demented Parkinson's disease (PD) outpatients.

  • Effects of a second-generation human anti-ErbB2 ImmunoRNase on trastuzumab-resistant tumors and cardiac cells.
    Publication Date: 01/03/2014, on Protein engineering, design & selection : PEDS
    by D'Avino C, Paciello R, Riccio G, Coppola C, Laccetti P, Maurea N, Raines RT, De Lorenzo C
    DOI: 10.1093/protein/gzt065

    The inhibition of ErbB2 by the use of human antibodies can be a valuable strategy for the treatment of breast and gastric cancer. Trastuzumab, a humanized anti-ErbB2 antibody in clinical use, is effective but can engender resistance as well as cardiotoxicity. ImmunoRNases, made up of a human anti-ErbB2 scFv and human pancreatic ribonucleases (HP-RNases), have been engineered to overcome the limits of other immunotoxins, such as immunogenicity and nonspecific toxicity. Here, we report that a novel anti-ErbB2 immunoRNase, called Erb-HPDDADD-RNase, obtained by fusing Erbicin, a human ErbB2-directed scFv, with an HP-RNase variant that resists the cytosolic inhibitor protein, binds with high affinity to a panel of ErbB2-positive gastric tumor cells and inhibits their growth more than does the parental immunoRNase, which is not resistant to the inhibitor. Moreover, Erb-HP-DDADD-RNase is endowed with antiproliferative activity for trastuzumab-resistant cancer cells both in vitro and in vivo that is more potent than that of the parental immunoRNase. Importantly, Erb-HP-DDADD-RNase does not show cardiotoxic effects in vitro on human cardiomyocytes and does not impair cardiac function in a mouse model. Thus, Erb-HP-DDADD-RNase could fulfil the therapeutic need of cancer patients ineligible for trastuzumab treatment due to primary or acquired trastuzumab resistance or to cardiac dysfunction.

  • Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis.
    Publication Date: 01/03/2014, on Nucleic acids research
    by Salvati E, Zizza P, Rizzo A, Iachettini S, Cingolani C, D'Angelo C, Porru M, Randazzo A, Pagano B, Novellino E, Pisanu ME, Stoppacciaro A, Spinella F, Bagnato A, Gilson E, Leonetti C, Biroccio A
    DOI: 10.1093/nar/gkt1289

    Tumor angiogenesis is mainly mediated by vascular endothelial growth factor (VEGF), a pro-angiogenic factor produced by cancer cells and active on the endothelium through the VEGF receptor 2 (VEGFR-2). Here we identify a G-rich sequence within the proximal promoter region of vegfr-2, able to form an antiparallel G-quadruplex (G4) structure. This G4 structure can be efficiently stabilized by small molecules with the consequent inhibition of vegfr-2 expression. Functionally, the G4-mediated reduction of VEGFR-2 protein causes a switching off of signaling components that, converging on actin cytoskeleton, regulate the cellular events leading to endothelial cell proliferation, migration and differentiation. As a result of endothelial cell function impairment, angiogenic process is strongly inhibited by G4 ligands both in vitro and in vivo. Interestingly, the G4-mediated antiangiogenic effect seems to recapitulate that observed by using a specific interference RNA against vegfr-2, and it is strongly antagonized by overexpressing the vegfr-2 gene. In conclusion, we describe the evidence for the existence of G4 in the promoter of vegfr-2, whose expression and function can be markedly inhibited by G4 ligands, thereby revealing a new, and so far undescribed, way to block VEGFR-2 as target for anticancer therapy.

