@article{%a1:%Y_304,

title = {A cascade screening approach for the identification of Bcr-Abl myristate pocket binders active against wild type and T315I mutant.},

author = {Radi M and Schneider R and Fallacara AL and Botta L and Crespan E and Tintori C and Maga G and Kissova M and Calgani A and Richters A and Musumeci F and Rauh D and Schenone S},

url = {http://www.sciencedirect.com/science/article/pii/S0960894X1630662X},

doi = {10.1016/j.bmcl.2016.06.051},

year  = {2016},

date = {2016-02-17},

journal = {Bioorganic & Medicinal Chemistry Letters},

volume = {26},

number = {15},

pages = {3436-3440},

abstract = {The major clinical challenge in drug-resistant chronic myelogenous leukemia (CML) is currently represented by the Bcr-Abl T315I mutant, which is unresponsive to treatment with common first and second generation ATP-competitive tyrosine kinase inhibitors (TKIs). Allosteric inhibition of Bcr-Abl represent a new frontier in the fight against resistant leukemia and few candidates have been identified in the last few years. Among these, myristate pocket (MP) binders discovered by Novartis (e.g. GNF2/5) showed promising results, although they proved to be active against the T315I mutant only in combination with first and second generation ATP-competitive inhibitors. Here we used a cascade screening approach based on sequential fluorescence polarization (FP) screening, in silico docking/dynamics studies and kinetic-enzymatic studies to identify novel MP binders. A pyrazolo[3,4-d]pyrimidine derivative (6) has been identified as a promising allosteric inhibitor active on 32D leukemia cell lines (expressing Bcr-Abl WT and T315I) with no need of combination with any ATP-competitive inhibitor.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_307,

title = {Collagen VI-NG2 axis in human tendon fibroblasts under conditions mimicking injury response.},

author = {Sardone F and Santi S and Tagliavini F and Traina F and Merlini L and Squarzoni S and Cescon M and Wagener R and Maraldi NM and Bonaldo P and Faldini C and Sabatelli P},

url = {https://www.sciencedirect.com/science/article/pii/S0945053X16300233?via%3Dihub},

doi = {10.1016/j.matbio.2016.02.012},

year  = {2016},

date = {2016-02-17},

journal = {Matrix Biology},

volume = {55},

pages = {90-105},

abstract = {In response to injury, tendon fibroblasts are activated, migrate to the wound, and contribute to tissue repair by producing and organizing the extracellular matrix. Collagen VI is a microfibrillar collagen enriched in the pericellular matrix of tendon fibroblasts with a potential regulatory role in tendon repair mechanism. We investigated the molecular basis of the interaction between collagen VI and the cell membrane both in tissue sections and fibroblast cultures of human tendon, and analyzed the deposition of collagen VI during migration and myofibroblast trans-differentiation, two crucial events for tendon repair. Tendon fibroblast displayed a collagen VI microfibrillar network closely associated with the cell surface. Binding of collagen VI with the cell membrane was mediated by NG2 proteoglycan, as demonstrated by in vitro perturbation of collagen VI-NG2 interaction with a NG2-blocking antibody. Cultures subjected to wound healing scratch assay displayed collagen VI-NG2 complexes at the trailing edge of migrating cells, suggesting a potential role in cell migration. In fact, the addition of a NG2-blocking antibody led to an impairment of cell polarization and delay of wound closure. Similar results were obtained after in vitro perturbation of collagen VI extracellular assembly with the 3C4 anti-collagen VI antibody and in collagen VI-deficient tendon cultures of a Ullrich congenital muscular dystrophy patient carrying mutations in COL6A2 gene. Moreover, in vitro treatment with transforming growth factor beta1 (TGFbeta1) induced a dramatic reduction of NG2 expression, both at protein and mRNA transcript level, and the impairment of collagen VI association with the cell membrane. Instead, collagen VI was still detectable in the extracellular matrix in association with ED-A fibronectin and collagen I, which were strongly induced by TGFbeta1 treatment. Our findings reveal a critical role of the NG2 proteoglycan for the binding of collagen VI to the surface of tendon fibroblasts. By interacting with NG2 proteoglycan and other extracellular matrix proteins, collagen VI regulates fibroblasts behavior and the assembly of tendon matrix, thereby playing a crucial role in tendon repair. Copyright 2016 The Authors. Published by Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_310,

title = {Deep RNA profiling identified clock and molecular clock genes as pathophysiological signatures in collagen VI myopathy.},

author = {Scotton C and Bovolenta M and Schwartz E and Falzarano MS and Martoni E and Passarelli C and Armaroli A and Osman H and Rodolico C and Messina S and Pegoraro E and D'Amico A and Bertini E and Gualandi F and Neri M and Selvatici R and Boffi P and Maioli MA and Lochmüller H and Straub V and Bushby K and Castrignanò T and Pesole G and Sabatelli P and Merlini L and Braghetta P and Bonaldo P and Bernardi P and Foley R and Cirak S and Zaharieva I and Muntoni F and Capitanio D and Gelfi C and Kotelnikova E and Yuryev A and Lebowitz M and Zhang X and Hodge B and Esser KA and Ferlini A},

url = {http://jcs.biologists.org/content/early/2016/03/04/jcs.175927.long},

doi = {10.1242/jcs.175927},

year  = {2016},

date = {2016-02-17},

journal = {Journal of Cell Science},

volume = {129},

number = {8},

pages = {1671-1684},

abstract = {Collagen VI myopathies are genetic disorders due to mutations in collagen 6 A1, 2, and 3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem Myopathy, which is recapitulated by collagen VI null (Col6a1-/-) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies we performed a deep RNA profiling in both Col6a1-/- mice and ColVI patients. Interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1-/- mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and autophagy-related genes.The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that may modify muscle damage pathogenesis. 2016. Published by The Company of Biologists Ltd.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_319,

title = {USP7 is essential for maintaining Rad18 stability and DNA damage tolerance.},

author = {Zlatanou A and Sabbioneda S and Miller ES and Greenwalt A and Aggathanggelou A and Maurice MM and Lehmann AR and Stankovic T and Reverdy C and Colland F and Vaziri C and Stewart GS},

url = {http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2015149a.html},

doi = {10.1038/onc.2015.149},

year  = {2016},

date = {2016-02-16},

journal = {Oncogene},

volume = {35},

number = {8},

pages = {965-976},

abstract = {965	976},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_248,

title = {Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance.},

author = {Avnet S and Lemma S and Cortini M and Pellegrini P and Perut F and Zini N and Kusuzaki K and Chano T and Grisendi G and Dominici M and De Milito A and Baldini N},

url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=11503&pubmed-linkout=1},

