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Using immunoselection with an H-2Kk-specific monoclonal antibody following mutagenesis on an (H-2
k/H-2d) F1 cell line we have obtained variants that do not react with the selecting monoclonal antibody but continue to react with other monoclonal antibodies directed against the same gene product. The mutants fall into two classes based on their serological profile. This phenotype is suggestive of a structural mutation in the selected gene. If the genetic change involved is a point mutation (as opposed to a deletion), one should be able to obtain revertants. Using the fluorescence-activated cell sorter, we have been able to obtain from one of the monoclonal-antibody-nonseactive mutants cells that do bind the selecting antibody. In order to prove that the presumptive revertant is not a contaminant wild-type cell that inadvertantly got mixed into the resistant mutant, we first introduced an outside marker, resistance to the purine analogue 2-amino-6-mercaptopurine (6-thioguanine), into the monoclonal-antibody-resistant mutant. The revertants obtained using the cell sorter continue to express the nonselective phenotype of resistance to 6-thioguanine, showing that they are not wild-type cells. In addition, their serological characteristics are different from those of either the wild-type cells or the hybrid oma-resistant mutants from which they were derived. Based on the serological analyses, it would seem that we have isolated at least three variant forms of the H-2Kk-gene product. 相似文献
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Atul A. Lohade Rajesh R. Jain Krishna Iyer Sushant K. Roy Hemant H. Shimpi Yogita Pawar M. G. R. Rajan Mala D. Menon 《AAPS PharmSciTech》2016,17(6):1298-1311
Targeted drug delivery systems for cancer improves anti-tumor efficacy and reduces systemic toxicity by restricting availability of cytotoxic drugs within tumors. Targeting moieties, such as natural ligands (folic acid, transferrin, and biotin) which are overexpressed on tumors, have been used to enhance liposome-encapsulated drug accumulation within tumors and resulted in better control. In this report, we explored the scope of targeting ligand folic acid, which is incorporated in liposome systems using folic acid-modified cholesterol (CPF), enabled highly selective tumor-targeted delivery of liposome-encapsulated doxorubicin and resulted in increased cytotoxicity within tumors. Folate-tagged poloxamer-coated liposomes (FDL) were found to have significantly higher cellular uptake than conventional poloxamer-coated liposomes (DL), as confirmed by fluorometric analysis in B16F10 melanoma cells. Biodistribution study of the radiolabeled liposomal system indicated the significantly higher tumor uptake of FDL as compared to DL. Anti-tumor activity of FDL against murine B16F10 melanoma tumor-bearing mice revealed that FDL inhibited tumor growth more efficiently than the DL. Taken together, the results demonstrated the significant potential of the folate-conjugated nanoliposomal system for drug delivery to tumors. 相似文献
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Mindy I. Davis Atsuo T. Sasaki Min Shen Brooke M. Emerling Natasha Thorne Sam Michael Rajan Pragani Matthew Boxer Kazutaka Sumita Koh Takeuchi Douglas S. Auld Zhuyin Li Lewis C. Cantley Anton Simeonov 《PloS one》2013,8(1)
Phosphoinositide kinases regulate diverse cellular functions and are important targets for therapeutic development for diseases, such as diabetes and cancer. Preparation of the lipid substrate is crucial for the development of a robust and miniaturizable lipid kinase assay. Enzymatic assays for phosphoinositide kinases often use lipid substrates prepared from lyophilized lipid preparations by sonication, which result in variability in the liposome size from preparation to preparation. Herein, we report a homogeneous 1536-well luciferase-coupled bioluminescence assay for PI5P4Kα. The substrate preparation is novel and allows the rapid production of a DMSO-containing substrate solution without the need for lengthy liposome preparation protocols, thus enabling the scale-up of this traditionally difficult type of assay. The Z’-factor value was greater than 0.7 for the PI5P4Kα assay, indicating its suitability for high-throughput screening applications. Tyrphostin AG-82 had been identified as an inhibitor of PI5P4Kα by assessing the degree of phospho transfer of γ-32P-ATP to PI5P; its inhibitory activity against PI5P4Kα was confirmed in the present miniaturized assay. From a pilot screen of a library of bioactive compounds, another tyrphostin, I-OMe tyrphostin AG-538 (I-OMe-AG-538), was identified as an ATP-competitive inhibitor of PI5P4Kα with an IC50 of 1 µM, affirming the suitability of the assay for inhibitor discovery campaigns. This homogeneous assay may apply to other lipid kinases and should help in the identification of leads for this class of enzymes by enabling high-throughput screening efforts. 相似文献
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Ravi babu. Kalahasthi Rajmohan. Hirehal Raghavendra rao Rajan. Bagalur Krishna murthy 《Biomarkers》2006,11(3):241-249
The objectives were to investigate the plasma lipid peroxidation and erythrocyte antioxidants status in workers exposed to nickel. The study groups comprised 69 nickel plating workers and 50 office workers residing in the same city, but away from the place of work of the study group subjects, considered as control group. Urinary nickel concentration was determined by graphite furnace atomic absorption spectrophotometry. The plasma lipid peroxidation and erythrocyte antioxidants were measured by spectrophotmetric methods. The plasma lipid peroxidation level was significantly increased in nickel-platers and their helpers as compared with controls. Erythrocyte antioxidants were significantly decreased in the nickel-platers compared with the controls. The level of plasma lipid peroxidation was positively and erythrocyte antioxidants were negatively and significantly correlated with the urine nickel levels. Multiple regression analysis assessed the oxidative stress associated with nickel and other potential confounding factors such as body mass index, the consumption of green vegetables, coffee, tea, smoking and alcohol consumption. Analysis showed that the lifestyle confounding factors: the consumption of green vegetables, smoking and alcohol, were not significantly associated with oxidative stress. The exposure to nickel, body mass index and coffee consumption were significantly associated with oxidative stress. The results show that the increased plasma lipid peroxidation and decreased erythrocyte antioxidants levels observed in nickel-exposed workers could be used as biomarkers of oxidative stress. 相似文献
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The mechanism by which the hinge regions of glycoprotein hormone receptors couple hormone binding to activation of downstream effecters is not clearly understood. In the present study, agonistic (311.62) and antagonistic (311.87) monoclonal antibodies (MAbs) directed against the TSH receptor extracellular domain were used to elucidate role of the hinge region in receptor activation. MAb 311.62 which identifies the LRR/Cb-2 junction (aa 265-275), increased the affinity of TSHR for the hormone while concomitantly decreasing its efficacy, whereas MAb 311.87 recognizing LRR 7-9 (aa 201-259) acted as a non-competitive inhibitor of Thyroid stimulating hormone (TSH) binding. Binding of MAbs was sensitive to the conformational changes caused by the activating and inactivating mutations and exhibited differential effects on hormone binding and response of these mutants. By studying the effects of these MAbs on truncation and chimeric mutants of thyroid stimulating hormone receptor (TSHR), this study confirms the tethered inverse agonistic role played by the hinge region and maps the interactions between TSHR hinge region and exoloops responsible for maintenance of the receptor in its basal state. Mechanistic studies on the antibody-receptor interactions suggest that MAb 311.87 is an allosteric insurmountable antagonist and inhibits initiation of the hormone induced conformational changes in the hinge region, whereas MAb 311.62 acts as a partial agonist that recognizes a conformational epitope critical for coupling of hormone binding to receptor activation. The hinge region, probably in close proximity with the α-subunit in the hormone-receptor complex, acts as a tunable switch between hormone binding and receptor activation. 相似文献
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