Tumour cell growth may be accelerated by protein kinase C (PKC) agonists
such as phorbol esters and receptor tyrosine kinases, but receptor tyrosine
kinases are in turn desensitized to growth factors by PKC agonists. To
clarify this apparent PKC bifunctionality, we have used phosphoantibodies
to determine the relationship between PKC- dependent phosphorylation events
affecting the ErbB2 oncoprotein in G8/DHFR 3T3 cells. Neither the kinetics
nor the extent of phorbol- induced juxtamembrane domain (Thr686)
phosphorylation vary directly with C-terminal (Tyr1222) dephosphorylation,
with Tyr1222 continuing to be dephosphorylated long after Thr686
phosphorylation has also declined. Platelet-derived growth factor (PDGF)
mimics the short-term effects of phorbol on Thr686 and Tyr1222
phosphorylation, and confocal microscopy reveals that both of these PKC
agonists induce rapid internalization of PKC-modified ErbB2. Phorbol causes
sustained cytoplasmic accumulation of PKC-phosphorylated receptors,
however, whereas PDGF triggers the appearance of this ErbB2 subset only
briefly. Metabolic labelling and co-precipitation studies fail to implicate
heterologous molecules in either the tyrosine dephosphorylation or
internalization of PKC-modified ErbB2. Taken in the context of earlier
juxtamembrane domain mutagenesis studies, these findings indicate that
phorbol-activated PKC may desensitize growth factor receptors to
extracellular ligands solely by triggering sustained receptor
internalization. We submit that PKC-dependent juxtamembrane domain
phosphorylation represents a physiological mechanism for shortening the
duration and enhancing the specificity of growth factor signalling by
promoting internalization of liganded and unliganded receptors,
respectively.
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AimsThe use of postoperative radiation therapy (PORT) is predicated by an assessment of the potential benefits and risks, including radiation-induced lung injury. In this study, the risk of radiation-induced lung injury is assessed in patients who received PORT, and compared with a group of patients who received radiation without prior surgery, to determine if surgery increases the risk of radiation pneumonitis.Materials and methodsFrom 1991 to 2003, 251 patients with lung cancer were enrolled into a prospective study to assess radiation-induced lung injury. All patients received three-dimensional-planned, external-beam radiotherapy. One hundred and seventy-seven patients with over 6-months follow-up were eligible. For the current analysis, 49 patients (28%) had surgical intervention before radiotherapy. The rates of Grade 2 symptomatic pneumonitis in subgroups, based on the type of pre-radiation surgery, were computed and compared using Fisher's Exact Test. To consider the confounding factor of irradiated lung volume, patient subgroups were further defined on the basis of the mean lung dose.ResultsSurgical procedures included pneumonectomy (n = 9), lobectomy (n = 16), wedge resection (n = 8) and exploration without resection (n = 16). Radiation-induced lung injury occurred in 33 out of 177 (19%) patients, including 18% of the surgical group and 19% of the non-surgical group. Additionally, no statistically significant difference was found in the rate of radiation-induced lung injury based on the extent of resection.ConclusionsThe incidence of pneumonitis is similar in the surgical and non-surgical groups. Thus, PORT may be safely given to selected patients after surgical exploration or resection. 相似文献
Factor V and factor VIII are homologous cofactors in the blood coagulation cascade that have the domain structure A1-A2-B-A3-C1-C2, of which the B domain has extensively diverged. In transfected COS-1 monkey cells, expression of factor VIII is approximately 10-fold less efficient than that of factor V, primarily because of inefficient protein secretion and, to a lesser extent, reduced mRNA expression. To study the functional significance and effect of the B domain on expression and activity, chimeric cDNAs were constructed in which the B domains of factor V and factor VIII were exchanged. Expression of a factor VIII chimera harboring the B-domain of factor V yielded a fully functional factor VIII molecule that was expressed twofold more efficiently than wild-type factor VIII because of increased mRNA expression. Thus, sequences within the factor VIII B domain were not responsible for the inefficient secretion of factor VIII compared with factor V. Expression of a factor V chimera harboring the B domain of factor VIII was slightly reduced compared with wild-type factor V, although the secreted molecule had significantly reduced procoagulant activity correlating with dissociated heavy and light chains and resistance to thrombin activation. Interestingly, the factor V chimera containing the factor VIII B domain was efficiently activated by Russell's viper venum (RVV). A factor V B domain deletion (residues 710- 1545) molecule also exhibited significantly reduced procoagulant activity caused by resistance to thrombin cleavage and activation, although this molecule was activatable by RVV. These results show that, in contrast to factor VIII, thrombin activation of factor V requires sequences within the B domain. In addition, thrombin activation of factor V occurs through a different mechanism than activation by RVV. 相似文献