doi = {10.18632/oncotarget.11503},

year  = {2016},

date = {2016-02-12},

journal = {Oncotarget},

volume = {7},

number = {39},

pages = {63408-63423},

abstract = {Current therapy of osteosarcoma (OS), the most common primary bone malignancy, is based on a combination of surgery and chemotherapy. Multidrug resistance mediated by P-glycoprotein (P-gp) overexpression has been previously associated with treatment failure and progression of OS, although other mechanisms may also play a role. We considered the typical acidic extracellular pH (pHe) of sarcomas, and found that doxorubicin (DXR) cytotoxicity is reduced in P-gp negative OS cells cultured at pHe 6.5 compared to standard 7.4. Short-time (24-48 hours) exposure to low pHe significantly increased the number and acidity of lysosomes, and the combination of DXR with omeprazole, a proton pump inhibitor targeting lysosomal acidity, significantly enhanced DXR cytotoxicity. In OS xenografts, the combination treatment of DXR and omeprazole significantly reduced tumor volume and body weight loss. The impaired toxicity of DXR at low pHe was not associated with increased autophagy or lysosomal acidification, but rather, as shown by SNARF staining, with a reversal of the pH gradient at the plasma membrane (ΔpHcm), eventually leading to a reduced DXR intracellular accumulation. Finally, the reversal of ΔpHcm in OS cells promoted resistance not only to DXR, but also to cisplatin and methotrexate, and, to a lesser extent, to vincristine. Altogether, our findings show that, in OS cells, short-term acidosis induces resistance to different chemotherapeutic drugs by a reversal of ΔpHcm, suggesting that buffer therapies or regimens including proton pump inhibitors in combination to low concentrations of conventional anticancer agents may offer novel solutions to overcome drug resistance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_264,

title = {Autofluorescence discrimination of metabolic fingerprint in nutritional and genetic fatty liver models.},

author = {Croce AC and Ferrigno A and Di Pasqua LG and Berardo C and Piccolini VM and Bertone V and Bottiroli G and Vairetti M},

url = {http://www.sciencedirect.com/science/article/pii/S1011134416302913},

doi = {10.1016/j.jphotobiol.2016.09.015},

year  = {2016},

date = {2016-02-11},

journal = {Journal of Photochemistry and Photobiology. B, Biology.},

volume = {164},

pages = {13-20},

abstract = {Liver tissue autofluorescence (AF) has been characterized in two models with a different potential to undergo disease progression to steatohepatitis: Wistar rats, administered with a methionine, choline deficient diet (MCD), and Zucker (fa/fa) rats, homozygous for a spontaneous mutation of leptin receptor. AF spectra were recorded from liver tissue cryostatic sections by microspectrofluorometry, under 366nm excitation. Curve fitting analysis was used to estimate the contribution of different endogenous fluorophores (EFs) to the overall AF emission: i) fluorescing fatty acids, a fraction of liver lipids up to now poorly considered and complicated to detect by conventional procedures; ii) lipofuscin-like lipopigments, biomarkers of oxidizing events; iii) NAD(P)H and flavins, biomarkers of energy metabolism and tissue redox state. AF data and biochemical correlates of hepatocellular injury resulted to depend more on rat strain than on intratissue bulk lipid or ROS levels, reflecting a different metabolic ability of the two models to counteract potentially harmful agents. AF analysis can thus be proposed for extensive applications ranging from experimental hepatology to the clinics. AF based diagnostic procedures are expected to help both the prediction of the risk of fatty liver disease progression and the prescreening of marginal organs to be recruited as donors for transplantation. A support is also foreseen in the advancement and personalization of strategies to ameliorate the donor organ preservation outcome and the follow up of therapeutic interventions. Copyright 2016 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_273,

title = {In vitro and in vivo characterization of graphene oxide coated porcine bone granules},

author = {Ettorrea V and De Marcoa P and Zaraa S and Perrottib V and Scarano A and Di Crescenzo A and Petrini M and Hadad C and Bosco D and Zavan B and Valbonetti L and Spoto G and Iezzi G and Piattelli A and Cataldi A and Fontana A},

url = {https://www.sciencedirect.com/science/article/pii/S0008622316301993},

doi = {10.1016/j.carbon.2016.03.010},

year  = {2016},

date = {2016-02-11},

journal = {Carbon},

volume = {103},

pages = {291-298},

abstract = {Graphene oxide (GO) demonstrated to improve the wound healing properties of materials intended for bone replacement. The main objective of this study was the setting up of a simple and effective procedure for the production of GO-coated porcine bone (PB) granules and the characterization of the obtained material in order to improve its properties by exploiting chemical, physical, biological and mechanical features that the GO coating could confer to pre-formed PB granules. The obtained coating was homogeneously distributed on PB granule surface and demonstrated to confer PB an increased resistance to fracture load. Biological analyses evidenced no toxic effects of GO-coated PB samples on primary human gingival fibroblasts, and no inflammatory response around the grafted particles when implanted in vivo on a sheep model although GO-coated PB samples did not appear to improve new bone formation efficacy compared with the control within the investigated time. A small loss of GO was however detected, indicating the opportunity to investigate less GO concentrated samples. In conclusion, this study presents a novel and low cost approach to the development of functionalized biomimetic hybrid materials which can be applied to other bone substitute materials in order to improve their performances.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_276,

title = {Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.},

author = {Fan Q and Guo X and Tideman JW and Williams KM and Yazar S and Hosseini SM and Howe LD and Pourcain BS and Evans DM and Timpson NJ and McMahon G and Hysi PG and Krapohl E and Wang YX and Jonas JB and Baird PN and Wang JJ and Cheng CY and Teo YY and Wong TY and Ding X and Wojciechowski R and Young TL and Pärssinen O and Oexle K and Pfeiffer N and Bailey-Wilson JE and Paterson AD and Klaver CC and Plomin R and Hammond CJ and Mackey DA and He M and Saw SM and Williams C and Guggenheim JA and CREAM Consortium},

url = {http://www.nature.com/articles/srep25853},

doi = {10.1038/srep25853},

year  = {2016},

date = {2016-02-11},

journal = {Scientific Reports},

volume = {6},

pages = {25853},

abstract = {Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_299,

title = {DNA Polymerases lambda and beta: The Double-Edged Swords of DNA Repair.},

author = {Mentegari E and Kissova M and Bavagnoli L and Maga G and Crespan E},

url = {http://www.mdpi.com/2073-4425/7/9/57},

doi = {10.3390/genes7090057},

year  = {2016},

date = {2016-02-11},

journal = {Genes (Basel)},

volume = {7},

number = {9},

pages = {e57},

abstract = {DNA is constantly exposed to both endogenous and exogenous damages. More than 10,000 DNA modifications are induced every day in each cell's genome. Maintenance of the integrity of the genome is accomplished by several DNA repair systems. The core enzymes for these pathways are the DNA polymerases. Out of 17 DNA polymerases present in a mammalian cell, at least 13 are specifically devoted to DNA repair and are often acting in different pathways. DNA polymerases beta and lambda are involved in base excision repair of modified DNA bases and translesion synthesis past DNA lesions. Polymerase lambda also participates in non-homologous end joining of DNA double-strand breaks. However, recent data have revealed that, depending on their relative levels, the cell cycle phase, the ratio between deoxy- and ribo-nucleotide pools and the interaction with particular auxiliary proteins, the repair reactions carried out by these enzymes can be an important source of genetic instability, owing to repair mistakes. This review summarizes the most recent results on the ambivalent properties of these enzymes in limiting or promoting genetic instability in mammalian cells, as well as their potential use as targets for anticancer chemotherapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_314,

