Latest PUBLICATIONS

  • Phosphocholine-decorated superparamagnetic iron oxide nanoparticles: defining the structure and probing in vivo applications.
    Publication Date: 21/05/2016, on Nanoscale
    by Luchini A, Irace C, Santamaria R, Montesarchio D, Heenan RK, Szekely N, Flori A, Menichetti L, Paduano L
    DOI: 10.1039/c5nr08486e

    Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are performing contrast agents for Magnetic Resonance Imaging (MRI). A functionalization strategy for SPIONs based on hydrophobic interactions is a versatile approach easily extendable to several kinds of inorganic nanoparticles and suitable for obtaining stable and biocompatible systems. Here we report on the original preparation of functionalized SPIONs with an 8 nm radius exploiting the hydrophobic interaction between a phosphocholine and an inner amphiphilic. With respect to other similarly functionalized SPIONs, characterized by the typical nanoparticle clustering that leads to large aggregates, our phosphocholine-decorated SPIONs are demonstrated to be monodisperse. We report the in vitro and in vivo study that proves the effective applicability of phosphocholine-decorated SPIONs as MRI contrast agents. The versatility of this functionalization approach is highlighted by introducing on the SPION surface a ruthenium-based potential antitumoral drug, named ToThyCholRu. Even if in this case we observed the formation of SPION clusters, ascribable to the presence of the amphiphilic ruthenium complex, interesting and promising antiproliferative activity points at the ToThyCholRu-decorated SPIONs as potential theranostic agents.

  • Hepatitis C viraemia after apparent spontaneous clearance in a vertically infected child.
    Publication Date: 07/05/2016, on Lancet (London, England)
    by Indolfi G, Mangone G, Bartolini E, Moriondo M, Azzari C, Resti M
    DOI: 10.1016/S0140-6736(16)00085-4

  • Trastuzumab and target-therapy side effects: Is still valid to differentiate anthracycline Type I from Type II cardiomyopathies?
    Publication Date: 03/05/2016, on Human vaccines & immunotherapeutics
    by Riccio G, Coppola C, Piscopo G, Capasso I, Maurea C, Esposito E, De Lorenzo C, Maurea N
    DOI: 10.1080/21645515.2015.1125056

    The improvement in cancer therapy and the increasing number of long term survivors unearth the issue of cardiovascular side effects of anticancer treatments. As a paradox in cancer survivors, delayed cardiotoxicity has emerged as a significant problem. Two categories of cardiotoxic side effects of antineoplastic drugs have been previously proposed: Type I cardiotoxicity, defined as permanent cardiotoxicity, is usually caused by anthracyclines; Type II cardiotoxicity, considered as reversible cardiotoxicity, has been mainly related to monoclonal antibodies. The cardiotoxicity of antibodies has been associated to trastuzumab, a humanized anti-ErbB2 monoclonal antibody currently in clinical use for the therapy of breast carcinomas, which induces cardiac dysfunction when used in monotherapy, or in combination with anthracyclines. Furthermore, recent retrospective studies have shown an increased incidence of heart failure and/or cardiomyopathy in patients treated with trastuzumab, that can persist many years after the conclusion of the therapy, thus suggesting that the side toxic effects are not always reversible as it was initially proposed. On the other hand, early detection and prompt therapy of anthracycline associated cardiotoxicity can lead to substantial recovery of cardiac function. On the basis of these observations, we propose to find a new different classification for cardiotoxic side effects of drugs used in cancer therapy.

  • Cardiotoxicity from anthracycline and cardioprotection in paediatric cancer patients.
    Publication Date: 01/05/2016, on Journal of cardiovascular medicine (Hagerstown, Md.)
    by Bassareo PP, Monte I, Romano C, Deidda M, Piras A, Cugusi L, Coppola C, Galletta F, Mercuro G
    DOI: 10.2459/JCM.0000000000000375

    Notwithstanding the steady progress in survival rates of children and adolescents suffering from cancer, the benefits associated with chemotherapy do not come without risks involving multiple organs and systems, including the cardiovascular apparatus. Anthracyclines-often administered in combination with radiation therapy and/or surgery-are the most used chemotherapeutic compounds in order to treat tumours and blood malignancies even in paediatric age. Being an important side-effect of anthracyclines, carduitoxicity may limit their efficacy during the treatment and induce long-term sequelae, observed even many years after therapy completion. The purpose of this review was to perform an overview about all the possible strategies to prevent and/or limit the anthracyclines adverse side-effects for the cardiovascular system in childhood cancer survivors.

