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31.
Lisa M. Petti Kristina Talbert-Slagle Megan L. Hochstrasser Daniel DiMaio 《The Journal of biological chemistry》2013,288(38):27273-27286
Receptors for PDGF play an important role in cell proliferation and migration and have been implicated in certain cancers. The 44-amino acid E5 protein of bovine papillomavirus binds to and activates the PDGFβ receptor (PDGFβR), resulting in oncogenic transformation of cultured fibroblasts. Previously, we isolated an artificial 36-amino acid transmembrane protein, pTM36-4, which transforms cells because of its ability to activate the PDGFβR despite limited sequence similarity to E5. Here, we demonstrated complex formation between the PDGFβR and three pTM36-4 mutants: T21E, T21Q, and T21N. T21Q retained wild type transforming activity and activated the PDGFβR in a ligand-independent manner as a consequence of binding to the transmembrane domain of the PDGFβR, but T21E and T21N were severely defective. In fact, T21N substantially inhibited E5-induced PDGFβR activation and transformation in both mouse and human fibroblasts. T21N did not prevent E5 from binding to the receptor, and genetic evidence suggested that T21N and E5 bind to nonidentical sites in the transmembrane domain of the receptor. T21N also inhibited transformation and PDGFβR activation induced by v-Sis, a viral homologue of PDGF-BB, as well as PDGF-induced mitogenesis and signaling by preventing phosphorylation of the PDGFβR at particular tyrosine residues. These results demonstrated that T21N acts as a novel inhibitor of the PDGFβR and validated a new strategy for designing highly specific short transmembrane protein inhibitors of growth factor receptors and possibly other transmembrane proteins. 相似文献
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J. R. Castro P. L. Petti I. K. Daftari J. M. Collier T. Renner B. Ludewigt W. Chu S. Pitluck T. Fleming J. Alonso E. Blakely 《Radiation and environmental biophysics》1992,31(3):233-240
Summary The feasibility of dynamic conformal heavy charged particle radiotherapy has been investigated at UCLBL, and shows high promise of: 1. an improved therapeutic ratio and 2. reduction in the number of treatment portals required for efficient treatment delivery. Assessment of dose to tumor and critical structures for several anatomical sites have been carried out using a normal tissue complication algorithm developed at LBL. For high-LET charged particle treatment delivery, dynamic conformal therapy using a raster scanned beam with variable modulation and multileaf collimator appears to be the optimal technique for treatment delivery.Paper given on the fourth workshop on Heavy Charged Particles in Biology and Medicine GSI, Darmstadt, FRG, September 23–25,1991. Supported in part by NIH-NCI Grant CA19138 and DOE Contract DE-AC03-76SF00098 相似文献
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Wang M Basu A Palm T Hua J Youngster S Hwang L Liu HC Li X Peng P Zhang Y Zhao H Zhang Z Longley C Mehlig M Borowski V Sai P Viswanathan M Jang E Petti G Liu S Yang K Filpula D 《Bioconjugate chemistry》2006,17(6):1447-1459
Arginine is an important metabolite in the normal function of several biological systems, and arginine deprivation has been investigated in animal models and human clinical trials for its effects on inhibition of tumor growth, angiogenesis, or nitric oxide synthesis. In order to design an optimal arginine-catabolizing enzyme bioconjugate, a novel recombinant arginine deiminase (ADI) from Mycoplasma arthritidis was prepared, and multi-PEGylated derivatives were examined for enzymatic and biochemical properties in vitro, as well as pharmacokinetic and pharmacodynamic behavior in rats and mice. ADI bioconjugates constructed with 12 kDa or 20 kDa monomethoxy-poly(ethylene glycol) polymers with linear succinimidyl carbonate linkers were investigated via intravenous, intramuscular, or subcutaneous administration in rodents. The selected PEG-ADI compounds have 22 +/- 2 PEG strands per protein dimer, providing an additional molecular mass of about 0.2-0.5 x 10(6) Da and prolonging the plasma mean residence time of the enzyme over 30-fold in mice. Prolonged plasma arginine deprivation was demonstrated with each injection route for these bioconjugates. Pharmacokinetic analysis employed