title = {Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family.},

author = {Tintori C and Brai A and Dasso Lang MC and Deodato D and Greco AM and Bizzarri BM and Cascone L and Casian A and Zamperini C and Dreassi E and Crespan E and Maga G and Vanham G and Ceresola E and Canducci F and Arien KK and Botta M},

url = {http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01979},

doi = {10.1021/acs.jmedchem.5b01979},

year  = {2016},

date = {2016-02-10},

journal = {Journal of medicinal chemistry},

volume = {59},

number = {6},

pages = {2747-2759},

abstract = {Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_265,

title = {Flow cytometric analysis of circulating endothelial cells and endothelial progenitors for clinical purposes in oncology: A critical evaluation.},

author = {Danova M and Comolli G and Manzoni M and Torchio M and Mazzini G},

url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888001/},

doi = {10.3892/mco.2016.823},

year  = {2016},

date = {2016-02-04},

journal = {Molecular and Clinical Oncology},

volume = {4},

number = {6},

pages = {909-917},

abstract = {Malignant tumors are characterized by uncontrolled cell growth and metastatic spread, with a pivotal importance of the phenomenon of angiogenesis. For this reason, research has focused on the development of agents targeting the vascular component of the tumor microenvironment and regulating the angiogenic switch. As a result, the therapeutic inhibition of angiogenesis has become an important component of anticancer treatment, however, its utility is partly limited by the lack of an established methodology to assess its efficacy in vivo. Circulating endothelial cells (CECs), which are rare in healthy subjects and significantly increased in different tumor types, represent a promising tool for monitoring the tumor clinical outcome and the treatment response. A cell population circulating into the blood also able to form endothelial colonies in vitro and to promote vasculogenesis is represented by endothelial progenitor cells (EPCs). The number of both of these cell types is extremely low and they cannot be identified using a single marker, therefore, in absence of a definite consensus on their phenotype, require discrimination using combinations of antigens. Multiparameter flow cytometry (FCM) is ideal for rapid processing of high numbers of cells per second and is commonly utilized to quantify CECs and EPCs, however, remains technically challenging since there is as yet no standardized protocol for the identification and enumeration of these rare events. Methodology in studies on CECs and/or EPCs as clinical biomarkers in oncology is heterogeneous and data have been obtained from different studies leading to conflicting conclusions. The present review presented a critical review of the issues that limit the comparability of results of the most significant studies employing FCM for CEC and/or EPC detection in patients with cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_267,

title = {Involvement of cyclic-nucleotide response element-binding family members in the radiation response of Ramos B lymphoma cells.},

author = {{Di Nisio C} and Sancilio S and Di Giacomo V and Rapino M and Sancillo L and Genovesi D and Di Siena A and Rana RA and Cataldi A and Di Pietro R},

url = {http://www.spandidos-publications.com/ijo/48/1/28},

doi = {10.3892/ijo.2015.3238},

year  = {2016},

date = {2016-01-28},

journal = {International Journal of Oncology},

volume = {48},

number = {1},

abstract = {The aim of the present study was to investigate the role of Cyclic-nucleotide Response Element-Binding (CREB) family members and related nuclear transcription factors in the radiation response of human B lymphoma cell lines (Daudi and Ramos). Unlike the more radiosensitive Daudi cells, Ramos cells demonstrated only a moderate increase in early apoptosis after 3-5 Gy irradiation doses, which was detected with Annexin V/PI staining. Moreover, a significant and dose-dependent G2/M phase accumulation was observed in the same cell line at 24 h after both ionizing radiation (IR) doses. Western blot analysis showed an early increase in CREB protein expression that was still present at 3 h and more evident after 3 Gy IR in Ramos cells, along with the dose-dependent upregulation of p53 and NF-κB. These findings were consistent with real-time RT-PCR analysis that showed an early- and dose-dependent upregulation of NFKB1, IKBKB and XIAP gene expression. Unexpectedly, pre-treatment with SN50 did not increase cell death, but cell viability. Taken together, these findings let us hypothesise that the early induction and activation of NF-κB1 in Ramos cells could mediate necrotic cell death and be linked to other molecules belonging to CREB family and involved in the cell cycle regulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_255,

title = {Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB.},

author = {Buontempo F and Orsini E and Lonetti A and Cappellini A and Chiarini F and Evangelisti C and Evangelisti C and Melchionda F and Pession A and Bertaina A and Locatelli F and Bertacchini J and Neri LM and McCubrey JA and Martelli AM},

url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=6361&pubmed-linkout=1},

doi = {10.18632/oncotarget.6361},

year  = {2016},

date = {2016-01-22},

journal = {Oncotarget},

volume = {7},

number = {2},

pages = {1323-1340},

abstract = {The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX-4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomib-mediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_309,

title = {Site-directed Mutagenesis of Key Residues Unveiled a Novel Allosteric Site on Human Adenosine Kinase for Pyrrolobenzoxa(thia)zepinone-Non-Nucleoside Inhibitors.},

author = {Savi L and Brindisi M and Alfano G and Butini S and La Pietra V and Novellino E and Marinelli L and Lossani A and Focher F and Cavella C and Campiani G and Gemma S},

url = {https://onlinelibrary.wiley.com/doi/full/10.1111/cbdd.12630},

doi = {10.1111/cbdd.12630},

year  = {2016},

date = {2016-01-20},

journal = {Chemical Biology & Drug Design},

volume = {87},

number = {1},

pages = {112-120},

abstract = {Most nucleoside kinases, besides the catalytic domain, feature an allosteric domain which modulates their activity. Generally, non-substrate analogs, interacting with allosteric sites, represent a major opportunity for developing more selective and safer therapeutics. We recently developed a series of non-nucleoside non-competitive inhibitors of human Adenosine Kinase (hAK), based on a pyrrolobenzoxa(thia)zepinone scaffold. Based on computational analysis, we hypothesized the existence of a novel allosteric site on hAK, topographically distinct from the catalytic site. In this study, we have adopted a multidisciplinary approach including molecular modeling, biochemical studies and site-directed mutagenesis to validate our hypothesis. Based on a three-dimensional model of interaction between hAK and our molecules, we designed, cloned and expressed specific, single and double point mutants of hAK (Q74A, Q78A, H107A, K341A, F338A and Q74A-F338A). Kinetic characterization of recombinant enzymes indicated that these mutations did not affect enzyme functioning; conversely, mutated enzymes are endowed of reduced susceptibility to our non-nucleoside inhibitors, while maintaining comparable affinity for nucleoside inhibitors to the wild type enzyme. This study represents the first characterization and validation of a novel allosteric site in hAK, and may pave the way to the development of novel selective and potent non-nucleoside inhibitors of hAK endowed with therapeutic potential. This article is protected by copyright. All rights reserved. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_286,

