Latest PUBLICATIONS

  • A novel GBE1 mutation and features of polyglucosan bodies autophagy in adult polyglucosan body disease.
    Publication Date: 01/03/2015, on Neuromuscular disorders : NMD
    by Sampaolo S, Esposito T, Gianfrancesco F, Napolitano F, Lombardi L, Lucà R, Roperto F, Di Iorio G
    DOI: 10.1016/j.nmd.2014.11.006

    We report the clinical, neuro-imaging, pathological and biochemical features of an Italian family in which two siblings have the Adult Polyglucosan Body Disease (APBD). APBD is a rare autosomal recessive disorder characterized by a gradually progressive involvement of both the central and peripheral nervous systems caused by the deficiency of the glycogen branching enzyme (GBE1). The two affected siblings, a 64-year-old man and his 67-year-old sister who had complained of urinary urgency and sporadic incontinence and also progressive gait difficulty for 6 and 7 years respectively, had severely impaired deep sensations on direct examination and a moderately severe symmetrical, axonal sensory-motor neuropathy on electrophysiological testing. GBE1 activity was below 25% of the normal rate in leukocytes and sural nerves. The siblings were homozygous for the novel GBE1 mutation p.N541D. All other members of the pedigree are heterozygous and manifest no symptoms, even in the very elderly. The affected siblings showed polyglucosan bodies (PBs) included within non-myelinating Schwann cells and within lymphocyte vesicles, which were positive for the autophagy markers P62 and LC3-II at immunofluorescence microscopy.

  • Decreased <i>BECN1</i> mRNA Expression in Human Breast Cancer is Associated with Estrogen Receptor-Negative Subtypes and Poor Prognosis.
    Publication Date: 01/03/2015, on EBioMedicine
    by Tang H, Sebti S, Titone R, Zhou Y, Isidoro C, Ross TS, Hibshoosh H, Xiao G, Packer M, Xie Y, Levine B
    DOI: 10.1016/j.ebiom.2015.01.008

    Both BRCA1 and Beclin 1 (BECN1) are tumor suppressor genes, which are in close proximity on the human chromosome 17q21 breast cancer tumor susceptibility locus and are often concurrently deleted. However, their importance in sporadic human breast cancer is not known. To interrogate the effects of BECN1 and BRCA1 in breast cancer, we studied their mRNA expression patterns in breast cancer patients from two large datasets: The Cancer Genome Atlas (TCGA) (n=1067) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n=1992). In both datasets, low expression of BECN1 was more common in HER2-enriched and basal-like (mostly triple-negative) breast cancers compared to luminal A/B intrinsic tumor subtypes, and was also strongly associated with TP53 mutations and advanced tumor grade. In contrast, there was no significant association between low BRCA1 expression and HER2-enriched or basal-like subtypes, TP53 mutations or tumor grade. In addition, low expression of BECN1 (but not low BRCA1) was associated with poor prognosis, and BECN1 (but not BRCA1) expression was an independent predictor of survival. These findings suggest that decreased mRNA expression of the autophagy gene BECN1 may contribute to the pathogenesis and progression of HER2-enriched, basal-like, and TP53 mutant breast cancers.

  • Guanine-based amphiphiles: synthesis, ion transport properties and biological activity.
    Publication Date: 01/03/2015, on Bioorganic & medicinal chemistry
    by Musumeci D, Irace C, Santamaria R, Milano D, Tecilla P, Montesarchio D
    DOI: 10.1016/j.bmc.2014.12.055

    Novel amphiphilic guanine derivatives, here named Gua1 and Gua2, have been prepared through few, simple and efficient synthetic steps. In ion transport experiments through phospholipid bilayers, carried out to evaluate their ability to mediate H(+) transport, Gua2 showed high activity. When this compound was investigated for ion-selective transport activities, no major differences were observed in the behaviour with cations while, in the case of anions, selective activity was observed in the series I(-)>Br(-)>Cl(-)>F(-). The bioactivity of these guanine analogues has been evaluated on a panel of human tumour and non-tumour cell lines in preliminary in vitro cytotoxicity assays, showing a relevant antiproliferative profile for Gua2.

  • Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner.
    Publication Date: 01/03/2015, on Biochimica et biophysica acta
    by Fiorini C, Cordani M, Gotte G, Picone D, Donadelli M
    DOI: 10.1016/j.bbamcr.2014.12.016

    Onconase® (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Rana pipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantly increased because of its high cytotoxicity and anticancer properties. Onconase is currently used in clinical trials for cancer therapy; however, the precise mechanisms determining cytotoxicity in cancer cells have not yet been fully investigated. In the present manuscript, we evaluate the antitumoral property of onconase in pancreatic adenocarcinoma cells and in non-tumorigenic cells as a control. We demonstrate that ONC stimulates a strong antiproliferative and proapoptotic effect in cancer cells by reporting for the first time that ONC triggers Beclin1-mediated autophagic cancer cell death. In addition, ONC inhibits the expression of mitochondrial uncoupling protein 2 (UCP2) and of manganese-dependent superoxide dismutase (MnSOD) triggering mitochondrial superoxide ion production. ONC-induced reactive oxygen species (ROS) are responsible for Akt/mTOR pathway stimulation determining the sensitivity of cancer cells to mTOR inhibitors and lessening autophagic stimulation. This indicates ROS/Akt/mTOR axis as a strategy adopted by cancer cells to reduce ONC-mediated cytotoxic autophagy stimulation. In addition, we demonstrate that ONC can sensitize pancreatic cancer cells to the standard chemotherapeutic agent gemcitabine allowing a reduction of drug concentration when used in combination settings, thus suggesting a lowering of chemotherapy-related side effects. Altogether, our results shed more light on the mechanisms lying at the basis of ONC antiproliferative effect in cancer cells and support its potential use to develop new anticancer strategies.

  • Application of a new xylanase activity from <i>Bacillus amyloliquefaciens</i> XR44A in brewer's spent grain saccharification.
    Publication Date: 01/03/2015, on Journal of chemical technology and biotechnology (Oxford, Oxfordshire : 1986)
    by Amore A, Parameswaran B, Kumar R, Birolo L, Vinciguerra R, Marcolongo L, Ionata E, La Cara F, Pandey A, Faraco V
    DOI: 10.1002/jctb.4589

    Cellulases and xylanases are the key enzymes involved in the conversion of lignocelluloses into fermentable sugars. Western Ghat region (India) has been recognized as an active hot spot for the isolation of new microorganisms. The aim of this work was to isolate new microorganisms producing cellulases and xylanases to be applied in brewer's spent grain saccharification.

  • Sporadic Creutzfeldt-Jakob disease in a native Puerto Rican patient.
    Publication Date: 01/03/2015, on Puerto Rico health sciences journal
    by Del Pilar-Morales EA, Cali I, Chapas J, Bertrán-Pasarell J, Puoti G, Gambetti P, Nobo U
    DOI:

    The diagnosis of Creutzfeldt-Jakob disease (CJD) is often a challenge for most physicians given its extremely low incidence and different clinico-pathological presentations. We report the case of a 56-year old patient native to Puerto Rico suspected of sporadic Creutzfeldt-Jakob disease (sCD). The symptoms at onset were notorious for bilateral cortical blindness followed by rapidly progressive cognitive decline, visual deficit, increased levels of CSF 14-3-3 and tau along with positive brain MRI and EEG, are highly indicative of CJD. The definite diagnosis was confirmed by the National Prion Disease Pathology Surveillance Center (NPDPSC), in Cleveland, Ohio, USA. Lack of genetic mutations in the prion protein (PrP) gene, widespread histopathological changes and the accumulation of scrapie PrP (PrPSc) in the brain confirmed the diagnosis of sCJD. The patient, admitted to our institution in 2011, represents the first detailed report of sCJD in a native Puerto Rican patient living in Puerto Rico.