  • Pathophysiology of cardiotoxicity from target therapy and angiogenesis inhibitors.
    Publication Date: 01/05/2016, on Journal of cardiovascular medicine (Hagerstown, Md.)
    by Maurea N, Coppola C, Piscopo G, Galletta F, Riccio G, Esposito E, De Lorenzo C, De Laurentiis M, Spallarossa P, Mercuro G
    DOI: 10.2459/JCM.0000000000000377

    The progress in cancer therapy and the increase in number of long-term survivors reveal the issue of cardiovascular side-effects of anticancer drugs. Cardiotoxicity has become a significant problem, and the risks of adverse cardiac events induced by systemic drugs need to be seriously considered. Potential cardiovascular toxicities linked to anticancer agents include arrhythmias, myocardial ischemia and infarction, hypertension, thromboembolism, left ventricular dysfunction, and heart failure. It has been shown that several anticancer drugs seriously affect the cardiovascular system, such as ErbB2 inhibitors, vascular endothelial growth factor (VEGF) inhibitors, multitargeted kinase inhibitors, Abelson murine leukemia viral oncogene homolog inhibitors, and others. Each of these agents has a different mechanism through which it affects the cardiovascular system. ErbB2 inhibitors block the ErbB4/ErbB2 heterodimerization pathway triggered by Neuregulin-1, which is essential for cardiomyocyte survival. VEGF signaling is crucial for vascular growth, but it also has a major impact on myocardial function, and the VEGF pathway is also essential for maintenance of cardiovascular homeostasis. Drugs that inhibit the VEGF signaling pathway lead to a net reduction in capillary density and loss of contractile function. Here, we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of ErbB2 inhibitors and antiangiogenic drugs. Moreover, we highlight the role of cardioncology in recognizing these toxicities, developing strategies to prevent or minimize cardiovascular toxicity, and reducing long-term cardiotoxic effects.

  • Cardiotoxicity from anthracycline and cardioprotection in paediatric cancer patients.
    Publication Date: 01/05/2016, on Journal of cardiovascular medicine (Hagerstown, Md.)
    by Bassareo PP, Monte I, Romano C, Deidda M, Piras A, Cugusi L, Coppola C, Galletta F, Mercuro G
    DOI: 10.2459/JCM.0000000000000375

    Notwithstanding the steady progress in survival rates of children and adolescents suffering from cancer, the benefits associated with chemotherapy do not come without risks involving multiple organs and systems, including the cardiovascular apparatus. Anthracyclines-often administered in combination with radiation therapy and/or surgery-are the most used chemotherapeutic compounds in order to treat tumours and blood malignancies even in paediatric age. Being an important side-effect of anthracyclines, carduitoxicity may limit their efficacy during the treatment and induce long-term sequelae, observed even many years after therapy completion. The purpose of this review was to perform an overview about all the possible strategies to prevent and/or limit the anthracyclines adverse side-effects for the cardiovascular system in childhood cancer survivors.

  • Pathophysiology of cardiotoxicity from target therapy and angiogenesis inhibitors.
    Publication Date: 01/05/2016, on Journal of cardiovascular medicine (Hagerstown, Md.)
    by Maurea N, Coppola C, Piscopo G, Galletta F, Riccio G, Esposito E, De Lorenzo C, De Laurentiis M, Spallarossa P, Mercuro G
    DOI: 10.2459/JCM.0000000000000377

    The progress in cancer therapy and the increase in number of long-term survivors reveal the issue of cardiovascular side-effects of anticancer drugs. Cardiotoxicity has become a significant problem, and the risks of adverse cardiac events induced by systemic drugs need to be seriously considered. Potential cardiovascular toxicities linked to anticancer agents include arrhythmias, myocardial ischemia and infarction, hypertension, thromboembolism, left ventricular dysfunction, and heart failure. It has been shown that several anticancer drugs seriously affect the cardiovascular system, such as ErbB2 inhibitors, vascular endothelial growth factor (VEGF) inhibitors, multitargeted kinase inhibitors, Abelson murine leukemia viral oncogene homolog inhibitors, and others. Each of these agents has a different mechanism through which it affects the cardiovascular system. ErbB2 inhibitors block the ErbB4/ErbB2 heterodimerization pathway triggered by Neuregulin-1, which is essential for cardiomyocyte survival. VEGF signaling is crucial for vascular growth, but it also has a major impact on myocardial function, and the VEGF pathway is also essential for maintenance of cardiovascular homeostasis. Drugs that inhibit the VEGF signaling pathway lead to a net reduction in capillary density and loss of contractile function. Here, we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of ErbB2 inhibitors and antiangiogenic drugs. Moreover, we highlight the role of cardioncology in recognizing these toxicities, developing strategies to prevent or minimize cardiovascular toxicity, and reducing long-term cardiotoxic effects.