title = {TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.},

author = {Harley ME and Murina O and Leitch A and Higgs MR and Bicknell LS and Yigit G and Blackford AN and Zlatanou A and Mackenzie KJ and Reddy K and Halachev M and McGlasson S and Reijns MA and Fluteau A and Martin CA and Sabbioneda S and Elcioglu NH and Altmüller J and Thiele H and Greenhalgh L and Chessa L and Maghnie M and Salim M and Bober MB and Nürnberg P and Jackson SP and Hurles ME and Wollnik B and Stewart GS and Jackson AP},

url = {http://www.nature.com/ng/journal/v48/n1/full/ng.3451.html},

doi = {doi:10.1038/ng.3451},

year  = {2016},

date = {2016-01-07},

journal = {Nature Genetics},

volume = {48},

number = {1},

pages = {36-43},

abstract = {DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_270,

title = {p21CDKN1A Regulates the Binding of Poly(ADP-Ribose) Polymerase-1 to DNA Repair Intermediates.},

author = {Dutto I and Sukhanova M and Tillhon M and Cazzalini O and Stivala LA and Scovassi AI and Lavrik O and Prosperi E},

url = {http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146031},

doi = {10.1371/journal.pone.0146031.},

year  = {2016},

date = {2016-01-05},

journal = {Plos One},

volume = {11},

number = {1},

pages = {e0146031},

abstract = {The cell cycle inhibitor p21CDKN1A was previously found to interact directly with DNA nick-sensor poly(ADP-ribose) polymerase-1 (PARP-1) and to promote base excision repair (BER). However, the molecular mechanism responsible for this BER-related association of p21 with PARP-1 remains to be clarified. In this study we investigate the capability of p21 to influence PARP-1 binding to DNA repair intermediates in a reconstituted BER system in vitro. Using model photoreactive BER substrates containing single-strand breaks, we found that full-length recombinant GST-tagged p21 but not a C-terminal domain truncated form of p21 was able to stimulate the PARP-1 binding to BER intermediates with no significant influence on the catalytic activity of PARP-1. In addition, we investigate whether the activation of PARP-1 through poly(ADP-ribose) (PAR) synthesis, is required for its interaction with p21. We have found that in human fibroblasts and in HeLa cells treated with the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the interaction of p21 with PARP-1 was greatly dependent on PAR synthesis. In fact, an anti-PAR antibody was able to co-immunoprecipitate p21 and PARP-1 from extracts of MNNG-treated cells, while blocking PAR synthesis with the PARP-1 inhibitor Olaparib, drastically reduced the amount of p21 co-immunoprecipitated by a PARP-1 antibody. Our results provide the first evidence that p21 can stimulate the binding of PARP-1 to DNA repair intermediates, and that this cooperation requires PAR synthesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_367,

title = {Helicobacter pylori ATCC 43629/NCTC 11639 Outer Membrane Vesicles (OMVs) from Biofilm and Planktonic Phase Associated with Extracellular DNA (eDNA).},

author = {Grande R and Di Marcantonio MC and Robuffo I and Pompilio A and Celia C and {Di Marzio L} and Paolino D and Codagnone M and Muraro R and Stoodley P and Hall-Stoodley L and Mincione G},

url = {https://www.frontiersin.org/articles/10.3389/fmicb.2015.01369/full},

doi = {10.3389/fmicb.2015.01369},

year  = {2015},

date = {2015-12-16},

journal = {Frontiers in virology},

volume = {6},

pages = {1369},

abstract = {Helicobacter pylori persistence is associated with its capacity to develop biofilms as a response to changing environmental conditions and stress. Extracellular DNA (eDNA) is a component of H. pylori biofilm matrix but the lack of DNase I activity supports the hypothesis that eDNA might be protected by other extracellular polymeric substances (EPS) and/or Outer Membrane Vesicles (OMVs), which bleb from the bacteria surface during growth. The aim of the present study was to both identify the eDNA presence on OMVs segregated from H. pylori ATCC 43629/NCTC 11639 biofilm (bOMVs) and its planktonic phase (pOMVs) and to characterize the physical-chemical properties of the OMVs. The presence of eDNA in bOMVs and pOMVs was initially carried out using DNase I-gold complex labeling and Transmission Electron Microscope analysis (TEM). bOMVs and pOMVs were further isolated and physical-chemical characterization carried out using dynamic light scattering (DLS) analysis. eDNA associated with OMVs was detected and quantified using a PicoGreen spectrophotometer assay, while its extraction was performed with a DNA Kit. TEM images showed that eDNA was mainly associated with the OMV membrane surfaces; while PicoGreen staining showed a four-fold increase of dsDNA in bOMVs compared with pOMVs. The eDNA extracted from OMVs was visualized using gel electrophoresis. DLS analysis indicated that both planktonic and biofilm H. pylori phenotypes generated vesicles, with a broad distribution of sizes on the nanometer scale. The DLS aggregation assay suggested that eDNA may play a role in the aggregation of OMVs, in the biofilm phenotype. Moreover, the eDNA associated with vesicle membrane may impede DNase I activity on H. pylori biofilms. These results suggest that OMVs derived from the H. pylori biofilm phenotype may play a structural role by preventing eDNA degradation by nucleases, providing a bridging function between eDNA strands on OMV surfaces and promoting aggregation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_368,

title = {Heritability of young- and old-onset ischaemic stroke.},

author = {Bluher A and Devan WJ and Holliday EG and Nalls M and Parolo S and Bione S and Giese AK and Boncoraglio GB and Maguire JM and Muller-Nurasyid M and Gieger C and Meschia JF and Rosand J and Rolfs A and Kittner SJ and Mitchell BD and O'Connell JR and Cheng YC},

url = {https://onlinelibrary.wiley.com/doi/full/10.1111/ene.12827},

doi = {10.1111/ene.12827},

year  = {2015},

date = {2015-11-27},

journal = {European Journal of Neurology},

volume = {22},

number = {11},

pages = {1488-1491},

abstract = {Although the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. METHODS: This analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age < 55 years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age ≥ 55 years). RESULTS: Heritabilities for young-onset stroke and old-onset stroke were estimated at 42% (±8%, P < 0.001) and 34% (±10%, P < 0.001), respectively. CONCLUSIONS: Our data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant. 2015 EAN.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_417,

title = {Tumor Necrosis Factor Related Apoptosis Inducing Ligand (Trail) in Endothelial Response to Biomechanical and Biochemical Stresses in Arteries.},

author = {D'Auria F and Centurione L and Centurione MA and Angelini A and {Di Pietro R}},

