Latest PUBLICATIONS

  • A pilot study for development of a novel tool for clinical decision making to identify fallers among ophthalmic patients.
    Publication Date: 01/01/2015, on BMC medical informatics and decision making
    by Melillo P, Orrico A, Attanasio M, Rossi S, Pecchia L, Chirico F, Testa F, Simonelli F
    DOI: 10.1186/1472-6947-15-S3-S6

    Falls in the elderly is a major problem. Although falls have a multifactorial etiology, a commonly cited cause of falls in older people is poor vision. This study proposes a method to discriminate fallers and non-fallers among ophthalmic patients, based on data-mining algorithms applied to health and socio-demographic information.

  • The Genesis of Graphic Perseverations in Alzheimer's Disease and Vascular Dementia.
    Publication Date: 01/01/2015, on The Clinical neuropsychologist
    by De Lucia N, Grossi D, Trojano L
    DOI: 10.1080/13854046.2015.1119313

    Perseveration is the involuntary production of iterative responses. This study explored graphic perseverative errors in Alzheimer's disease and vascular dementia, to comprehend the neuropsychological correlates of this behavior.

  • Closing-in in Parkinson's disease individuals with dementia: An experimental study.
    Publication Date: 01/01/2015, on Journal of clinical and experimental neuropsychology
    by De Lucia N, Grossi D, Mauro A, Trojano L
    DOI: 10.1080/13803395.2015.1071339

    The tendency to reproduce figures close to or superimposed on the model in copying tasks, the so-called Closing-in (CI) phenomenon, has been rarely reported in individuals affected by Parkinson's disease and associated dementia (PD-D). We aimed to comprehend the genesis of CI in PD-D individuals by assessing whether reduction of attention/executive resources can increase the tendency to deviate toward the model.

  • Analysis of the ABCA4 genomic locus in Stargardt disease.
    Publication Date: 20/12/2014, on Human molecular genetics
    by Zernant J, Xie YA, Ayuso C, Riveiro-Alvarez R, Lopez-Martinez MA, Simonelli F, Testa F, Gorin MB, Strom SP, Bertelsen M, Rosenberg T, Boone PM, Yuan B, Ayyagari R, Nagy PL, Tsang SH, Gouras P, Collison FT, Lupski JR, Fishman GA, Allikmets R
    DOI: 10.1093/hmg/ddu396

    Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65-70% of patients and only one mutation in 15-20% of patients. This study was designed to find the missing disease-causing ABCA4 variation by a combination of next-generation sequencing (NGS), array-Comparative Genome Hybridization (aCGH) screening, familial segregation and in silico analyses. The entire 140 kb ABCA4 genomic locus was sequenced in 114 STGD patients with one known ABCA4 exonic mutation revealing, on average, 200 intronic variants per sample. Filtering of these data resulted in 141 candidates for new mutations. Two variants were detected in four samples, two in three samples, and 20 variants in two samples, the remaining 117 new variants were detected only once. Multimodal analysis suggested 12 new likely pathogenic intronic ABCA4 variants, some of which were specific to (isolated) ethnic groups. No copy number variation (large deletions and insertions) was detected in any patient suggesting that it is a very rare event in the ABCA4 locus. Many variants were excluded since they were not conserved in non-human primates, were frequent in African populations and, therefore, represented ancestral, and not disease-associated, variants. The sequence variability in the ABCA4 locus is extensive and the non-coding sequences do not harbor frequent mutations in STGD patients of European-American descent. Defining disease-associated alleles in the ABCA4 locus requires exceptionally well characterized large cohorts and extensive analyses by a combination of various approaches.

  • Sleep memory processing: the sequential hypothesis.
    Publication Date: 16/12/2014, on Frontiers in systems neuroscience
    by Giuditta A
    DOI: 10.3389/fnsys.2014.00219

    According to the sequential hypothesis (SH) memories acquired during wakefulness are processed during sleep in two serial steps respectively occurring during slow wave sleep (SWS) and rapid eye movement (REM) sleep. During SWS memories to be retained are distinguished from irrelevant or competing traces that undergo downgrading or elimination. Processed memories are stored again during REM sleep which integrates them with preexisting memories. The hypothesis received support from a wealth of EEG, behavioral, and biochemical analyses of trained rats. Further evidence was provided by independent studies of human subjects. SH basic premises, data, and interpretations have been compared with corresponding viewpoints of the synaptic homeostatic hypothesis (SHY). Their similarities and differences are presented and discussed within the framework of sleep processing operations. SHY's emphasis on synaptic renormalization during SWS is acknowledged to underline a key sleep effect, but this cannot marginalize sleep's main role in selecting memories to be retained from downgrading traces, and in their integration with preexisting memories. In addition, SHY's synaptic renormalization raises an unsolved dilemma that clashes with the accepted memory storage mechanism exclusively based on modifications of synaptic strength. This difficulty may be bypassed by the assumption that SWS-processed memories are stored again by REM sleep in brain subnuclear quantum particles. Storing of memories in quantum particles may also occur in other vigilance states. Hints are provided on ways to subject the quantum hypothesis to experimental tests.