  • An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies.
    Publication Date: 01/03/2014, on Pharmacology & therapeutics
    by Musumeci D, Roviello GN, Montesarchio D
    DOI: 10.1016/j.pharmthera.2013.11.001

    HMGB1 (High-Mobility Group Box-1) is a nuclear protein that acts as an architectural chromatin-binding factor involved in the maintenance of nucleosome structure and regulation of gene transcription. It can be released into the extracellular milieu from immune and non-immune cells in response to various stimuli. Extracellular HMGB1 contributes to the pathogenesis of numerous chronic inflammatory and autoimmune diseases, including sepsis, rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus (SLE), as well as cancer pathogenesis. Interaction of released HMGB1 with the cell-surface receptor for advanced glycation end products (RAGE) is one of the main signaling pathways triggering these diseases. It has been also demonstrated that the inhibition of the HMGB1-RAGE interaction represents a promising approach for the modulation of the inflammatory and tumor-facilitating activity of HMGB1. In this review we describe various approaches recently proposed in the literature to inhibit HMGB1 and the related inflammatory processes, especially focusing on the block of RAGE-HMGB1 signaling. Several strategies are based on molecules which mainly interact with RAGE as competitive antagonists of HMGB1. As an alternative, encouraging results have been obtained with HMGB1-targeting, leading to the identification of compounds that directly bind to HMGB1, ranging from small natural or synthetic molecules, such as glycyrrhizin and gabexate mesilate, to HMGB1-specific antibodies, peptides, proteins as well as bent DNA-based duplexes. Future perspectives are discussed in the light of the overall body of knowledge acquired by a large number of research groups operating in different but related fields.

  • Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome.
    Publication Date: 01/03/2014, on Scandinavian journal of gastroenterology
    by Giardino G, Cirillo E, Maio F, Gallo V, Esposito T, Naddei R, Grasso F, Pignata C
    DOI: 10.3109/00365521.2013.855814

    OBJECTIVE. Enteropathy is a very common feature in patients with primary immunodeficiencies. In patients with Del22 gastrointestinal (GI) alterations, including feeding disorders and congenital abnormalities have been often reported, mostly in the first year of life. MATERIAL AND METHODS. Aim of this monocentric study is to better define the GI involvement in a cohort of 26 patients affected with Del22 syndrome. Anamnestic information was retrospectively collected for each patient. Weight and height parameters at the time of the screening were recorded. Plasma levels of hemoglobin, iron, ferritin, albumin, total protein, calcium, phosphorus, transaminase levels, antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers were measured. RESULTS. A GI involvement was identified in the 58% of patients. The prominent problems were abdominal pain, vomiting, gastroesophageal reflux and chronic constipation. Weight deficiency, short stature and failure to thrive were reported in 54, 42, and 30% of the patients, respectively. The evidence of sideropenic anemia, in keeping with hypoproteinemia, impaired acid steatocrit or cellobiose/mannitol test suggested an abnormal intestinal permeability. In this cohort, a high prevalence of AGA IgA and IgG positivity was observed. Celiac disease (CD) was suspected in three patients, and in one of them confirmed by histology. In this patient, a long-lasting gluten-free diet failed to restore the intestinal architecture. CONCLUSIONS. In conclusion, GI involvement is a very common feature in Del22 patients. A better characterization of GI involvement would be very useful to improve the management of these patients.

  • Local gene expression in nerve endings.
    Publication Date: 01/03/2014, on Developmental neurobiology
    by Crispino M, Chun JT, Cefaliello C, Perrone Capano C, Giuditta A
    DOI: 10.1002/dneu.22109

    At the Nobel lecture for physiology in 1906, Ramón y Cajal famously stated that "the nerve elements possess reciprocal relationships in contiguity but not in continuity," summing up the neuron doctrine. Sixty years later, by the time the central dogma of molecular biology formulated the axis of genetic information flow from DNA to mRNA, and then to protein, it became obvious that neurons with extensive ramifications and long axons inevitably incur an innate problem: how can the effect of gene expression be extended from the nucleus to the remote and specific sites of the cell periphery? The most straightforward solution would be to deliver soma-produced proteins to the target sites. The influential discovery of axoplasmic flow has supported this scheme of protein supply. Alternatively, mRNAs can be dispatched instead of protein, and translated locally at the strategic target sites. Over the past decades, such a local system of protein synthesis has been demonstrated in dendrites, axons, and presynaptic terminals. Moreover, the local protein synthesis in neurons might even involve intercellular trafficking of molecules. The innovative concept of glia-neuron unit suggests that the local protein synthesis in the axonal and presynaptic domain of mature neurons is sustained by a local supply of RNAs synthesized in the surrounding glial cells and transferred to these domains. Here, we have reviewed some of the evidence indicating the presence of a local system of protein synthesis in axon terminals, and have examined its regulation in various model systems.