  • Strain Analysis in the Assessment of a Mouse Model of Cardiotoxicity due to Chemotherapy: Sample for Preclinical Research.
    Publication Date: 01/05/2016, on In vivo (Athens, Greece)
    by Rea D, Coppola C, Barbieri A, Monti MG, Misso G, Palma G, Bimonte S, Zarone MR, Luciano A, Liccardo D, Maiolino P, Cittadini A, Ciliberto G, Arra C, Maurea N
    DOI:

    In recent years, the development of more effective anticancer drugs has provided great benefits in patients' quality of life by improving both prognosis and disease-free survival. Nevertheless, the frequency and severity of side-effects, with particular reference to cardiac toxicity, have gained particular attention. The purpose of this study was to create a precise and sensitive preclinical model, able to identify early contractile dysfunction in mice treated with chemotherapy, through use of speckle-tracking echocardiography.

  • Cyclodextrin-assisted assembly of PEGylated polyester nanoparticles decorated with folate.
    Publication Date: 01/05/2016, on Colloids and surfaces. B, Biointerfaces
    by Conte C, Fotticchia I, Tirino P, Moret F, Pagano B, Gref R, Ungaro F, Reddi E, Giancola C, Quaglia F
    DOI: 10.1016/j.colsurfb.2016.01.035

    In the last decades, nano-oncologicals bearing a polyethylene glycol (PEG) coating are being emerging as biomimetic devices able to drive their drug cargo to solid tumors through passive mechanisms. To improve selectivity toward cancer cells, nanocarriers decorated with the small ligand folate have been widely investigated. Nevertheless, a great challenge remains the effective exposition of folate on nanoparticles (NPs), which is a key prerequisite to ensure the correct binding to receptor and the following endocytic uptake. On these premises, in this study we propose a novel strategy to produce core-shell folate-targeted NPs based on diblock copolymers of poly(ε-caprolactone) (PCL) and PEG through the aid of (2-hydroxypropyl)-β-cyclodextrin (HPβCD). PCL4300-PEG2000 and PCL4300-PEG2000-Fol copolymers were synthesized, characterized and employed to produce NPs without and with HPβCD by a melting/sonication procedure. Colloidal properties of targeted NPs produced with HPβCD demonstrated a highly extended conformation of PEG chains in the shell, an enhanced interaction with a specific antibody against folate and a higher uptake in cells overexpressing folate receptor. Overall, these results suggest that proper manipulation of PEG shell conformation through HPβCD can represent a novel non-covalent strategy to modify shell features.

  • Assessment of neuroactive steroids in cerebrospinal fluid comparing acute relapse and stable disease in relapsing-remitting multiple sclerosis.
    Publication Date: 01/05/2016, on The Journal of steroid biochemistry and molecular biology
    by Orefice N, Carotenuto A, Mangone G, Bues B, Rehm R, Cerillo I, Saccà F, Calignano A, Orefice G
    DOI: 10.1016/j.jsbmb.2016.02.012

    Previous studies have reported an involvement of neuroactive steroids as neuroprotective and anti-inflammatory agents in neurological disorders such as multiple sclerosis (MS); an analysis of their profile during a specific clinical phase of MS is largely unknown. The pregnenolone (PREG), dehydroepiandrosterone (DHEA), and allopregnanolone (ALLO) profile was evaluated in cerebrospinal fluid (CSF) in relapsing-remitting multiple sclerosis (RR-MS) patients as well as those in patients affected by non-inflammatory neurological (control group I) and without neurological disorders (control group II). An increase of PREG and DHEA values was shown in CSF of male and female RR-MS patients compared to those observed in both control groups. The ALLO values were significantly lower in female RR-MS patients than those found in male RR-MS patients and in female without neurological disorder. During the clinical relapse, we observed female RR-MS patients showing significantly increased PREG values compared to female RR-MS patients in stable phase, while their ALLO values showed a significant decrease compared to male RR-MS patients of the same group. Male RR-MS patients with gadolinium-enhanced lesions showed PREG and DHEA values higher than those found in female RR-MS patients with gadolinium-enhanced lesions. Similary, male RR-MS patients with gadolinium-enhanced lesions showed PREG and DHEA values higher than male without gadolinium-enhanced lesions. Female RR-MS patients with gadolinium-enhanced lesions showed DHEA values higher than those found in female RR-MS patients with gadolinium-enhanced lesions. Male and female RR-MS patients with gadolinium-enhanced lesions showed ALLO values higher than those found in respective gender groups without gadolinium-enhanced lesions. ALLO values were lower in male than in female RR-MS patients without gadolinium-enhanced lesions. Considering the pharmacological properties of neuroactive steroids and the observation that neurological disorders influence their concentrations, these endogenous compounds may have an important role as prognostic factors of the disease and used as markers of MS activity such as relapses.

