排序方式: 共有46条查询结果,搜索用时 15 毫秒
21.
Plasmid vectors encoding cholera toxin or the heat-labile enterotoxin from Escherichia coli are strong adjuvants for DNA vaccines 总被引:5,自引:0,他引:5
Arrington J Braun RP Dong L Fuller DH Macklin MD Umlauf SW Wagner SJ Wu MS Payne LG Haynes JR 《Journal of virology》2002,76(9):4536-4546
Two plasmid vectors encoding the A and B subunits of cholera toxin (CT) and two additional vectors encoding the A and B subunits of the Escherichia coli heat-labile enterotoxin (LT) were evaluated for their ability to serve as genetic adjuvants for particle-mediated DNA vaccines administered to the epidermis of laboratory animals. Both the CT and the LT vectors strongly augmented Th1 cytokine responses (gamma interferon [IFN-gamma]) to multiple viral antigens when codelivered with DNA vaccines. In addition, Th2 cytokine responses (interleukin 4 [IL-4]) were also augmented by both sets of vectors, with the effects of the LT vectors on IL-4 responses being more antigen dependent. The activities of both sets of vectors on antibody responses were antigen dependent and ranged from no effect to sharp reductions in the immunoglobulin G1 (IgG1)-to-IgG2a ratios. Overall, the LT vectors exhibited stronger adjuvant effects in terms of T-cell responses than did the CT vectors, and this was correlated with the induction of greater levels of cyclic AMP by the LT vectors following vector transfection into cultured cells. The adjuvant effects observed in vivo were due to the biological effects of the encoded proteins and not due to CpG motifs in the bacterial genes. Interestingly, the individual LT A and B subunit vectors exhibited partial adjuvant activity that was strongly influenced by the presence or absence of signal peptide coding sequences directing the encoded subunit to either intracellular or extracellular locations. Particle-mediated delivery of either the CT or LT adjuvant vectors in rodents and domestic pigs was well tolerated, suggesting that bacterial toxin-based genetic adjuvants may be a safe and effective strategy to enhance the potency of both prophylactic and therapeutic DNA vaccines for the induction of strong cellular immunity. 相似文献
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Fraley ME Rubino RS Hoffman WF Hambaugh SR Arrington KL Hungate RW Bilodeau MT Tebben AJ Rutledge RZ Kendall RL McFall RC Huckle WR Coll KE Thomas KA 《Bioorganic & medicinal chemistry letters》2002,12(24):8723-3541
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described. 相似文献
23.
Brnardic EJ Garbaccio RM Fraley ME Tasber ES Steen JT Arrington KL Dudkin VY Hartman GD Stirdivant SM Drakas BA Rickert K Walsh ES Hamilton K Buser CA Hardwick J Tao W Beck SC Mao X Lobell RB Sepp-Lorenzino L Yan Y Ikuta M Munshi SK Kuo LC Kreatsoulas C 《Bioorganic & medicinal chemistry letters》2007,17(21):5989-5994
The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC(50)=3.1 nM). 相似文献
24.