url = {https://onlinelibrary.wiley.com/doi/full/10.1002/jcb.25223},

doi = {10.1002/jcb.25223},

year  = {2015},

date = {2015-11-27},

journal = {Journal of Cellular Biochemistry},

volume = {116},

number = {11},

pages = {2427-2434},

abstract = {"Shear stress is determined by three physical components described in a famous triad: blood flow, blood viscosity and vessel geometry. Through the direct action on endothelium, shear stress is able to radically interfere with endothelial properties and the physiology of the vascular wall. Endothelial cells (ECs) have also to sustain biochemical stresses represented by chemokines, growth factors, cytokines, complement, hormones, nitric oxide (NO), oxygen and reactive oxygen species (ROS). Many growth factors, cytokines, chemokines, hormones, and chemical substances, like NO, act and regulate endothelium functions and homeostasis. Among these cytokines Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) has been assigned a regulatory role in ECs physiology and physiopathology. Thus, the aim of this review is to provide a general overview of the endothelial response pathways after different types of biomechanical and biochemical stress in in vitro models and to analyze the crucial role of TRAIL under pathological conditions of the cardiocirculatory system like atherosclerosis, coronary artery disease, and diabetes. 2015 Wiley Periodicals, Inc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_366,

title = {Height-reducing variants and selection for short stature in Sardinia.},

author = {Zoledziewska M and Sidore C and Chiang CW and Sanna S and Mulas A and Steri M and Busonero F and Marcus JH and Marongiu M and Maschio A and Del Vecchyo DO and Floris M and Meloni A and Delitala A and Concas MP and Murgia F and Biino G and Vaccargiu S and Nagaraja R and Lohmueller KE and UK10K Consortium and Timpson NJ and Soranzo N and Tachmazidou I and Dedoussis G and Zeggini E and Understanding Society Scientific Group and Uzzau S and Jones C and Lyons R and Angius A and Abecasis GR and Novembre J and Schlessinger D and Cucca F},

url = {https://www.nature.com/articles/ng.3403},

doi = {10.1038/ng.3403},

year  = {2015},

date = {2015-11-25},

journal = {Nature Genetics},

volume = {47},

number = {11},

pages = {1352-1356},

abstract = {We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_370,

title = {Homology Model-Based Virtual Screening for the Identification of Human Helicase DDX3 Inhibitors.},

author = {Fazi R and Tintori C and Brai A and Botta L and Selvaraj M and Garbelli A and Maga G and Botta M},

url = {https://pubs.acs.org/doi/10.1021/acs.jcim.5b00419},

doi = {10.1021/acs.jcim.5b00419},

year  = {2015},

date = {2015-11-23},

journal = {Journal of Chemical Information and Modeling},

volume = {55},

number = {11},

pages = {2443-2454},

abstract = {Targeting cellular cofactors instead of viral enzymes represents a new strategy to combat infectious diseases, which should help to overcome the problem of viral resistance. Recently, it has been revealed that the cellular ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3) is an essential host factor for the replication of several viruses such as HIV, HCV, JEV, Dengue, and West Nile. Accordingly, a drug targeting DDX3 could theoretically inhibit all viruses that are dependent on this host factor. Herein, for the first time, a model of hDDX3 in its closed conformation, which binds the viral RNA was developed by using the homology module of Prime through the Maestro interface of Schrodinger. Next, a structure-based virtual screening protocol was applied to identify DDX3 small molecule inhibitors targeting the RNA binding pocket. As a result, an impressive hit rate of 40% was obtained with the identification of 10 active compounds out of the 25 tested small molecules. The best poses of the active ligands highlighted the crucial residues to be targeted for the inhibition of the helicase activity of DDX3. The obtained results confirm the reliability of the constructed DDX3/RNA model and the proposed computational strategy for investigating novel DDX3 inhibitors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_416,

title = {Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.},

author = {Kato N and Loh M and {et al}},

url = {https://www.nature.com/articles/ng.3405},

doi = {10.1038/ng.3405},

year  = {2015},

date = {2015-11-11},

journal = {Nature Genetics},

volume = {47},

number = {11},

abstract = {We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10-11 to 5.0 × 10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_375,

title = {Lamin A/C sustains PcG protein architecture, maintaining transcriptional repression at target genes.},

author = {Cesarini E and Mozzetta C and Marullo F and Gregoretti F and Gargiulo A and Columbaro M and Cortesi A and Antonelli L and Di Pelino S and Squarzoni S and Palacios D and Zippo A and Bodega B and Oliva G and Lanzuolo C},

url = {https://rupress.org/jcb/article-lookup/doi/10.1083/jcb.201504035},

doi = {10.1083/jcb.201504035},

year  = {2015},

date = {2015-11-09},

journal = {Journal of Cell Biology},

volume = {211},

number = {3},

pages = {533-551},

abstract = {Beyond its role in providing structure to the nuclear envelope, lamin A/C is involved in transcriptional regulation. However, its cross talk with epigenetic factors-and how this cross talk influences physiological processes-is still unexplored. Key epigenetic regulators of development and differentiation are the Polycomb group (PcG) of proteins, organized in the nucleus as microscopically visible foci. Here, we show that lamin A/C is evolutionarily required for correct PcG protein nuclear compartmentalization. Confocal microscopy supported by new algorithms for image analysis reveals that lamin A/C knock-down leads to PcG protein foci disassembly and PcG protein dispersion. This causes detachment from chromatin and defects in PcG protein-mediated higher-order structures, thereby leading to impaired PcG protein repressive functions. Using myogenic differentiation as a model, we found that reduced levels of lamin A/C at the onset of differentiation led to an anticipation of the myogenic program because of an alteration of PcG protein-mediated transcriptional repression. Collectively, our results indicate that lamin A/C can modulate transcription through the regulation of PcG protein epigenetic factors. 2015 Cesarini et al.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_414,

title = {The novel influenza A virus protein PA-X and its naturally deleted variant show different enzymatic properties in comparison to the viral endonuclease PA.},

author = {Bavagnoli L and Cucuzza S and Campanini G and Rovida F and Paolucci S and Baldanti F and Maga G},

url = {https://academic.oup.com/nar/article/43/19/9405/2528196},

doi = {10.1093/nar/gkv926},

year  = {2015},

date = {2015-10-15},

journal = {Nucleic Acids Research},

volume = {43},

number = {19},

pages = {9405-9417},

abstract = {The PA protein of Influenza A virus (IAV) encoded by segment 3 acts as a specialized RNA endonuclease in the transcription of the viral genome. The same genomic segment encodes for a second shorter protein, termed PA-X, with the first 191 N-terminal aminoacids (aa) identical to PA, but with a completely different C-ter domain of 61 aa, due to a ribosomal frameshifting. In addition, it has been shown that several IAV isolates encode for a naturally truncated PA-X variant, PAXΔC20, missing the last 20 aa. The biochemical properties of PA-X and PAXΔC20 have been poorly investigated so far. Here, we have carried out an enzymatic characterization of PA-X and its naturally deleted form, in comparison with PA from the human IAV strain A/WSN/33 (H1N1). Our results showed, to the best of our knowledge for the first time, that PA-X possesses an endonucleolytic activity. Both PA and PA-X preferentially cut single stranded RNA regions, but with some differences. In addition, we showed that PAXΔC20 has severely reduced nuclease activity. These results point to a previously undetected role of the last C-ter 20 aa for the catalytic activity of PA-X and support distinct roles for these proteins in the viral life cycle. The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_411,