Cerebral malaria is thought to involve specific attachment of Plasmodium falciparum-infected knobby red cells to venular endothelium. The nature of surface ligands on host endothelial cells that may mediate cytoadherence is poorly understood. We have investigated the effects of soluble thrombospondin, rabbit antiserum raised against thrombospondin, and human immune serum on cytoadherence of parasitized erythrocytes in ex vivo mesocecum vasculature. Preincubation of infected red cells with soluble thrombospondin or human immune serum inhibits binding of infected red cells to rat venular endothelium. Infusion of the microcirculatory preparation with rabbit antithrombospondin antibodies before perfusion of parasitized erythrocytes also resulted in decreased cytoadherence. In addition, incubation of infected cells with human immune sera obtained from malaria patients significantly inhibited the observed cytoadherence. Our results indicate that thrombospondin mediates binding of infected red cells to venular endothelium and may thus be involved in the pathogenesis of cerebral malaria. 相似文献
Posaconazole is a new investigational triazole with broad-spectrum antifungal activity. The in vitro activities of posaconazole were compared with those of itraconazole and fluconazole against 3,685 isolates of Candida spp. (3,312 isolates) and C. neoformans (373 isolates) obtained from over 70 different medical centers worldwide. The MICs of the antifungal drugs were determined by broth microdilution tests performed according to the National Committee for Clinical Laboratory Standards method using RPMI 1640 as the test medium. Posaconazole was very active against all Candida spp. (MIC at which 90% of the isolates were inhibited [MIC(90)], 0.5 microg/ml; 97% of MICs were < or =1 microg/ml) and C. neoformans (MIC(90), 0.5 microg/ml; 100% of MICs were < or =1 microg/ml). Candida albicans was the most susceptible species of Candida (MIC(90), 0.06 microg/ml), and Candida glabrata was the least susceptible (MIC(90), 4 microg/ml). Posaconazole was more active than itraconazole and fluconazole against all Candida spp. and C. neoformans. These results provide further evidence for the spectrum and potency of posaconazole against a large and geographically diverse collection of clinically important fungal pathogens. 相似文献
Objectives—(a) To compare the use of high dose intramuscular midazolam with and without intranasal flumazenil in children after suturing. (b) To compare the use of high dose intramuscular midazolam with low dose intramuscular ketamine in children before suturing.
Methods—87 children, aged between 1 and 7 years, presenting with simple wounds needing sedation, were studied. Children considered combative (n=47) were given ketamine (2.5 mg/kg intramuscularly). The remaining 40 children were given midazolam (0.4 mg/kg intramuscularly) with and without flumazenil (25 µg/kg, intranasally).
Results—The median oxygen saturation was 97% in both midazolam groups. Flumazenil significantly reduced the amount of agitation during recovery (p=0.048) and also the time at which children were ready for discharge (median 55 versus 95 minutes, p value <0.001). After discharge both midazolam groups had an unsteady gait (75%) and there was no significant difference in the duration. As expected because of the deliberate selection of combative children into the ketamine group, the pre-sedation behaviour was slightly more disturbed compared with the midazolam group (p=0.10). However, the ketamine group was less agitated during local anaesthetic and suturing p<0.001.
Conclusion—Intramuscular midazolam (0.4 mg/kg) did not effectively sedate the children, in that a significant number still had to be restrained. However, none could remember the suturing. Intranasal flumazenil seems to be effective in shortening the time to discharge. If midazolam is to be used then a dose high enough to produce full amnesia should be used, there seems to be no advantage in increasing the dose further. Low dose intramuscular ketamine remains the drug of choice.