  • Apathy in multiple sclerosis: a validation study of the apathy evaluation scale.
    Publication Date: 15/12/2014, on Journal of the neurological sciences
    by Raimo S, Trojano L, Spitaleri D, Petretta V, Grossi D, Santangelo G
    DOI: 10.1016/j.jns.2014.10.027

    Apathy is defined as lack of motivation affecting cognitive, emotional, and behavioral domains and is usually assessed by standardized scales, such as the Apathy Evaluation Scale (AES). Recently, apathy has been recognized as a frequent behavioral symptom in multiple sclerosis (MS).

  • Thermodynamic signature of secondary nano-emulsion formation by isothermal titration calorimetry.
    Publication Date: 09/12/2014, on Langmuir : the ACS journal of surfaces and colloids
    by Fotticchia I, Fotticchia T, Mattia CA, Netti PA, Vecchione R, Giancola C
    DOI: 10.1021/la503558w

    The stabilization of oil in water nano-emulsions by means of a polymer coating is extremely important; it prolongs the shelf life of the product and makes it suitable for a variety of applications ranging from nutraceutics to cosmetics and pharmaceutics. To date, an effective methodology to assess the best formulations in terms of thermodynamic stability has yet to be designed. Here, we perform a complete physicochemical characterization based on isothermal titration calorimetry (ITC) compared to conventional dynamic light scattering (DLS) to identify polymer concentration domains that are thermodynamically stable and to define the degree of stability through thermodynamic functions depending upon any relevant parameter affecting the stability itself, such as type of polymer coating, droplet distance, etc. For instance, the method was proven by measuring the energetics in the case of two different biopolymers, chitosan and poly-L-lysine, and for different concentrations of the emulsion coated with poly-L-lysine.

  • Shading the TRF2 recruiting function: a new horizon in drug development.
    Publication Date: 03/12/2014, on Journal of the American Chemical Society
    by Di Maro S, Zizza P, Salvati E, De Luca V, Capasso C, Fotticchia I, Pagano B, Marinelli L, Gilson E, Novellino E, Cosconati S, Biroccio A
    DOI: 10.1021/ja5080773

    The shelterin protein TRF2 has come to the limelight for its role in telomere maintenance and tumorigenesis. Herein, the application of rational design and synthesis allowed identifying the first TRF2TRFH binder able to elicit a marked DNA damage response in cancer cells. This work paves the way for the unprecedented employment of a chemical tool to finely tune specific mechanisms underlying telomere maintenance.

  • Apathy in untreated, de novo patients with Parkinson's disease: validation study of Apathy Evaluation Scale.
    Publication Date: 01/12/2014, on Journal of neurology
    by Santangelo G, Barone P, Cuoco S, Raimo S, Pezzella D, Picillo M, Erro R, Moccia M, Pellecchia MT, Amboni M, Santangelo F, Grossi D, Trojano L, Vitale C
    DOI: 10.1007/s00415-014-7498-1

    Apathy is a behavioural disturbance occurring alone or in concomitance with depression in Parkinson's disease (PD). Here we present a validation study for the self-report version of the Apathy Evaluation Scale (AES-S), carried out in a sample of 60 non-demented, non-depressed untreated, drug-naïve, de novo PD patients; 20 patients of the sample (33.3%) were classified as apathetic according to current clinical criteria. All enrolled patients completed the AES-S and a neurological and cognitive assessment. Mean AES-S score was 34.43. AES-S did not show floor or ceiling effect. Cronbach's alpha was 0.872. Principal component analysis revealed three factors: the first (34.4% of the variance) represented constitutive aspects of the construct of apathy; the second (8.5% of the variance) represented a social dimension; the third factor (7.9% of the variance) represented a dimension related to insight. With respect to clinical criteria for apathy considered as the gold standard, receiver operating characteristics curve analysis showed that a cut-off of 36/37 has the maximum discrimination power. High sensitivity and negative predictive values were obtained with cut-off scores of 33/34 or lower; high specificity and positive predictive values were obtained with cut-off scores of 38/39 or higher. AES-S score correlated with scores on frontal tasks, but not on Beck Depression Inventory, Unified Parkinson's Disease Rating Scale, Hoehn and Yahr scale. The AES-S is a reliable and valid questionnaire for detecting apathy in PD. For screening purposes a 33/34 cut-off score is indicated, but a 38/39 cut-off score is necessary when a high specificity is desired.

  • Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research.
    Publication Date: 01/12/2014, on Clinical science (London, England : 1979)
    by Forte A, Rinaldi B, Berrino L, Rossi F, Galderisi U, Cipollaro M
    DOI: 10.1042/CS20140131

    Restenosis is the pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.

  • Xanthomonas campestris lipooligosaccharides trigger innate immunity and oxidative burst in Arabidopsis.
    Publication Date: 01/12/2014, on Plant physiology and biochemistry : PPB
    by Proietti S, Giangrande C, Amoresano A, Pucci P, Molinaro A, Bertini L, Caporale C, Caruso C
    DOI: 10.1016/j.plaphy.2014.10.011

    Plants lack the adaptive immunity mechanisms of jawed vertebrates, so they rely on innate immune responses to defense themselves from pathogens. The plant immune system perceives the presence of pathogens by recognition of molecules known as pathogen-associated molecular patterns (PAMPs). PAMPs have several common characteristics, including highly conserved structures, essential for the microorganism but absent in host organisms. Plants can specifically recognize PAMPs using a large set of receptors and can respond with appropriate defenses by activating a multicomponent and multilayered response. Lipopolysaccharides (LPSs) and lipooligosaccharides (LOSs) are major components of the cell surface of Gram-negative bacteria with diverse roles in bacterial pathogenesis of animals and plants that include elicitation of host defenses. Little is known on the mechanisms of perception of these molecules by plants and the associated signal transduction pathways that trigger plant immunity.Here we addressed the question whether the defense signaling pathway in Arabidopsis thaliana was triggered by LOS from Xanthomonas campestris pv. campestris (Xcc), using proteomic and transcriptomic approaches. By using affinity capture strategies with immobilized LOS and LC-MS/MS analyses, we identified 8 putative LOS protein ligands. Further investigation of these interactors led to the definition that LOS challenge is able to activate a signal transduction pathway that uses nodal regulators in common with salicylic acid-mediated pathway. Moreover, we proved evidence that Xcc LOS are responsible for oxidative burst in Arabidopsis either in infiltrated or systemic leaves. In addition, gene expression studies highlighted the presence of gene network involved in reactive oxygen species transduction pathway.

  • Platelet-activating factor mediates the cytotoxicity induced by W7FW14F apomyoglobin amyloid aggregates in neuroblastoma cells.
    Publication Date: 01/12/2014, on Journal of cellular biochemistry
    by Sirangelo I, Giovane A, Maritato R, D'Onofrio N, Iannuzzi C, Giordano A, Irace G, Balestrieri ML
    DOI: 10.1002/jcb.24888

    W7FW14F apomyoglobin (W7FW14F ApoMb) amyloid aggregates induce cytotoxicity in SH-SY5Y human neuroblastoma cells through a mechanism not fully elucidated. Amyloid neurotoxicity process involves calcium dyshomeostasis and reactive oxygen species (ROS) production. Another key mediator of the amyloid neurotoxicity is Platelet-Activating Factor (PAF), an inflammatory phospholipid implicated in neurodegenerative diseases. Here, with the aim at evaluating the possible involvement of PAF signaling in the W7FW14F ApoMb-induced cytotoxicity, we show that the presence of CV3899, a PAF receptor (PAF-R) antagonist, prevented the detrimental effect of W7FW14F ApoMb aggregates on SH-SY5Y cell viability. Noticeably, we found that the activation of PAF signaling, following treatment with W7FW14F ApoMb, involves a decreased expression of the PAF acetylhydroase II (PAF-AH II). Interestingly, the reduced PAF-AH II expression was associated with a decreased acetylhydrolase (AH) activity and to an increased sphingosine-transacetylase activity (TA(S)) with production of N-acetylsphingosine (C2-ceramide), a well known mediator of neuronal caspase-dependent apoptosis. These findings suggest that an altered PAF catabolism takes part to the molecular events leading to W7FW14F ApoMb amyloid aggregates-induced cell death.