  • Psychometric properties of the Italian version of the multifactorial memory questionnaire for adults and the elderly.
    Publication Date: 01/05/2016, on Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
    by Raimo S, Trojano L, Siciliano M, Cuoco S, D'Iorio A, Santangelo F, Abbamonte L, Grossi D, Santangelo G
    DOI: 10.1007/s10072-016-2562-5

    Reliable and valid metamemory measures are needed to assess subjective memory complaints that can be distinct from objective memory performance. The Multifactorial Memory Questionnaire (MMQ) evaluates dimensions of subjective memory functioning such as frequency of memory problems (Ability), affect related to memory abilities (Contentment), and strategy use in everyday life (Strategy). To examine the psychometric properties of the Italian version of the MMQ, six hundred Italian healthy individuals (aged 25-91 years) completed MMQ, a questionnaire assessing metacognition (Cognitive Failures Questionnaire, CFQ) and two batteries assessing cognitive global status (Montreal Cognitive Assessment, MoCA; Mini Mental State Examination, MMSE). MMQ was easy to administer, acceptable, and had good test-retest reliability (r for the total MMQ score 0.95), and internal consistency (Cronbach's α for the total MMQ score = 0.83). An exploratory factor analysis provided a four-factor solution: "Ability" (α = 0.99), "Contentment" (α = 0.91), "External Strategies" (α = 0.85) and "Internal Strategies" (α = 0.78) factors. MMQ total score and MMQ-Ability factor score showed good convergent validity when compared to CFQ score (r rho ≥ 0.51), whereas MMQ total score and the four MMQ factors showed good divergent validity when compared to MoCA and MMSE score (r rho ≤ 0.27). Demographic variables significantly influenced MMQ total score and most subscale scores. From the derived linear equations, we computed correction factors for raw scores and percentile distribution of adjusted scores. The Italian version of MMQ is reliable and valid to assess dimensions of metamemory in adult and elderly subjects.

  • Proteome analysis of human amniotic mesenchymal stem cells (hA-MSCs) reveals impaired antioxidant ability, cytoskeleton and metabolic functionality in maternal obesity.
    Publication Date: 29/04/2016, on Scientific reports
    by Capobianco V, Caterino M, Iaffaldano L, Nardelli C, Sirico A, Del Vecchio L, Martinelli P, Pastore L, Pucci P, Sacchetti L
    DOI: 10.1038/srep25270

    Maternal obesity increases the risk of obesity and/or obesity-related diseases in the offspring of animal models. The aim of this study was to identify metabolic dysfunctions that could represent an enhanced risk for human obesity or obesity-related diseases in newborn or in adult life, similar to what occurs in animal models. To this aim, we studied the proteome of 12 obese (Ob-) and 6 non-obese (Co-) human amniotic mesenchymal stem cells (hA-MSCs) obtained from women at delivery by cesarean section (pre-pregnancy body mass index [mean ± SD]: 42.7 ± 7.7 and 21.3 ± 3.3 kg/m(2), respectively). The proteome, investigated by two-dimensional fluorescence difference gel electrophoresis/mass spectrometry, revealed 62 differently expressed proteins in Ob- vs Co-hA-MSCs (P < 0.05), nine of which were confirmed by western blotting. Bioinformatics analysis showed that these 62 proteins are involved in several statistically significant pathways (P < 0.05), including the stress response, cytoskeleton and metabolic pathways. Oxidative stress was shown to be an early triggering factor of tissue fat accumulation and obesity-related disorders in the offspring of obese animal models. Our finding of a reduced stress response in Ob-hA-MSCs suggests that a similar mechanism could occur also in humans. Long-term follow-up studies of newborns of obese mothers are required to verify this hypothesis.

