Viral tumor cell killing and the host immunologic response it engenders produce potent, lasting antineoplastic effects in animal tumor models. Clinical application of this principle depends on unequivocal Bromosporine cost demonstration of safety in primate models for paralytic poliomyelitis. We conducted extensive dose-range-finding, toxicity, biodistribution, shedding, and neutralizing antibody studies of the prototype oncolytic poliovirus recombinant, PVS-RIPO, after intrathalamic inoculation in Macaca fascicularis. These studies suggest that intracerebral PVS-RIPO inoculation does not lead to viral propagation
in the central nervous system (CNS), does not cause histopathological CNS lesions or neurological symptoms that can be attributed to the virus, is not associated with extraneural virus dissemination or replication and does not induce shedding of virus with stool. Intrathalamic PVS-RIPO inoculation induced neutralizing antibody responses against poliovirus serotype 1 in all animals studied.”
“The human CHRNA5 D398N polymorphism (rs16969968) causes an aspartic acid to asparagine change in the nicotinic acetylcholine receptor (nAChR) alpha 5 subunit gene. The N398 variant of CHRNA5 is linked to increased
risk for nicotine dependence. In this study, we explored the effect of the CHRNA5 D398N polymorphism on the properties of human alpha 3 beta 4* nicotinic acetylcholine receptors in human embryonic kidney (HEK) cells.
Addition of either D398 or N398 variant of alpha 5 subunit in the alpha 3 TGF-beta/Smad inhibitor beta 4* receptor did not affect total [I-125]-epibatidine binding or surface expression of the receptor. However, addition of alpha 5(D398) into alpha 3 beta 4* receptor decreased the maximal response to agonist without significantly affecting EC50 in aequorin intracellular
calcium assay. alpha 3 beta 4 alpha 5(N398) nAChRs showed further decreased maximal response. The differences in agonist efficacy between the receptor subtypes were found to be dependent upon the concentration of external calcium but independent of external sodium. Moreover, activation of alpha 3 beta 4 alpha 5 nAChRs led to significantly greater intracellular calcium release from IP3 stores relative www.selleck.cn/products/pf-477736.html to alpha 3 beta 4 nAChRs although no effect of the alpha 5 polymorphism was observed. Finally, inclusion of the alpha 5 variant caused a small shift to the left in IC50 for some of the antagonists tested, depending upon alpha 5 variant but did not affect sensitivity of alpha 3 beta 4* receptors to desensitization in response to incubation with nicotine.
In conclusion, addition of either variant of alpha 5 into an alpha 3 beta 4 alpha 5 receptor similarly effects receptor pharmacology and function. However, the N398 variant exhibits a reduced response to agonists when extracellular calcium is high and it may lead to distinct downstream cellular signaling. (C) 2012 Elsevier Ltd. All rights reserved.