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991.
992.
Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration 总被引:20,自引:0,他引:20
Montini E Cesana D Schmidt M Sanvito F Ponzoni M Bartholomae C Sergi Sergi L Benedicenti F Ambrosi A Di Serio C Doglioni C von Kalle C Naldini L 《Nature biotechnology》2006,24(6):687-696
Insertional mutagenesis represents a major hurdle to gene therapy and necessitates sensitive preclinical genotoxicity assays. Cdkn2a-/- mice are susceptible to a broad range of cancer-triggering genetic lesions. We exploited hematopoietic stem cells from these tumor-prone mice to assess the oncogenicity of prototypical retroviral and lentiviral vectors. We transduced hematopoietic stem cells in matched clinically relevant conditions, and compared integration site selection and tumor development in transplanted mice. Retroviral vectors triggered dose-dependent acceleration of tumor onset contingent on long terminal repeat activity. Insertions at oncogenes and cell-cycle genes were enriched in early-onset tumors, indicating cooperation in tumorigenesis. In contrast, tumorigenesis was unaffected by lentiviral vectors and did not enrich for specific integrants, despite the higher integration load and robust expression of lentiviral vectors in all hematopoietic lineages. Our results validate a much-needed platform to assess vector safety and provide direct evidence that prototypical lentiviral vectors have low oncogenic potential, highlighting a major rationale for application to gene therapy. 相似文献
993.
994.
Carmi C Cavazzoni A Zuliani V Lodola A Bordi F Plazzi PV Alfieri RR Petronini PG Mor M 《Bioorganic & medicinal chemistry letters》2006,16(15):4021-4025
A series of 1,5-disubstituted hydantoins, whose structure was designed to interact at the ATP-binding site of EGFR, was synthesized and evaluated for inhibition of EGFR kinase activity and antiproliferative action. Some of these compounds, characterized by a 1-phenethyl and a 5-(E)-benzylidene substituent, inhibited EGFR autophosphorylation and polyGAT phosphorylation, and also inhibited the growth and proliferation of human A431 cells, which overexpress EGFR. These compounds can therefore be regarded as examples of a new scaffold for tyrosine kinase inhibitors. 相似文献
995.
Morini G Comini M Rivara M Rivara S Lorenzi S Bordi F Mor M Flammini L Bertoni S Ballabeni V Barocelli E Plazzi PV 《Bioorganic & medicinal chemistry letters》2006,16(15):4063-4067
A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a biphenyl fragment. Modulation of the distance between the two amine groups, and of their alkyl substituents, was driven by superposition of molecular models and docking into a receptor model, resulting in the identification of 1,1'-[biphenyl-4,4'-diylbis(methylene)]bis-piperidine (5) as a subtype-selective H3 antagonist with high binding affinity (pKi=9.47) at human H3 histamine receptor. 相似文献
996.
Notch1b and neuregulin are required for specification of central cardiac conduction tissue 总被引:4,自引:0,他引:4
Milan DJ Giokas AC Serluca FC Peterson RT MacRae CA 《Development (Cambridge, England)》2006,133(6):1125-1132
Normal heart function is critically dependent on the timing and coordination provided by a complex network of specialized cells: the cardiac conduction system. We have employed functional assays in zebrafish to explore early steps in the patterning of the conduction system that previously have been inaccessible. We demonstrate that a ring of atrioventricular conduction tissue develops at 40 hours post-fertilization in the zebrafish heart. Analysis of the mutant cloche reveals a requirement for endocardial signals in the formation of this tissue. The differentiation of these specialized cells, unlike that of adjacent endocardial cushions and valves, is not dependent on blood flow or cardiac contraction. Finally, both neuregulin and notch1b are necessary for the development of atrioventricular conduction tissue. These results are the first demonstration of the endocardial signals required for patterning central ;slow' conduction tissue, and they reveal the operation of distinct local endocardial-myocardial interactions within the developing heart tube. 相似文献
997.
