Bonetti D.,University of Milan Bicocca
PLoS genetics | Year: 2010
Eukaryotic cells distinguish their chromosome ends from accidental DNA double-strand breaks (DSBs) by packaging them into protective structures called telomeres that prevent DNA repair/recombination activities. Here we investigate the role of key telomeric proteins in protecting budding yeast telomeres from degradation. We show that the Saccharomyces cerevisiae shelterin-like proteins Rif1, Rif2, and Rap1 inhibit nucleolytic processing at both de novo and native telomeres during G1 and G2 cell cycle phases, with Rif2 and Rap1 showing the strongest effects. Also Yku prevents telomere resection in G1, independently of its role in non-homologous end joining. Yku and the shelterin-like proteins have additive effects in inhibiting DNA degradation at G1 de novo telomeres, where Yku plays the major role in preventing initiation, whereas Rif1, Rif2, and Rap1 act primarily by limiting extensive resection. In fact, exonucleolytic degradation of a de novo telomere is more efficient in yku70Delta than in rif2Delta G1 cells, but generation of ssDNA in Yku-lacking cells is limited to DNA regions close to the telomere tip. This limited processing is due to the inhibitory action of Rap1, Rif1, and Rif2, as their inactivation allows extensive telomere resection not only in wild-type but also in yku70Delta G1 cells. Finally, Rap1 and Rif2 prevent telomere degradation by inhibiting MRX access to telomeres, which are also protected from the Exo1 nuclease by Yku. Thus, chromosome end degradation is controlled by telomeric proteins that specifically inhibit the action of different nucleases.
Gambacorti Passerini C.,University of Milan Bicocca
Journal of the National Cancer Institute | Year: 2014
Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.
Pacchioni G.,University of Milan Bicocca
Chemistry - A European Journal | Year: 2012
The last decade has seen spectacular progress in the design, preparation, and characterization down to the atomic scale of oxide ultrathin films of few nanometers thickness grown on a different material. This has paved the way towards several sophisticated applications in advanced technologies. By playing around with the low-dimensionality of the oxide layer, which sometimes leads to truly two-dimensional systems, one can exploit new properties and functionalities that are not present in the corresponding bulk materials or thick films. In this review we provide some clues about the most recent advances in the design of these systems based on modern electronic structure theory and on their preparation and characterization with specifically developed growth techniques and analytical methods. We show how two-dimensional oxides can be used in mature technologies by providing added value to existing materials, or in new technologies based on completely new paradigms. The fields in which two-dimensional oxides are used are classified based on the properties that are exploited, chemical or physical. With respect to chemical properties we discuss use of oxide ultrathin films in catalysis, solid oxide fuel cells, gas sensors, corrosion protection, and biocompatible materials; regarding the physical properties we discuss metal-oxide field effect transistors and memristors, spintronic devices, ferroelectrics and thermoelectrics, and solar energy materials. Oxide ultrathin films: Currently, it is possible to prepare oxide films with a thickness of a few nanometers. By playing around with the low-dimensionality of the oxide layer (see figure), one can exploit new properties and functionalities that are not present in the corresponding bulk materials. The applications range from catalysis, fuel cells, gas sensors, corrosion protection, and biocompatible materials to microelectronic and spintronic devices, ferroelectrics, thermoelectrics, and solar energy materials. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Becchetti A.,University of Milan Bicocca
American Journal of Physiology - Cell Physiology | Year: 2011
Progress through the cell mitoticcycle requires precise timing of the intrinsic molecular steps and tightcoordination with the environmental signals that maintain a cell intothe proper physiological context. Because of their great functionalflexibility, ion channels coordinate the upstream and downstreamsignals that converge on the cell cycle machinery. Both voltage- andligand-gated channels have been implicated in the control of differentcell cycle checkpoints in normal as well as neoplastic cells. Ionchannels mediate the calcium signals that punctuate the mitoticprocess, the cell volume oscillations typical of cycling cells, and theexocytosis of autocrine or angiogenetic factors. Other functions of ionchannels in proliferation are still matter of debate. These may or maynot depend on ion transport, as the channel proteins can form macromolecularcomplexes with growth factor and cell adhesion receptors.Direct conformational coupling with the cytoplasmic regulatoryproteins is also possible. Derangement or relaxed control of the aboveprocesses can promote neoplasia. Specific types of ion channels haveturned out to participate in the different stages of the tumor progression,in which cell heterogeneity is increased by the selection ofmalignant cell clones expressing the ion channel types that bettersupport unrestrained growth. However, a comprehensive mechanisticpicture of the functional relations between ion channels and cellproliferation is yet not available, partly because of the considerableexperimental challenges offered by studying these processes in livingmammalian cells. No doubt, such studies will constitute one of themost fruitful research fields for the next generation of cell physiologists. © 2011 the American Physiological Society.
Pacchioni G.,University of Milan Bicocca
ACS Catalysis | Year: 2014
Carboxylic acids play a fundamental role in the transformation of biomass into liquid fuels and other useful chemicals. In order to reduce the O/C content of biofuels, carboxylic acids need to be decomposed by decarboxylation, dehydroxylation, or decarbonylation unimolecular reactions, or they need to be converted into ketones via complex bimolecular reaction mechanisms. Ketonization, that is, the transformation of carboxylic acids into ketones, carbon dioxide, and water, is promoted by heterogeneous catalysts based on oxide materials. Among the most active catalysts are titania and zirconia surfaces. In recent years, a large body of experimental data has been complemented by specific investigations performed with first-principles electronic structure calculations based on density functional theory (DFT). In this review, I discuss the present level of understanding of the bonding modes of carboxylic acids (acetic acid in particular) on the TiO2 and ZrO2 surfaces as obtained from DFT calculations. Enolization and ketonization reaction mechanisms determined at the DFT level on TiO2 and ZrO2 surfaces are also discussed, and the results are analyzed in view of the experimental evidence. Finally, the role of supported metal particles, of the redox properties of the oxide catalyst, and the nature of the active sites on the surface of titania and zirconia are discussed. © 2014 American Chemical Society.