parallel measurement of enzyme activity in bioassays and enzyme assays and demonstrated a correlation with the pharmacodynamic analysis of plasma arginine concentrations. Either ADI bioconjugate depressed plasma arginine to undetectable levels for 10 days when administered intravenously at 5 IU per mouse, while the subcutaneous and intramuscular routes exhibited only slightly reduced potency. Both bioconjugates exhibited potent growth inhibition of several cultured tumor lines that are deficient in the anabolic enzyme, argininosuccinate synthetase. Investigations of structure-activity optimization for PEGylated ADI compounds revealed a benefit to constraining the PEG size and number of attachments to both conserve catabolic activity and streamline manufacturing of the experimental therapeutics. Specifically, ADI with either 12 kDa or 20 kDa PEG attachments on 33% of the primary amines retained about 60% or 48% of enzyme activity, respectively; the Km and pH profiles were nearly unchanged; IC50 values were diminished by less than 30%; while stability studies demonstrated full retention of activity at 4 degrees C for 5 months. A comparison of the enzymatic properties of a second ADI from Pseudomonas putida illustrated the superior characteristics of the M. arthritidis ADI enzyme. 相似文献
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Petti S Divizia M Donia D D' Arca AS Tarsitani G Fabi G Panà A 《The new microbiologica》2006,29(3):207-209
Anti-HCV and HCV-RNA prevalence among adults from an isolated Central Italian community were 16.3% and 9.0%; 3.0%, 2.3% among 25-to-49-year-olds, 27.6%, 14.7% among older subjects. 1b genotype prevailed (88.5%). 1a, la/1b, 4 were also isolated. Seropositivity was associated with age > 50 years, public dental health care, glass syringe use, surgical interventions. The transmission pattern seems to be shifting from that typical of Southern Italy (high prevalence, particularly in the elderly, 1b genotype predominant, various routes of transmission involved, cohort effect), to that typical of Europe (lower prevalence, particularly among younger adults, other genotypes involved, association with intravenous drug use and immigrants). 相似文献
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Filpula D Yang K Basu A Hassan R Xiang L Zhang Z Wang M Wang QC Ho M Beers R Zhao H Peng P Zhou J Li X Petti G Janjua A Liu J Wu D Yu D Zhang Z Longley C FitzGerald D Kreitman RJ Pastan I 《Bioconjugate chemistry》2007,18(3):773-784
Recombinant immunotoxins exhibit targeting and cytotoxic functions needed for cell-specific destruction. However, antitumor efficacy, safety, and pharmacokinetics of these therapeutics might be improved by further macromolecular engineering. SS1P is a recombinant anti-mesothelin immunotoxin in clinical trials in patients with mesothelin-expressing tumors. We have modified this immunotoxin using several PEGylation strategies employing releasable linkages between the protein and the PEG polymers, and observed superior performance of these bioconjugates when compared to similar PEG derivatives bearing permanent linkages to the polymers. PEGylated derivatives displayed markedly diminished cytotoxicity on cultured mesothelin-overexpressing A431-K5 cells; however, the releasable PEGylated immunotoxins exhibited increased antitumor activity in A431-K5 xenografts in mice, with a diminished animal toxicity. Most significantly, complete tumor regressions were achievable with single dose administration of the bioconjugates but not the native immunotoxin. Pharmacokinetic analysis of the releasable PEGylated derivatives in mice demonstrated an over 80-fold expansion of the area under the curve exposure of bioactive protein when compared to native immunotoxin. A correlation in degree of derivatization, release kinetics, and polymer size with potency was observed in vivo, whereas in vitro cytotoxicity was not predictive of efficacy in animal models. The potent antitumor efficacy of the releasable PEGylated mesothelin-targeted immunotoxins was not exhibited by similar untargeted PEG immunotoxins in this model. Since the bioconjugates can also exhibit the attributes of passive targeting via enhanced permeability and retention, this is the first demonstration of a pivotal role of active targeting for immunotoxin bioconjugate efficacy. 相似文献