title = {The alternative splicing factor Nova2 regulates vascular development and lumen formation.},

author = {Giampietro C and Deflorian G and Gallo S and {Di Matteo A} and Pradella D and Bonomi S and Belloni E and Nyqvist D and Quaranta V and Confalonieri S and Bertalot G and Orsenigo F and Pisati F and Ferrero E and Biamonti G and Fredrickx E and Taveggia C and Wyatt CD and Irimia M and Di Fiore PP and Blencowe BJ and Dejana E and Ghigna C},

url = {https://www.nature.com/articles/ncomms9479},

doi = {10.1038/ncomms9479},

year  = {2015},

date = {2015-10-08},

urldate = {2015-10-08},

journal = {Nature communications},

volume = {6},

pages = {8479},

abstract = {Vascular lumen formation is a fundamental step during angiogenesis; yet, the molecular mechanisms underlying this process are poorly understood. Recent studies have shown that neural and vascular systems share common anatomical, functional and molecular similarities. Here we show that the organization of endothelial lumen is controlled at the post-transcriptional level by the alternative splicing (AS) regulator Nova2, which was previously considered to be neural cell-specific. Nova2 is expressed during angiogenesis and its depletion disrupts vascular lumen formation in vivo. Similarly, Nova2 depletion in cultured endothelial cells (ECs) impairs the apical distribution and the downstream signalling of the Par polarity complex, resulting in altered EC polarity, a process required for vascular lumen formation. These defects are linked to AS changes of Nova2 target exons affecting the Par complex and its regulators. Collectively, our results reveal that Nova2 functions as an AS regulator in angiogenesis and is a novel member of the 'angioneurins' family.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_364,

title = {Genome-wide association analysis on normal hearing function identifies PCDH20 and SLC28A3 as candidates for hearing function and loss.},

author = {Vuckovic D and Dawson S and Scheffer DI and Rantanen T and Morgan A and Di Stazio M and Vozzi D and Nutile T and Concas MP and Biino G and Nolan L and Bahl A and Loukola A and Viljanen A and Davis A and Ciullo M and Corey DP and Pirastu M and Gasparini P and Girotto G},

url = {https://academic.oup.com/hmg/article/24/19/5655/584102},

doi = {10.1093/hmg/ddv279},

year  = {2015},

date = {2015-10-01},

journal = {Human Molecular Genetics },

volume = {24},

number = {19},

pages = {5655-5664},

abstract = {Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium- and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E-10 and rs7032430, P = 2.39E-09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_391,

title = {Personalized reference intervals for platelet count reduce the number of subjects with unexplained thrombocytopenia.},

author = {Zaninetti C and Biino G and Noris P and Melazzini F and Civaschi E and Balduini CL},

url = {http://www.haematologica.org/content/100/9/e338.long},

doi = {10.3324/haematol.2015.127597},

year  = {2015},

date = {2015-09-26},

journal = {Haematologica},

volume = {100},

number = {9},

pages = {e338-340},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_317,

title = {Peri-Synaptic Glia Recycles Brain-Derived Neurotrophic Factor for LTP Stabilization and Memory Retention.},

author = {Vignoli B and Battistini G and Melani R and Blum R and Santi S and Berardi N and Canossa M},

url = {http://www.sciencedirect.com/science/article/pii/S0896627316306328},

doi = {10.1016/j.neuron.2016.09.031},

year  = {2015},

date = {2015-09-17},

journal = {Neuron},

volume = {92},

number = {4},

pages = {873-887},

abstract = {Glial cells respond to neuronal activation and release neuroactive molecules (termed "gliotransmitters") that can affect synaptic activity and modulate plasticity. In this study, we used molecular genetic tools, ultra-structural microscopy, and electrophysiology to assess the role of brain-derived neurotrophic factor (BDNF) on cortical gliotransmission in vivo. We find that glial cells recycle BDNF that was previously secreted by neurons as pro-neurotrophin following long-term potentiation (LTP)-inducing electrical stimulation. Upon BDNF glial recycling, we observed tight, temporal, highly localized TrkB phosphorylation on adjacent neurons, a process required to sustain LTP. Engagement of BDNF recycling by astrocytes represents a novel mechanism by which cortical synapses can expand BDNF action and provide synaptic changes that are relevant for the acquisition of new memories. Accordingly, mice deficient in BDNF glial recycling fail to recognize familiar from novel objects, indicating a physiological requirement for this process in memory consolidation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_380,

title = {Methods for genetic optimization of biocatalysts for biofuel production from dairy waste through synthetic biology.},

author = {Pasotti L and Zucca S and Casanova M and Politi N and Massaiu I and Mazzini G and Micoli G and Calvio C and Cusella De Angelis MG and Magni P},

url = {https://ieeexplore.ieee.org/document/7318521},

doi = {10.1109/EMBC.2015.7318521},

year  = {2015},

date = {2015-08-26},

journal = {Conference proceedings : Annual International Conference of the IEEE Engineering in Medicine and Biology Society.},

volume = {2015},

pages = {953-956},

abstract = {Whey is an abundant by-product of cheese production process and it is considered a special waste due to its high nutritional load and hypertrophic potential. Technologies for whey valorization are available. They can convert such waste into high-value products, like whey proteins. However, the remaining liquid (called permeate) is still considered as a polluting waste due to its high lactose concentration. The alcoholic fermentation of lactose into ethanol will simultaneously achieve two important goals: safe disposal of a pollutant waste and green energy production. This methodology paper illustrates the workflow carried out to design and realize an optimized microorganism that can efficiently perform the lactose-to-ethanol conversion, engineered via synthetic biology experimental and computational approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_376,

title = {Liposome-induced exfoliation of graphite to few-layer graphene dispersion with antibacterial activity.},

author = {Zappacosta R and {Di Giulio M} and Ettorre V and Bosco D and Hadad C and Siani G and Di Bartolomeo S and Cataldi A and Cellini L and Fontana A},

url = {https://pubs.rsc.org/en/content/articlelanding/2015/tb/c5tb00798d#!divAbstract},

doi = {10.1039/c5tb00798d},

year  = {2015},

date = {2015-08-21},

journal = {Journal of Materials Chemistry B},

volume = {3},

number = {31},

pages = {6520-6527},

abstract = {Few-layer graphene aqueous dispersions are obtained by exploiting liposomes as effective exfoliating agents for graphite. Raman measurements evidence the presence of non-oxidized double layer graphene as well as amphiphilic phospholipid molecules organized in bilayers in the samples. TEM analyses confirmed that the obtained homogeneous graphene nanosheets are embedded in the liposomal bilayer. The as-prepared graphene aqueous dispersion is stable for days and demonstrates significant antibacterial activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) strains, with a reduction in the growth of S. aureus and E. coli as high as 60 and 78%, respectively.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_403,