Razzoli M Roncari E Guidi A Carboni L Arban R Gerrard P Bacchi F 《Hormones and behavior》2006,50(2):245-251
To develop a socially based model of anxiety, the contextual fear conditioning properties of social defeat were examined in rats. Social threat consisted of exposing intruders to aggressive residents in resident home cage, separated by a partition. During 3 daily encounters, intruders were either defeated or threatened by residents, providing the defeated-threatened (DT) and threatened-threatened (TT) groups respectively. On Day 4, both DT and TT animals were subjected to a social threat only. Additional animals received a 4-day exposure to a novel empty cage (EC group). Further DT, TT, and EC rats were confronted to a different context on Day 4. DT rats exhibited a robust and context-specific anxiety-like response, characterized by significant behavioral and biochemical alterations. DT rats showed increased risk assessment and decreased exploration compared to TT and EC rats that in turn were not different towards each other. DT and TT rats exhibited increased ACTH levels, while only DT rats showed enhanced corticosterone and decreased testosterone levels compared to EC. These differences were context-specific since they were absent confronting animals to a different context and since they were not long lasting. Overall, these data demonstrate the induction of an anxiety-like state in rats through a context conditioning process based upon social factors. The social basis of this paradigm offers good face validity with anxiety disorders, which in humans are mainly related to social factors and associated with HPA axis deregulations. The present procedure may provide a useful experimental model to further investigate the neurobiological mechanisms underlying anxiety-related disorders. 相似文献
998.
Giampietri C Petrungaro S Coluccia P Antonangeli F Paone A Padula F De Cesaris P Ziparo E Filippini A 《FEBS letters》2006,580(26):6109-6114
Apoptosis represents a fundamental process during fetal/post-natal testis development. Therefore pro- and anti-apoptotic proteins are essential to regulate testis physiology. c-Flip(L) is a known inhibitor of caspase 8/10 activity; in this study its perinatal expression in mouse male germ cells was investigated. In testis sections and seminiferous tubule whole mount c-Flip(L) was found to be expressed in undifferentiated spermatogonia and to co-localize with germ stem cells markers. In vivo investigations in the vitamin-A deficient mouse, lacking differentiated germ cells, confirmed c-Flip(L) expression in undifferentiated spermatogonia. Further analyses showed Fas expression but no significant caspase 8/10 activity when c-Flip(L) was highly expressed. Altogether these data suggest that c-Flip may control the survival rate of undifferentiated spermatogonia. 相似文献
999.
The P2Y4 receptor forms homo-oligomeric complexes in several CNS and PNS neuronal cells 总被引:2,自引:1,他引:1
D'Ambrosi N Iafrate M Vacca F Amadio S Tozzi A Mercuri NB Volonté C 《Purinergic signalling》2006,2(4):575-582
It is well established that several cell surface receptors interact with each other to form dimers and oligomers, which are essential for their activation. Since little is known about the quaternary structure of P2Y receptors, in the present work, we investigated the expression of the G-protein-coupled P2Y4 subunit as monomeric or higher-order complex protein. We examined both endogenously expressed P2Y4 subtype with the aid of specific anti-P2Y4 antiserum, and heterologously transfected P2Y4-tagged receptors with the use of antitag antibodies. In both cases, we found the P2Y4 receptor displaying molecular masses corresponding to monomeric, dimeric and oligomeric structures. Experiments performed in the absence of reducing agents demonstrated that there is a strict correlation among the multiple protein bands and that the multimeric forms are at least partially assembled by disulphide bonds. The direct demonstration of P2Y4 homodimerisation comes instead from co–transfection and differential co–immunoprecipitation experiments, with the use of differently tagged P2Y4 receptors and antitag antibodies. The structural propensity of the P2Y4 protein to form homo-oligomers may open the possibility of a novel regulatory mechanism of physiopathological functions for this and additional P2Y receptors. 相似文献
1000.
Laura Corte Paolo Rellini Monia Lattanzi Cristina Picchetta Fabrizio Fatichenti Gianluigi Cardinali 《Annals of microbiology》2006,56(4):363-368
Forty-two yeast strains from 27 species belonging to seven genera, selected for their ability to grow in 10% NaCl, have been analysed for their resistance to salt concentrations up to 5 M, by calculating the Minimum Inhibitory Concentrations (MIC). Using eight different NaCl concentrations from 0 to 5M, results show that halotolerance (MIC) ranges from 1.7 to 3.8 M NaCl, with an avera ge around 2.5 M and confirm that the most halotolerant strains belong to the speciesDebaryomyces hansenii. Since a real halophily could not be found in these isolates, and is generally questioned to be present among the yeast, the effects of NaCl has been measured as salt enhancement effect on growth (MSE), which is defined as the rate between the growth at a given NaCl concentration and theowth in the medium without addition of salt. The implications of these findings in food microbial ecology and technology are discussed. 相似文献