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111.
112.
Sergio Valente Ilaria Lepore Carmela Dell'Aversana Maria Tardugno Sabrina Castellano Gianluca Sbardella Stefano Tomassi Salvatore Di Maro Ettore Novellino Roberto Di Santo Roberta Costi Lucia Altucci Antonello Mai 《Biochimie》2012
Chemical manipulations undertaken on some bis(bromo- and dibromo-phenol) compounds previously reported by us as wide-spectrum epigenetic inhibitors let us to identify bis (bromo- and dibromo-methoxyphenyl) derivatives highly selective for PR-SET7 and EZH2 (compounds 4, 5, 9, and 10). Western blot analyses were carried out in U937 cells to determine the effects of such compounds on the methyl marks related to the tested enzymes (H3K4me1, H3K9me2, H4H20me1, and H3K27me3). The 1,5-bis(3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one 4 (EC50 vs EZH2 = 74.9 μM), tested in U937 cells at 50 μM, induced massive cell death and 28% of granulocytic differentiation, highlighting the potential use of EZH2 inhibitors in cancer. 相似文献
113.
The mainstream approaches to the study of speciation and clade diversification have extensively focused on genetic mechanisms and ecological contexts, while much less attention has been paid to the role of development. In this paper we provide materials to support the thesis that taking development into the picture of evolutionary processes can bring important insights on how species multiply and diversify. Evidence that developmentally entangled evolutionary factors are important in speciation comes from different lines of investigation that can be broadly grouped under three headings: evolvability, phenotypic plasticity, and phenology. Evolvability enters the scene through the complexity of the genotype-phenotype map, the developmental link between transmissible genetic information and selectable phenotypes. Phenotypic plasticity can act as a facilitator for speciation, promoting diversification at different stages of the speciation process, as well as generating novel targets and novel trade-offs for evolutionary processes. The formal inclusion of the developmental time axis in speciation models widens the scope for investigating the onset and/or reinforcement of reproductive barriers through a range of situations along an organism??s life cycle. Overall, developmental processes can contribute to speciation and diversification at different stages of the speciation process, at different levels of biological organization and along the organism??s whole life cycle. 相似文献
114.
Pothier J Riederer MA Peter O Leroy X Valdenaire A Gnerre C Fretz H 《Bioorganic & medicinal chemistry letters》2012,22(14):4660-4664
Hit-to-lead evolution of 2-(2-((2-(4-chlorophenoxy)ethyl)thio)-1H-benzo[d]imidazol-1-yl)acetic acid (1), discovered in a high-throughput screening campaign as a novel chemotype of CRTh2 receptor antagonist, is presented. SAR development as well as in vitro and in vivo DMPK properties of selected representatives of substituted 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids are discussed. 相似文献
115.
Yong He Jing Li Nin Yin Prudencio S. Herradura Larry Martel Yanzhi Zhang Andre L. Pearson Vidya Kulkarni Carmela Mascio Karen Howland Jared A. Silverman Dennis D. Keith Chester A. Metcalf 《Bioorganic & medicinal chemistry letters》2012,22(19):6248-6251
Daptomycin was shown to interact in vitro with pulmonary surfactant leading to reduction of its antibacterial activity. We report herein the preparation and anti-staphylococcal activity of a series of daptomycin analogs with reduced pulmonary surfactant interaction by replacing tryptophan with various amino acids. 相似文献
116.
Milena Sant Pamela Minicozzi Claudia Allemani Claudia Cirilli Massimo Federico Riccardo Capocaccia Mario Budroni Pina Candela Emanuele Crocetti Fabio Falcini Stefano Ferretti Mario Fusco Adriano Giacomin Francesco La Rosa Lucia Mangone Maurilio Natali Maurizio Ponz De Leon Adele Traina Rosario Tumino Paola Zambon 《Cancer epidemiology》2012,36(6):541-547
BackgroundPopulation-based cancer registry studies of care patterns can help elucidate reasons for the marked geographic variation in cancer survival across Italy. The article provides a snapshot of the care delivered to cancer patients in Italy.MethodsRandom samples of adult patients with skin melanoma, breast, colon and non-small cell lung cancers diagnosed in 2003–2005 were selected from 14 Italian cancer registries. Logistic models estimated odds of receiving standard care (conservative surgery plus radiotherapy for early breast cancer; surgery plus chemotherapy for Dukes C colon cancer; surgery for lung cancer; sentinel node biopsy for >1 mm melanoma, vs. other treatment) in each registry compared to the entire sample (reference).ResultsStage at diagnosis for breast, colon and melanoma was earlier in north/central than southern registries. Odds of receiving standard care were lower than reference in Sassari (0.68, 95%CI 0.51–0.90) and Napoli (0.48, 95%CI 0.35–0.67) for breast cancer; did not differ across registries for Dukes C colon cancer; were higher in Romagna (3.77, 95%CI 1.67–8.50) and lower in Biella (0.38, 95%CI 0.18–0.82) for lung cancer; and were higher in Reggio Emilia (2.37, 95%CI 1.12–5.02) and lower in Ragusa (0.27, 95%CI 0.14–0.54) for melanoma.ConclusionsNotwithstanding limitations due to variations in the availability of clinical information and differences in stage distribution between north/central and southern registries, our study shows that important disparities in cancer care persist across Italy. Thus the public health priority of reducing cancer survival disparities will not be achieved in the immediate future. 相似文献
117.