title = {Resection is responsible for loss of transcription around a double-strand break in Saccharomyces cerevisiae.},

author = {Manfrini N and Clerici M and Wery M and Colombo CV and Descrimes M and Morillon A and {d'Adda di Fagagna F} and Longhese MP},

url = {https://elifesciences.org/articles/08942},

doi = {10.7554/eLife.08942.},

year  = {2015},

date = {2015-07-31},

journal = {Elife},

volume = {4},

abstract = {Emerging evidence indicate that the mammalian checkpoint kinase ATM induces transcriptional silencing in cis to DNA double-strand breaks (DSBs) through a poorly understood mechanism. Here we show that in Saccharomyces cerevisiae a single DSB causes transcriptional inhibition of proximal genes independently of Tel1/ATM and Mec1/ATR. Since the DSB ends undergo nucleolytic degradation (resection) of their 5′-ending strands, we investigated the contribution of resection in this DSB-induced transcriptional inhibition. We discovered that resection-defective mutants fail to stop transcription around a DSB, and the extent of this failure correlates with the severity of the resection defect. Furthermore, Rad9 and generation of γH2A reduce this DSB-induced transcriptional inhibition by counteracting DSB resection. Therefore, the conversion of the DSB ends from double-stranded to single-stranded DNA, which is necessary to initiate DSB repair by homologous recombination, is responsible for loss of transcription around a DSB in S. cerevisiae.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_390,

title = {Osteogenic differentiation of human MSCs: Specific occupancy of the mitochondrial DNA by NFATc1 transcription factor.},

author = {Lambertini E and Penolazzi L and Morganti C and Lisignoli G and Zini N and Angelozzi M and Bonora M and Ferroni L and Pinton P and Zavan B and Piva R},

url = {https://www.sciencedirect.com/science/article/pii/S1357272515001120?via%3Dihub},

doi = {10.1016/j.biocel.2015.04.011},

year  = {2015},

date = {2015-07-29},

journal = {International Journal of Biochemistry & Cell Biology},

volume = {64},

pages = {212-219},

abstract = {A substantial body of evidence indicates that mitochondrial morphology and function change during osteogenic differentiation. However, molecular mechanisms linking mitochondrial dynamics with the regulation of osteoblast functions are poorly understood. Amongst the molecules that influence the decision of human mesenchymal stem cells (hMSCs) to become osteoblasts are Slug and NFATc1 transcription factors (TFs). These molecules also interfere with different mitochondria-dependent pathways in response to a variety of cellular demands. The present study investigated the recruitment of Slug and NFATc1 at the D-loop regulatory region of mitochondrial DNA (mtDNA) in osteogenic differentiated hMSCs with the aim of exploring whether Slug and NFATc1 also act as mitoTFs in the mitochondrial pool of nuclear TFs. The results demonstrate that NFATc1, but not Slug, is localized in the mitochondria. Using chromatin immunoprecipitation assay, we found that NFATc1 is recruited at mtDNA, but this occurs only when the calcification process is at its highest in osteo-induced MSC and the maximum level of differentiation is reached. Occupancy of the mtDNA by NFATc1 is associated with a decreased expression of crucial mitochondrial genes such as Cytochrome B and NADH dehydrogenase 1. This suggests that NFATc1 acts as a negative regulator of mtDNA transcription during the calcification process and interruption of aerobic energy demand. The finding of NFATc1 participation in osteogenic differentiation through its direct involvement in the regulatory machinery of mitochondria suggests a new role for this TF and adds information on communication between mitochondrial and nuclear genomes. Copyright © 2015 Elsevier Ltd. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_371,

title = {Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species.},

author = {Baglio SR and Rooijers K and Koppers-Lalic D and Verweij FJ and Perez Lanzon M and Zini N and Naaijkens B and Perut F and Niessen HW and Baldini N and Pegtel DM},

url = {https://stemcellres.biomedcentral.com/articles/10.1186/s13287-015-0116-z},

doi = {10.1186/s13287-015-0116-z},

year  = {2015},

date = {2015-07-01},

journal = {Stem Cell Research & Therapy},

volume = {6},

pages = {127},

abstract = {INTRODUCTION: Administration of mesenchymal stem cells (MSCs) represents a promising treatment option for patients suffering from immunological and degenerative disorders. Accumulating evidence indicates that the healing effects of MSCs are mainly related to unique paracrine properties, opening opportunities for secretome-based therapies. Apart from soluble factors, MSCs release functional small RNAs via extracellular vesicles (EVs) that seem to convey essential features of MSCs. Here we set out to characterize the full small RNAome of MSC-produced exosomes. METHODS: We set up a protocol for isolating exosomes released by early passage adipose- (ASC) and bone marrow-MSCs (BMSC) and characterized them via electron microscopy, protein analysis and small RNA-sequencing. We developed a bioinformatics pipeline to define the exosome-enclosed RNA species and performed the first complete small RNA characterization of BMSCs and ASCs and their corresponding exosomes in biological replicates. RESULTS: Our analysis revealed that primary ASCs and BMSCs have highly similar small RNA expression profiles dominated by miRNAs and snoRNAs (together 64-71 %), of which 150-200 miRNAs are present at physiological levels. In contrast, the miRNA pool in MSC exosomes is only 2-5 % of the total small RNAome and is dominated by a minor subset of miRNAs. Nevertheless, the miRNAs in exosomes do not merely reflect the cellular content and a defined set of miRNAs are overrepresented in exosomes compared to the cell of origin. Moreover, multiple highly expressed miRNAs are precluded from exosomal sorting, consistent with the notion that these miRNAs are involved in functional repression of RNA targets. While ASC and BMSC exosomes are similar in RNA class distribution and composition, we observed striking differences in the sorting of evolutionary conserved tRNA species that seems associated with the differentiation status of MSCs, as defined by Sox2, POU5F1A/B and Nanog expression. CONCLUSIONS: We demonstrate that primary MSCs release small RNAs via exosomes, which are increasingly implicated in intercellular communications. tRNAs species, and in particular tRNA halves, are preferentially released and their specific sorting into exosomes is related to MSC tissue origin and stemness. These findings may help to understand how MSCs impact neighboring or distant cells with possible consequences for their therapeutic usage.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_378,

title = {Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression.},

author = {Nahta R and Al-Mulla F and Al-Temaimi R and Amedei A and Andrade-Vieira R and Bay S and G Brown D and Calaf GM and Castellino RC and Cohen-Solal KA and Colacci A and Cruickshanks N and Dent P and Di Fiore R and Forte S and Goldberg GS and Hamid RA and Krishnan H and Laird DW and Lasfar A and Marignani PA and Memeo L and Mondello C and Naus CC and Ponce-Cusi R and Raju J and Roy D and Roy R and P Ryan E and Salem HK and Scovassi AI and Singh N and Vaccari M and Vento R and Vondracek J and Wade M and Woodrick J and Bisson WH},