  • Global transcriptome profiles of Italian Mediterranean buffalo embryos with normal and retarded growth.
    Publication Date: 28/02/2014, on PloS one
    by Strazzullo M, Gasparrini B, Neglia G, Balestrieri ML, Francioso R, Rossetti C, Nassa G, De Filippo MR, Weisz A, Di Francesco S, Vecchio D, D'Esposito M, D'Occhio MJ, Zicarelli L, Campanile G
    DOI: 10.1371/journal.pone.0090027

    The transcriptome profiles were compared for buffalo embryos with normal growth and embryos with retarded growth on Day 25 after mating. Embryos with retarded growth on Day 25 after mating have a reduced likelihood of undergoing attachment to the uterine endometrium and establishing a pregnancy. Italian Mediterranean buffaloes were mated by AI and on Day 25 underwent trans-rectal ultrasonography to ascertain embryo development. Embryos with an embryonic width (EW)>2.7 mm were classed as normal embryos and embryos with an EW<2.7 mm were classed as retarded embryos. Three buffaloes with embryos of the largest EW (3.7, 3.7 and 3.9 mm) and three buffaloes with embryos of the smallest EW (1.5, 1.6 and 1.9 mm) were slaughtered on Day 27 to recover embryos for transcriptome analysis using a bovine custom designed oligo array. A total of 1,047 transcripts were differentially expressed between embryos with normal growth and embryos with retarded growth. Retarded embryos showed 773/1,047 (74%) transcripts that were down-regulated and 274/1,047 (26%) transcripts that were up-regulated relative to normal embryos; in silico analyses focused on 680/1,047 (65%) of the differentially expressed transcripts. The most altered transcripts observed in retarded embryos were associated with membrane structure and function and with metabolic and homeostasis maintenance functions. Other notable functions altered in retarded embryos were developmental processes and in particular nervous system differentiation and function. Specific biochemical pathways such as the complement cascade and coagulation were also altered in retarded embryos. It was concluded from the findings that buffalo embryos with retarded growth on Day 25 after mating show altered gene expression compared with normal embryos, and some de-regulated functions are associated with attachment to the uterine endometrium.

  • Approaching threats elicit a freeze-like response in humans.
    Publication Date: 21/02/2014, on Neuroscience letters
    by Sagliano L, Cappuccio A, Trojano L, Conson M
    DOI: 10.1016/j.neulet.2013.12.038

    Freezing is one of the most widely recognized defensive reactions to approaching threats in animals. Here we tested whether the same stimuli can elicit freeze-like responses in healthy humans as well. We used a modified version of the two-frame apparent motion paradigm, in which both size and location of a stimulus within a background were manipulated; by these means, participants perceived the stimuli as approaching or receding. In Experiment 1, we showed that implicitly processed approaching threats (e.g., spiders or snakes) elicited a stronger freeze-like response (operationalized as slower reaction times) with respect to receding threats; freezing was significantly related to higher levels of participants' state anxiety. In Experiment 2, approaching/threatening animals were explicitly judged as more threatening than receding ones. Finally, in two further control experiments we observed that the same manipulation of stimuli's size and location, but in absence of apparent motion, did not affect freezing (Experiment 3) or explicit threat judgements (Experiment 4). The present findings demonstrated that approaching threats are critical to elicit freezing in humans, in line with animals' behaviour.

  • HDAC6 mediates the acetylation of TRIM50.
    Publication Date: 01/02/2014, on Cellular signalling
    by Fusco C, Micale L, Augello B, Mandriani B, Pellico MT, De Nittis P, Calcagnì A, Monti M, Cozzolino F, Pucci P, Merla G
    DOI: 10.1016/j.cellsig.2013.11.036

    The E3 Ubiquitin ligase TRIM50 promotes the formation and clearance of aggresome-associated polyubiquitinated proteins through HDAC6 interaction, a tubulin specific deacetylase that regulates microtubule-dependent aggresome formation. In this report we showed that TRIM50 is a target of HDAC6 with Lys-372 as a critical residue for acetylation. We identified p300 and PCAF as two TRIM50 acetyltransferases and we further showed that a balance between ubiquitination and acetylation regulates TRIM50 degradation.