  • Developing functionalized Fe3O4-Au nanoparticles: a physico-chemical insight.
    Publication Date: 28/02/2015, on Physical chemistry chemical physics : PCCP
    by Luchini A, Vitiello G, Rossi F, Ruiz De Ballesteros O, Radulescu A, D'Errico G, Montesarchio D, de Julián Fernández C, Paduano L
    DOI: 10.1039/c4cp05854b

    Nanotechnology for biomedicine has recently attracted increasing interest from the scientific community. In particular, among the different nanodevices suitable for this application, multifunctionalizable hybrid nanoparticles are one of the most investigated research topics. Here we present a detailed physico-chemical characterization of hybrid magneto-plasmonic iron oxide-gold nanoparticles (NPs) with core-shell structure. In particular, we underline all the synthetic difficulties concerning the preparation of these systems. Based on all our results, after different tests of a commonly reported protocol for the synthesis of the core-shell system, we believe that several issues are still open in the synthetic preparation of these particular NPs. Indeed, at least for the conditions that we adopted, core-shell morphology nanoparticles cannot be produced. However, independent of the core structure, we describe here an optimized and efficient functionalization protocol to obtain stable nanoparticle aqueous suspensions, which can be easily exported to other kinds of metal and metal-oxide NPs and used to develop biocompatible systems. Furthermore, reliable information that could be useful for researchers working in this field is extensively discussed.

  • Chronic hepatitis C virus infection and neurological and psychiatric disorders: an overview.
    Publication Date: 28/02/2015, on World journal of gastroenterology
    by Adinolfi LE, Nevola R, Lus G, Restivo L, Guerrera B, Romano C, Zampino R, Rinaldi L, Sellitto A, Giordano M, Marrone A
    DOI: 10.3748/wjg.v21.i8.2269

    Hepatitis C virus (HCV) infection is considered a systemic disease because of involvement of other organs and tissues concomitantly with liver disease. Among the extrahepatic manifestations, neuropsychiatric disorders have been reported in up to 50% of chronic HCV infected patients. Both the central and peripheral nervous system may be involved with a wide variety of clinical manifestations. Main HCV-associated neurological conditions include cerebrovascular events, encephalopathy, myelitis, encephalomyelitis, and cognitive impairment, whereas "brain fog", depression, anxiety, and fatigue are at the top of the list of psychiatric disorders. Moreover, HCV infection is known to cause both motor and sensory peripheral neuropathy in the context of mixed cryoglobulinemia, and has also been recently recognized as an independent risk factor for stroke. These extrahepatic manifestations are independent of severity of the underlying chronic liver disease and hepatic encephalopathy. The brain is a suitable site for HCV replication, where the virus may directly exert neurotoxicity; other mechanisms proposed to explain the pathogenesis of neuropsychiatric disorders in chronic HCV infection include derangement of metabolic pathways of infected cells, alterations in neurotransmitter circuits, autoimmune disorders, and cerebral or systemic inflammation. A pathogenic role for HCV is also suggested by improvement of neurological and psychiatric symptoms in patients achieving a sustained virologic response following interferon treatment; however, further ad hoc trials are needed to fully assess the impact of HCV infection and specific antiviral treatments on associated neuropsychiatric disorders.

  • Identification of novel interactors of human telomeric G-quadruplex DNA.
    Publication Date: 18/02/2015, on Chemical communications (Cambridge, England)
    by Pagano B, Margarucci L, Zizza P, Amato J, Iaccarino N, Cassiano C, Salvati E, Novellino E, Biroccio A, Casapullo A, Randazzo A
    DOI: 10.1039/c4cc07231f

    A chemoproteomic-driven approach was used to investigate the interaction network between human telomeric G-quadruplex DNA and nuclear proteins. We identified novel G-quadruplex binding partners, able to recognize these DNA structures at chromosome ends, suggesting a possible, and so far unknown, role of these proteins in telomere functions.

  • Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: a seven years experience.
    Publication Date: 08/02/2015, on Orphanet journal of rare diseases
    by Scala I, Concolino D, Della Casa R, Nastasi A, Ungaro C, Paladino S, Capaldo B, Ruoppolo M, Daniele A, Bonapace G, Strisciuglio P, Parenti G, Andria G
    DOI: 10.1186/s13023-015-0227-8

    Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase that catalyzes the conversion of phenylalanine to tyrosine, using tetrahydrobiopterin (BH4) as coenzyme. Besides dietary phenylalanine restriction, new therapeutic options are emerging, such as the treatment with BH4 in subgroups of PKU patients responding to a loading test with BH4.

  • Relationship between apathy and cognitive dysfunctions in de novo untreated Parkinson's disease: a prospective longitudinal study.
    Publication Date: 01/02/2015, on European journal of neurology
    by Santangelo G, Vitale C, Trojano L, Picillo M, Moccia M, Pisano G, Pezzella D, Cuoco S, Erro R, Longo K, Pellecchia MT, Amboni M, De Rosa A, De Michele G, Barone P
    DOI: 10.1111/ene.12467

    Apathy may be either a symptom of major depression or a behavioral disturbance occurring in concomitance with depression or alone in Parkinson's disease (PD). The aim of the present study was to determine the progression of cognitive impairment in drug-naïve untreated PD patients with or without clinically significant apathy.

  • An uncommon redox behavior sheds light on the cellular antioxidant properties of ergothioneine.
    Publication Date: 01/02/2015, on Free radical biology & medicine
    by Servillo L, Castaldo D, Casale R, D'Onofrio N, Giovane A, Cautela D, Balestrieri ML
    DOI: 10.1016/j.freeradbiomed.2014.11.017

    Ergothioneine (ESH), an aromatic thiol occurring in the human diet and which accumulates in particular cells, is believed to act as an antioxidant. However, its redox mechanism remains unclear and it does not seem to provide any advantage compared to other antioxidants, such as alkylthiols, which are better reducing agents and generally present in cells at higher levels. Here, we investigated by ESI-MS the products of ESH oxidation produced by neutrophils during oxidative burst and, to further elucidate ESH redox behavior, we also analyzed the oxidation products of the reaction of ESH with hypochlorite in cell-free solutions. Indeed, neutrophils are the main source of hypochlorite in humans. Furthermore, we also tested other biologically relevant oxidants, such as peroxynitrite and hydrogen peroxide. Our results indicate that treatment of human neutrophils with phorbol 12-myristate 13-acetate in the presence of ESH leads to a remarkable production of the sulfonated form (ESO3H), a compound never described before, and hercynine (EH), the desulfurated form of ESH. Similar results were obtained when ESH was subjected to cell-free oxidation in the presence of hypochlorite, as well as hydrogen peroxide or peroxynitrite. Furthermore, when the disulfide of ESH was reacted with those oxidants, we found that it was also oxidized, with production of EH and ESO3H, whose amount was dependent on the oxidant strength. These data reveal a unique ESH redox behavior, entirely different from that of alkylthiols, and suggest a mechanism, so far overlooked, through which ESH performs its antioxidant action in cells.

  • A targeted secretome profiling by multiplexed immunoassay revealed that secreted chemokine ligand 2 (MCP-1/CCL2) affects neural differentiation in mesencephalic neural progenitor cells.
    Publication Date: 01/02/2015, on Proteomics
    by Colucci-D'Amato L, Cicatiello AE, Reccia MG, Volpicelli F, Severino V, Russo R, Sandomenico A, Doti N, D'Esposito V, Formisano P, Chambery A
    DOI: 10.1002/pmic.201400360