url = {https://academic.oup.com/carcin/article/36/Suppl_1/S2/310663},

doi = {10.1093/carcin/bgv028},

year  = {2015},

date = {2015-06-30},

journal = {Carcinogenesis},

volume = {36},

number = {Suppl. 1},

pages = {S2-18},

abstract = {As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks. The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_397,

title = {Probing the factor structure of metabolic syndrome in Sardinian genetic isolates.},

author = {Graziano F and Grassi M and Sacco S and Concas MP and Vaccargiu S and Pirastu M and Biino G},

url = {https://www.sciencedirect.com/science/article/pii/S0939475315000472?via%3Dihub},

doi = {10.1016/j.numecd.2015.02.004},

year  = {2015},

date = {2015-06-26},

journal = {Nutrition, Metabolism, and Cardiovascular Diseases : Nmcd. Letter To Editor},

volume = {25},

pages = {548-555},

abstract = {BACKGROUND AND AIMS: Owing to the multiplicity of the key components of metabolic syndrome (MetS), its diagnosis is very complex. The lack of a unique definition is responsible for the prevalence variability observed among studies; therefore, a definition based on continuous variables was recommended. The aim of this study was to compare competing models of the MetS factor structure for selecting the one that explains the best clustering pattern and to propose an algorithm for computing MetS as a continuous variable. METHODS AND RESULTS: Data were from isolated Sardinian populations (n = 8102). Confirmatory factor analysis (CFA) and two-group CFA by gender were performed to evaluate the sex-specific factor structure of MetS. After selecting the best model, an algorithm was obtained using factor loadings/residual variances. The quality of the MetS score was evaluated by the receiver operating characteristics curve and the area under the curve. Cross-validation was performed to validate the score and to determine the best cut point. The best fit model was a bifactor one with a general factor (MetS) and three specific factors (f1: obesity/adiposity trait; f2: hypertension/blood pressure trait; and f3: lipid trait). Gender-specific algorithms were implemented to obtain MetS scores showing a good diagnostic performance (0.80 specificity and 0.80 sensitivity for the cut point). Furthermore, cross-validation confirmed these results. CONCLUSION: These analyses suggested that the bifactor model was the most representative one. In addition, they provided a score and a cut point that are both clinically accessible and interpretable measures for MetS diagnosis and likely useful for evaluating the association with adverse cardiovascular disease and diabetes and for investigating the MetS genetic component.Copyright © 2015 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_369,

title = {hnRNP L inhibits CD44 V10 exon splicing through interacting with its upstream intron},

author = {Loh TJ and Cho S and Moon H and Jang HN and Williams DR and Jung DW and Kim IC and Ghigna C and Biamonti G and Zheng X and Shen H},

url = {https://www.sciencedirect.com/science/article/pii/S1874939915000413?via%3Dihub},

doi = {10.1016/j.bbagrm.2015.01.004},

year  = {2015},

date = {2015-06-25},

journal = {Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms},

volume = {1849},

number = {6},

pages = {743-750},

abstract = {CD44 is a complex cell adhesion molecule that mediates communication and adhesion between adjacent cells as well as between cells and the extracellular matrix. CD44 pre-mRNA produces various mRNA isoforms through alternative splicing of 20 exons, among which exons 1-5 (C1-C5) and 16-20 (C6-C10) are constant exons, whereas exons 6-15 (V1-V10) are variant exons. CD44 V10 exon has important roles in breast tumor progression and Hodgkin lymphoma. Here we show that increased expression of hnRNP L inhibits V10 exon splicing of CD44 pre-mRNA, whereas reduced expression of hnRNP L promotes V10 exon splicing. In addition, hnRNP L also promotes V10 splicing of endogenous CD44 pre-mRNA. Through mutation analysis, we demonstrate that the effects of hnRNP L on V10 splicing are abolished when the CA-rich sequence on the upstream intron of V10 exon is disrupted. However, hnRNP L effects are stronger if more CA-repeats are provided. Furthermore, we show that hnRNP L directly contacts the CA-rich sequence. Importantly, we provide evidences that hnRNP L inhibits U2AF65 binding on the upstream Py tract of V10 exon. Our results reveal that hnRNP L is a new regulator for CD44 V10 exon splicing. Copyright  2015 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_413,

title = {The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis.},

author = {Ochieng J and Nangami GN and Ogunkua O and Miousse IR and Koturbash I and Odero-Marah V and McCawley L and Nangia-Makker P and Ahmed N and Luqmani Y and Chen Z and Papagerakis S and Wolf GT and Dong C and Zhou BP and Brown DG and Colacci A and Hamid RA and Mondello C and Raju J and Ryan EP and Woodrick J and Scovassi AI and Singh N and Vaccari M and Roy R and Forte S and Memeo L and Salem HK and Amedei A and Al-Temaimi R and Al-Mulla F and Bisson WH and Eltom SE},

url = {https://academic.oup.com/carcin/article/36/Suppl_1/S128/313982},

doi = {10.1093/carcin/bgv034},

year  = {2015},

date = {2015-06-19},

urldate = {2015-06-19},

journal = {Carcinogenesis},

volume = {36},

number = {Suppl. 1},

pages = {S128-159},

abstract = {The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis. The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_415,

title = {The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling.},

author = {Engstrom W and Darbre P and Eriksson S and Gulliver L and Hultman T and Karamouzis MV and Klaunig JE and Mehta R and Moorwood K and Sanderson T and Sone H and Vadgama P and Wagemaker G and Ward A and Singh N and Al-Mulla F and Al-Temaimi R and Amedei A and Colacci AM and Vaccari M and Mondello C and Scovassi AI and Raju J and Hamid RA and Memeo L and Forte S and Roy R and Woodrick J and Salem HK and Ryan E and Brown DG and Bisson WH},

url = {https://academic.oup.com/carcin/article/36/Suppl_1/S38/311505},

doi = {10.1093/carcin/bgv030},

year  = {2015},

date = {2015-06-12},

urldate = {2015-06-12},

journal = {Carcinogenesis},

volume = {36},

number = {Suppl. 1},

pages = {S38-60},

abstract = {The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_419,

title = {Studies on the ATP Binding Site of Fyn Kinase for the Identification of New Inhibitors and Their Evaluation as Potential Agents against Tauopathies and Tumors.},

author = {Tintori C and La Sala G and Vignaroli G and Botta L and Fallacara AL and Falchi F and Radi M and Zamperini C and Dreassi E and Dello Iacono L and Orioli D and Biamonti G and Garbelli M and Lossani A and Gasparrini F and Tuccinardi T and Laurenzana I and Angelucci A and Maga G and Schenone S and Brullo C and Musumeci F and Desogus A and Crespan E and Botta M},

url = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00140},

doi = {10.1021/acs.jmedchem.5b00140},

year  = {2015},

date = {2015-06-11},

journal = {Journal of Medicinal Chemistry},

volume = {58},

number = {11},

pages = {4590-4609},

abstract = {Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K(i) of about 2 μM, while derivative 4a, derived from our internal library, showed a K(i) of 0.9 μM. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 4d having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}