  • Turmeric toxicity in A431 epidermoid cancer cells associates with autophagy degradation of anti-apoptotic and anti-autophagic p53 mutant.
    Publication Date: 01/12/2014, on Phytotherapy research : PTR
    by Thongrakard V, Titone R, Follo C, Morani F, Suksamrarn A, Tencomnao T, Isidoro C
    DOI: 10.1002/ptr.5196

    The keratinocyte-derived A431 Squamous Cell Carcinoma cells express the p53R273H mutant, which has been reported to inhibit apoptosis and autophagy. Here, we show that the crude extract of turmeric (Curcuma longa), similarly to its bioactive component Curcumin, could induce both apoptosis and autophagy in A431 cells, and these effects were concomitant with degradation of p53. Turmeric and curcumin also stimulated the activity of mTOR, which notoriously promotes cell growth and acts negatively on basal autophagy. Rapamycin-mediated inhibition of mTOR synergized with turmeric and curcumin in causing p53 degradation, increased the production of autophagosomes and exacerbated cell toxicity leading to cell necrosis. Small-interference mediated silencing of the autophagy proteins BECLIN 1 or ATG7 abrogated the induction of autophagy and largely rescued p53 stability in Turmeric-treated or Curcumin-treated cells, indicating that macroautophagy was mainly responsible for mutant p53 degradation. These data uncover a novel mechanism of turmeric and curcumin toxicity in chemoresistant cancer cells bearing mutant p53.

  • Regulation of flavin-containing mono-oxygenase (Fmo3) gene expression by steroids in mice and humans.
    Publication Date: 01/12/2014, on Hormone molecular biology and clinical investigation
    by Esposito T, Varriale B, D'Angelo R, Amato A, Sidoti A
    DOI: 10.1515/hmbci-2014-0012

    Abstract Flavin-containing mono-oxygenases (FMOs) are a family of microsomal chemical- and drug-metabolizing enzymes. FMO3 is a major FMO form in adult mouse and human liver. FMO3 mutations have been associated with the incidence and severity of trimethylaminuria (TMAU), a metabolic disorder characterized by the inability of the affected individual to metabolize the odorous trimethylamine to its non-odorous N-oxide. In addition to this primary genetic form, there are other forms of TMAU that support the hypothesis that FMO3 activity may be modulated by steroid hormones. To understand the molecular mechanism involved in the regulation of Fmo3 gene expression by steroid hormones, we performed this study in an in vitro cellular system, mouse liver cells, and on the human FMO3 gene. Dexamethasone, 5α-dihydrotestosterone, thyroid hormone, and progesterone had no effect on the accumulation of Fmo3 mRNA. The use of increased concentration of theophylline inhibited estrogen receptor α (ERα)-mediated transcription of Fmo3 mRNA. 17β-Estradiol inhibited Fmo3 mRNA accumulation. The use of ICI 164,384 abolished the inhibitory effect induced by estrogen. Gel-shift analyses showed a binding in the 5' region of the Fmo3 gene. This binding was abrogated by an excess of a cDNA containing an estrogen-responsive element. An estrogen-binding site was also present in the first intron of the human gene, as demonstrated by the gel-shift assay. Supershift experiments confirmed the binding of ERα in both mouse and human samples. Furthermore, chromatin immunoprecipitation assay confirmed the binding of ERα in the promoter region of mouse Fmo3 and in the first intron of the human FMO3 gene. Thus, 17β-estradiol plays a fundamental role in the regulation of Fmo3 gene transcription.

  • Epstein Barr virus infection reactivation as a possible trigger of primary biliary cirrhosis-like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment.
    Publication Date: 01/12/2014, on Le infezioni in medicina : rivista periodica di eziologia, epidemiologia, diagnostica, clinica e terapia delle patologie infettive
    by Marrone A, Signoriello E, Alfieri G, Dalla Mora L, Rinaldi L, Rainone I, Adinolfi LE, Lus G
    DOI:

    Primary biliary cirrhosis (PBC) and multiple sclerosis (MS) are considered autoimmune diseases with a multifactorial aetiology which is thought to be due to a combination of genetic predisposition and environmental triggers. An association of both diseases has been previously described in sporadic case reports. Fingolimod, an antagonist of the sphingosine 1 phosphate receptor family (S1P1/3/4/5), is a promising and effective drug in the treatment of MS. Here we describe a case of PBC like syndrome that was unmasked, concomitantly or consequently to Epstein Barr virus (EBV) infection reactivation, in a 34 year old male patient with relapsing remitting multiple sclerosis who was receiving fingolimod treatment.