    Chemokines and cytokines, primarily known for their roles in the immune and inflammatory response, have also been identified as key components of the neurogenic niche where they are involved in the modulation of neural stem cell proliferation and differentiation. However, a complete understanding of the functional role played in neural differentiation and a comprehensive profiling of these secreted molecules are lacking. By exploiting the multiplexing capability of magnetic bead-based immunoassays, we have investigated the changes of the expression levels of a set of chemokines and cytokines released from the pluripotent neural cell line mes-c-myc A1 following its differentiation from a proliferating phenotype (A1P) toward a neural (A1D) phenotype. We found a subset of molecules exclusively released from A1P, whereas others were differentially detected in A1P and A1D conditioned media. Among them, we identified monocyte chemoattractant protein-1/chemokine ligand 2 (MCP-1/CCL2) as a proneurogenic factor able to affect neuronal differentiation of A1 cells as well as of neuroblasts from primary cultures and to induce the elongation and/or formation of neuritic processes. Altogether, data are suggestive of a main role played by the CCL2/CCR2 signaling pathway and in general of the network of secreted cytokines/chemokines in the differentiation of neural progenitor cells toward a neural fate.

  • Fingolimod efficacy in multiple sclerosis associated with Sjogren syndrome.
    Publication Date: 01/02/2015, on Acta neurologica Scandinavica
    by Signoriello E, Sagliocchi A, Fratta M, Lus G
    DOI: 10.1111/ane.12357

    Sjogren syndrome (SS) is a common autoimmune disease characterized by lymphocytic infiltration of the exocrine glands with neurological involvement in about 20% of patients. The neurological manifestations in the central nervous system CNS may vary and include a multiple sclerosis (MS)-like disease, and the treatments with immunosuppressive drugs have been undertaken.

  • A network centred on the inferior frontal cortex is critically involved in levodopa-induced dyskinesias.
    Publication Date: 01/02/2015, on Brain : a journal of neurology
    by Cerasa A, Koch G, Donzuso G, Mangone G, Morelli M, Brusa L, Stampanoni Bassi M, Ponzo V, Picazio S, Passamonti L, Salsone M, Augimeri A, Caltagirone C, Quattrone A
    DOI: 10.1093/brain/awu329

    Levodopa-induced dyskinesias are disabling motor complications of long-term dopamine replacement in patients with Parkinson's disease. In recent years, several alternative models have been proposed to explain the pathophysiological mechanisms underlying this hyperkinetic motor disorder. In particular, our group has shed new light on the role of the prefrontal cortex as a key site of interest, demonstrating that, among other areas, the inferior frontal cortex is particularly characterized by altered patterns of anatomical and functional changes. However, how neural activity varies depending on levodopa treatment in patients with dyskinesias and whether the reported prefrontal abnormalities may have a critical role in dyskinesias is debated. To answer these questions we performed independent functional magnetic resonance imaging and repetitive transcranial magnetic stimulation studies. In the first experiment we applied resting state functional magnetic resonance imaging on 12 patients with Parkinson's disease with levodopa-induced dyskinesias and 12 clinically matched patients without dyskinesias, before and after administration of levodopa. Functional connectivity of brain networks in the resting state was assessed in both groups. We chose the right inferior frontal cortex as the seed region given the evidence highlighting the role of this region in motor control. In a second experiment, we applied different forms of repetitive transcranial magnetic stimulation over the right inferior frontal cortex in a new group of dyskinetic patients who were taking a supramaximal dose of levodopa, to verify the clinical relevance of this area in controlling the development of hyperkinetic movements. The resting state functional imaging analysis revealed that in patients with levodopa-induced dyskinesias connectivity of the right inferior frontal cortex was decreased with the left motor cortex and increased with the right putamen when compared to patients without levodopa-induced dyskinesias. This abnormal pattern of connectivity was evident only during the ON phase of levodopa treatment and the degree of such alteration correlated with motor disability. The repetitive TMS experiments showed that a session of continuous but not intermittent or sham theta burst stimulation applied over the inferior frontal cortex was able to reduce the amount of dyskinesias induced by a supramaximal single dose of levodopa, suggesting that this area may play a key role in controlling the development of dyskinesias. Our combined resting state functional magnetic resonance and transcranial magnetic stimulation studies demonstrate that pathophysiological mechanisms underlying levodopa-induced dyskinesias may extend beyond the 'classical' basal ganglia dysfunctions model, including the modulation performed by the neural network centred on the inferior frontal cortex.