  • Drawing Disorders in Alzheimer's Disease and Other Forms of Dementia.
    Publication Date: 21/04/2016, on Journal of Alzheimer's disease : JAD
    by Trojano L, Gainotti G
    DOI: 10.3233/JAD-160009

    Drawing is a multicomponential process that can be impaired by many kinds of brain lesions. Drawing disorders are very common in Alzheimer's disease and other forms of dementia, and can provide clinical information for the distinction of the different dementing diseases. In our review we started from an overview of the neural and cognitive bases of drawing, and from a recollection of the drawing tasks more frequently used for assessing individuals with dementia. Then, we analyzed drawing disorders in dementia, paying special attention to those observed in Alzheimer's disease, from the prodromal stages of the amnesic mild cognitive impairment to the stages of full-blown dementia, both in the sporadic forms with late onset in the entorhino-hippocampal structures and in those with early onset in the posterior neocortical structures. We reviewed the drawing features that could differentiate Alzheimer's disease from vascular dementia and from the most frequent forms of degenerative dementia, namely frontotemporal dementia and Lewy body disease. Finally, we examined some peculiar aspects of drawing disorders in dementia, such as perseverations, rotations, and closing-in. We argue that a careful analysis of drawing errors helps to differentiate the different forms of dementia more than overall accuracy in drawing.

  • Dysfunctional Freezing Responses to Approaching Stimuli in Persons with a Looming Cognitive Style for Physical Threats.
    Publication Date: 19/04/2016, on Frontiers in psychology
    by Riskind JH, Sagliano L, Trojano L, Conson M
    DOI: 10.3389/fpsyg.2016.00521

    Immobilizing freezing responses are associated with anxiety and may be etiologically related to several anxiety disorders. Although recent studies have sought to investigate the underlying mechanisms in freezing responses that are so problematic in many forms of anxiety, cognitive factors related to anxiety have not been investigated. This study was designed to investigate the potential moderating role of a well-documented cognitive vulnerability to anxiety, the Looming Cognitive Style (i.e., LCS; Riskind et al., 2000), which assesses the extent to which individuals tend to routinely interpret ambiguous threats (e.g., physical or social threats) in a biased manner as approaching. We assessed participants' Reaction Times (RTs) when they made judgments about images of animals that differed in threat valence (threat or neutral) and motion direction (approach or recede). As expected, LCS for concerns about the approach of physical dangers appeared to moderate freeze reactions. Individuals who were high on this LCS factor tended to generally exhibit a freeze-response (slower RTs) and this was independent of the threat valence or motion direction of the animals. These general freezing reactions were in stark contrast to those of individuals who were low on the LCS factor for concerns about the approach of physical dangers. These participants tended to exhibit more selective and functional freezing responses that occurred only to threatening animals with approach motion; they did not exhibit freezing to neutral stimuli or any stimuli with receding motion. These findings did not appear to be explicable by a general slowing of RTs for the participants with high LCS. Moreover, the LCS factor for concerns about social threats (such as rejection or embarrassment) was not related to differences in freezing; there was also no additional relationship of freezing to behavioral inhibition scores on the Behavioral Inhibition System and the Behavioral Activation System Scales (BIS/BAS). It may prove fruitful to further explore cognitive factors related to anxiety to develop a more comprehensive understanding of how these factors are associated with anxiety-related freezing responses.

  • The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells.
    Publication Date: 19/04/2016, on Oncotarget
    by Romano G, Santi L, Bianco MR, Giuffrè MR, Pettinato M, Bugarin C, Garanzini C, Savarese L, Leoni S, Cerrito MG, Leone BE, Gaipa G, Grassilli E, Papa M, Lavitrano M, Giovannoni R
    DOI: 10.18632/oncotarget.7895

    TGF-β pathway is generally associated with the processes of metastasis, angiogenesis and EMT in cancer. Very little is known, however, about the role of TGF-β in cancer drug resistance. In this work, we show a specific activation of the TGF-β pathway in consequence of chemotherapeutic treatment in in vivo and in vitro models of colorectal carcinoma. 5-Fluorouracil (5FU) was able to stimulate the activation of SMAD3 and the transcription of specific genes such as ACVRL1, FN1 and TGFB1. On the other hand, the specific inhibition of TGF-βRI was able to repress the 5FU-induced genes transcription and to restore the sensitivity of chemoresistant cells to the toxic action of the drug, by decreasing the expression of BCL2L1 and ID1 genes. The role of the TGF-β molecule in the chemoresistant colon carcinoma cells' response to 5FU was further demonstrated by conditioned medium (CM) experiments: CM from 5FU-treated chemoresistant cells was able to protect chemosensitive cells against the toxic action of 5FU. In conclusion, these findings showed the pivotal role of TGF-β pathway in colon cancer mechanisms of drug resistance suggesting new possible approaches in diagnosis and treatment of colon cancer patients.