Carrie Luu Eileen L. Heinrich Marjun Duldulao Amanda K. Arrington Marwan Fakih Julio Garcia-Aguilar Joseph Kim 《PloS one》2013,8(8)
Recent reports have indicated that KRAS and TP53 mutations predict response to therapy in colorectal cancer. However, little is known about the relationship between these two common genetic alterations. Micro-RNAs (miRNAs), a class of noncoding RNA implicated in cellular processes, have been increasingly linked to KRAS and TP53. We hypothesized that lethal-7a (let-7a) miRNA regulates KRAS through TP53. To investigate the relationship between KRAS, TP53, and let-7a, we used HCT116 KRASmut human colorectal cancer cells with four different genotypic modifications in TP53 (TP53−/−, TP53+/−, TP53mut/+, and TP53mut/−). Using these cells we observed that K-Ras activity was higher in cells with mutant or knocked out TP53 alleles, suggesting that wild-type TP53 may suppress K-Ras activity. Let-7a was present in HCT116 KRASmut cells, though there was no correlation between let-7a level and TP53 genotype status. To explore how let-7a may regulate K-Ras in the different TP53 genotype cells we used let-7a inhibitor and demonstrated increased K-Ras activity across all TP53, thus corroborating prior reports that let-7a regulates K-Ras. To assess potential clinical implications of this regulatory network, we examined the influence of TP53 genotype and let-7a inhibition on colon cancer cell survival following chemoradiation therapy (CRT). We observed that cells with complete loss of wild-type TP53 alleles (−/− or −/mut) were resistant to CRT following treatment with 5-fluorouracil and radiation. Further increase in K-Ras activity with let-7a inhibition did not impact survival in these cells. In contrast, cells with single or double wild-type TP53 alleles were moderately responsive to CRT and exhibited resistance when let-7a was inhibited. In summary, our results show a complex regulatory system involving TP53, KRAS, and let-7a. Our results may provide clues to understand and target these interactions in colorectal cancer. 相似文献
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Garbaccio RM Fraley ME Tasber ES Olson CM Hoffman WF Arrington KL Torrent M Buser CA Walsh ES Hamilton K Schaber MD Fernandes C Lobell RB Tao W South VJ Yan Y Kuo LC Prueksaritanont T Slaughter DE Shu C Heimbrook DC Kohl NE Huber HE Hartman GD 《Bioorganic & medicinal chemistry letters》2006,16(7):1780-1783
2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy. 相似文献
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Fraley ME Garbaccio RM Arrington KL Hoffman WF Tasber ES Coleman PJ Buser CA Walsh ES Hamilton K Fernandes C Schaber MD Lobell RB Tao W South VJ Yan Y Kuo LC Prueksaritanont T Shu C Torrent M Heimbrook DC Kohl NE Huber HE Hartman GD 《Bioorganic & medicinal chemistry letters》2006,16(7):1775-1779
The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC(50)s<10nM. Ancillary hERG activity was evaluated for this series of inhibitors. 相似文献
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Isabella C. Glitza Keiran S. M. Smalley Priscilla K. Brastianos Michael A. Davies Ian McCutcheon James K. C. Liu Kamran A. Ahmed John A. Arrington Brittany R. Evernden Inna Smalley Zeynep Eroglu Nikhil Khushalani Kim Margolin Harriet Kluger Michael B. Atkins Hussein Tawbi Adrienne Boire Peter Forsyth 《Pigment cell & melanoma research》2020,33(4):527-541
In February 2018, the Melanoma Research Foundation and the Moffitt Cancer Center hosted the Second Summit on Melanoma Central Nervous System Metastases in Tampa, Florida. The meeting included investigators from multiple academic centers and disciplines. A consensus summary of the progress and challenges in melanoma parenchymal brain metastases was published (Eroglu et al., Pigment Cell & Melanoma Research, 2019, 32, 458). Here, we will describe the current state of basic, translational, clinical research, and therapeutic management, for melanoma patients with leptomeningeal disease. We also outline key challenges and barriers to be overcome to make progress in this deadly disease. 相似文献
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Lewis TA Young MA Arrington MP Bayless L Cai X Collart P Eckman JB Ellis JL Ene DG Libertine L Nicolas JM Scannell RT Wels BF Wenberg K Wypij DM 《Bioorganic & medicinal chemistry letters》2004,14(22):5591-5594
A series of compounds possessing both H(1) histamine receptor antagonist and 5-lipoxygenase (5-LO) inhibitory activities was synthesized. The H(1)-binding scaffolds of cetirizine, efletirizine, and loratadine were linked to a lipophilic N-hydroxyurea, the 5-LO inhibiting moiety of zileuton. Both activities were observed in vivo, as was increased CYP3A4 inhibition compared to their respective single-function drugs. Selected analogs in the series were shown to be orally active in guinea pig models. 相似文献