  • The role of embodied simulation in mental transformation of whole-body images: evidence from Parkinson's disease.
    Publication Date: 01/02/2014, on Human movement science
    by Conson M, Trojano L, Vitale C, Mazzarella E, Allocca R, Barone P, Grossi D, Santangelo G
    DOI: 10.1016/j.humov.2013.10.006

    It has been repeatedly demonstrated that mentally performing an action and mentally transforming body-parts entail simulation of one's own body movements, consistent with predictions of embodied cognition theories. However, the involvement of embodied simulation in mental transformation of whole-body images is still disputed. Here, we assessed own body transformation in Parkinson's disease (PD) patients with symptoms most affecting the left or the right body side. PD patients were required to perform left-right judgments on front-facing or back-facing human figures, and a letter rotation task. Results demonstrated that PD patients were selectively impaired in judging the side of back-facing human figures corresponding to their own most affected side, but performed as well as healthy subjects on mental transformation of front-facing bodies and on letter rotation. These findings demonstrate a parallel impairment between motor and mental simulation mechanisms in PD patients, thus highlighting the specific contribution of embodied cognition to mental transformation of whole-body images.

  • Mechanism of 3D domain swapping in bovine seminal ribonuclease.
    Publication Date: 01/02/2014, on The FEBS journal
    by Spadaccini R, Ercole C, Graziano G, Wechselberger R, Boelens R, Picone D
    DOI:

    3D domain swapping (3D-DS) is a complex protein aggregation process for which no unique mechanism exists. We report an analysis of 3D-DS in bovine seminal ribonuclease, a homodimeric protein whose subunits are linked by two disulfide bridges, based on NMR and biochemical studies. The presence of the covalent bonds between the subunits stabilizes the unswapped dimer, and allows distinct evaluation of the structural and dynamic effects of the swapping with respect to the dimerization process. In comparison with the monomeric subunit, which, in solution has a compact structure without any propensity for local unfolding, both swapped and unswapped dimers show increased flexibility. NMR analysis, together with urea denaturation and hydrogen–deuterium exchange data, indicates that the two dimers have increased conformational fluctuations. Furthermore, we found that the rate-limiting step of both the swapping and unswapping pathways is the detachment of the N-terminal helices from the monomers. These results suggest a new general mechanism in which a dimeric intermediate could facilitate 3D-DS in globular proteins.

  • Effective delivery of large genes to the retina by dual AAV vectors.
    Publication Date: 01/02/2014, on EMBO molecular medicine
    by Trapani I, Colella P, Sommella A, Iodice C, Cesi G, de Simone S, Marrocco E, Rossi S, Giunti M, Palfi A, Farrar GJ, Polishchuk R, Auricchio A
    DOI: 10.1002/emmm.201302948

    Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, AAV's limited cargo capacity prevents its application to therapies of inherited retinal diseases due to mutations of genes over 5 kb, like Stargardt's disease (STGD) and Usher syndrome type IB (USH1B). Previous methods based on 'forced' packaging of large genes into AAV capsids may not be easily translated to the clinic due to the generation of genomes of heterogeneous size which raise safety concerns. Taking advantage of AAV's ability to concatemerize, we generated dual AAV vectors which reconstitute a large gene by either splicing (trans-splicing), homologous recombination (overlapping), or a combination of the two (hybrid). We found that dual trans-splicing and hybrid vectors transduce efficiently mouse and pig photoreceptors to levels that, albeit lower than those achieved with a single AAV, resulted in significant improvement of the retinal phenotype of mouse models of STGD and USH1B. Thus, dual AAV trans-splicing or hybrid vectors are an attractive strategy for gene therapy of retinal diseases that require delivery of large genes.