Barba M Sobolev AP Zobnina V Bonaccorsi di Patti MC Cervoni L Spiezia MC Schininà ME Pietraforte D Mannina L Musci G Polticelli F 《PloS one》2012,7(2):e30739
Highly stable natural scaffolds which tolerate multiple amino acid substitutions represent the ideal starting point for the application of rational redesign strategies to develop new catalysts of potential biomedical and biotechnological interest. The knottins family of disulphide-constrained peptides display the desired characteristics, being highly stable and characterized by hypervariability of the inter-cysteine loops. The potential of knottins as scaffolds for the design of novel copper-based biocatalysts has been tested by engineering a metal binding site on two different variants of an ω-conotoxin, a neurotoxic peptide belonging to the knottins family. The binding site has been designed by computational modelling and the redesigned peptides have been synthesized and characterized by optical, fluorescence, electron spin resonance and nuclear magnetic resonance spectroscopy. The novel peptides, named Cupricyclin-1 and -2, bind one Cu(2+) ion per molecule with nanomolar affinity. Cupricyclins display redox activity and catalyze the dismutation of superoxide anions with an activity comparable to that of non-peptidic superoxide dismutase mimics. We thus propose knottins as a novel scaffold for the design of catalytically-active mini metalloproteins. 相似文献
118.
Bernasconi R Galli C Noack J Bianchi S de Haan CA Reggiori F Molinari M 《Molecular cell》2012,46(6):809-819
Several regulators of endoplasmic reticulum (ER)-associated degradation (ERAD) have a shorter half-life compared to conventional ER chaperones. At steady state, they are selectively removed from the ER by poorly defined events collectively referred to as ERAD tuning. Here we identify the complex comprising the type-I transmembrane protein SEL1L and the cytosolic protein LC3-I as an ERAD tuning receptor regulating the COPII-independent, vesicle-mediated removal of the lumenal ERAD regulators EDEM1 and OS-9 from the ER. Expression of?folding-defective polypeptides enhances the lumenal content of EDEM1 and OS-9 by inhibiting their SEL1L:LC3-I-mediated segregation. This raises ERAD activity in the absence of UPR-induction. The mouse hepatitis virus (MHV) subverts ERAD tuning for replication. Consistently, SEL1L or LC3 silencing impair the MHV life cycle. Collectively, our data provide new molecular information about the ERAD tuning mechanisms that regulate ERAD in mammalian cells at the post translational level and how these mechanisms are hijacked by a pathogen. 相似文献
119.
120.
Adriana Cordova Francesca Toia Carmela La Mendola Valentina Orlando Serena Meraviglia Gaetana Rinaldi Matilde Todaro Giuseppe Cicero Leonardo Zichichi Paolo Li Donni Nadia Caccamo Giorgio Stassi Francesco Dieli Francesco Moschella 《PloS one》2012,7(11)
T lymphocytes are often induced naturally in melanoma patients and infiltrate tumors. Given that γδ T cells mediate antigen-specific killing of tumor cells, we studied the representation and the in vitro cytokine production and cytotoxic activity of tumor infiltrating γδ T cells from 74 patients with primary melanoma. We found that γδ T cells represent the major lymphocyte population infiltrating melanoma, and both Vδ1+ and Vδ2+ cells are involved. The majority of melanoma-infiltrating γδ cells showed effector memory and terminally-differentiated phenotypes and, accordingly, polyclonal γδ T cell lines obtained from tumor-infiltrating immune cells produced IFN-γ and TNF-α and were capable of killing melanoma cell lines in vitro. The cytotoxic capability of Vδ2 cell lines was further improved by pre-treatment of tumor target cells with zoledronate. Moreover, higher rate of γδ T cells isolation and percentages of Vδ2 cells correlate with early stage of development of melanoma and absence of metastasis. Altogether, our results suggest that a natural immune response mediated by γδ T lymphocytes may contribute to the immunosurveillance of melanoma. 相似文献