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141.
142.
DaSilva JN Lourenco CM Meyer JH Hussey D Potter WZ Houle S 《European journal of nuclear medicine and molecular imaging》2002,29(12):1680-1683
Evidence of disruptions in cAMP-mediated signaling in several neuropsychiatric disorders has led to the development of R-[(11)C]rolipram for imaging phosphodiesterase-4 (PDE4) enzymes with positron emission tomography (PET). The high-affinity PDE4 inhibitor rolipram was previously reported to have an antidepressant effect in humans. PDE4 is abundant in the brain, and it hydrolyzes cAMP produced following stimulation of various neurotransmitter systems. PDE4 is regulated by intracellular cAMP levels. This paper presents the first PET study of R-[(11)C]rolipram in living human brain. Consistent with the wide distribution of PDE4, high radioactivity retention was observed in all regions representing the gray matter. Rapid metabolism was observed, and kinetic analysis demonstrated that the data fit in a two-tissue compartment model. R-[(11)C]Rolipram is thus suitable for imaging PDE4 and possibly cAMP signal transduction in the living human brain with PET. 相似文献
143.
144.
Ga?lle Nicolle Ahmad Daher Pascale Maillé Marcel Vermey Sylvain Loric Ashraf Bakkar Hervé Wallerand Dimitrios Vordos Francis Vacherot Sixtina Gil Diez de Medina Claude C Abbou Theodore Van der Kwast Jean-Paul Thiery Fran?ois Radvanyi Dominique K Chopin 《Clinical cancer research》2006,12(9):2937-2943
PURPOSE: Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC. EXPERIMENTAL DESIGN: Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC. RESULTS: Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens. CONCLUSIONS: Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders. 相似文献
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146.
Daniel Potreau Sylvain Richard Joel Nargeot Guy Raymond 《Pflügers Archiv : European journal of physiology》1987,410(3):326-334
The effect of alkali-earth cations (Ca2+, Sr2+, Ba2+) on the excitation-contraction coupling events of the frog atrial fibres were studied using a double mannitol gap voltage clamp technique coupled with a mechano-electric transducer. Photoremoval of the suppressive effect of nifedipine on the calcium channels allowed to obtain rapid transient Ca2+, Sr2+ or Ba2+ ions current jumps. The effect on the amplitude of the associated contraction was proportional to the current jumps. These results together with portional to the current jumps. These results together with the correlation established between the estimated increase in the internal concentration of divalent cations and the amplitude of the phasic tension suggest that the essential source of divalent cations for activation of contraction is the extracellular space. Also Ba2+ ions reduced the tonic tension and strongly slowed the relaxation of the phasic component whereas Sr2+ exhibited smaller effects. Sr2+ ions could be more efficient than Ba2+ ions in substituting for Ca2+ ions in the Na+–Ca2+ exchange mechanism known to regulate these two mechanical events. The conclusions are that the order of effectiveness of these ions (Ca2+>Sr2+>Ba2+) is the same with regard to transarcolemmal exchange for Na+ ions, presumed uptake by a second relaxing system, activation of contraction, and inactivation of the slow inward current. 相似文献
147.
148.
Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid 总被引:13,自引:0,他引:13
Vascular endothelial growth factor (VEGF) is a potent signalling molecule that acts through two tyrosine kinase receptors, VEGFR1 and VEGFR2. The upregulation of VEGF and its receptors is important in tumour-associated angiogenesis; however, recent studies suggest that several tumour cells express VEGF receptors and may be influenced by autocrine VEGF signalling. Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, and is dependent on autocrine signalling for its growth. The alveolar subtype of RMS is often characterized by the presence of a PAX3-FKHR translocation, and when introduced into non-RMS cells, the resultant fusion protein induces expression of VEGFR1. In our study, we examined the expression of VEGF and its receptors in RMS, and autocrine effects of VEGF on cell growth. VEGF and receptor mRNA and protein were found to be expressed in RMS cells. Exogenous VEGF addition resulted in extracellular signal-regulated kinase-1/2 phosphorylation and cell proliferation, and both were reduced by VEGFR1 blockade. Growth was also slowed by VEGFR1 inhibitor alone. Treatment of RMS cells with all-trans-retinoic acid decreased VEGF secretion and slowed cell growth, which was rescued by VEGF. These data suggest that autocrine VEGF signalling likely influences RMS growth and its inhibition may be an effective treatment for RMS. 相似文献
149.
Solassol I Bressolle F Caumette L Garcia F Poujol S Culine S Pinguet F 《Therapeutic drug monitoring》2005,27(4):491-498
Perception of pain by the patient is frequently one of the early signs preceding a diagnosis of cancer and, later, a sinister sign of disease progression. Among opioid drugs, transdermal fentanyl has been evaluated in the treatment of moderate to severe cancer pain. The objective of this study was to investigate the intra- and interindividual variabilities in pharmacokinetics after fentanyl drug delivery by the transdermal fentanyl patch delivery system in patients with cancer pain. As a first step, a liquid chromatography-mass spectrometry method was developed for the determination of the analgesic fentanyl in human plasma. This method was validated over the concentration range 0.15-100 ng/mL. The study group consisted of 29 inpatients (18 men and 11 women; age range 29-80 years). The initial transdermal fentanyl delivery rate was chosen depending on the patient's analgesic requirements. For 20 patients, the initial TTS fentanyl delivery rate was 25 or 50 microg/h. For 6 patients, the initial delivery rate was 75-150 microg/h. Two patients received up to 300 microg/h fentanyl delivery rate, and 3 patients received up to 350 microg/h fentanyl delivery rate. Fifteen of the 29 patients received rescue doses of subcutaneous or oral morphine, and 26 patients received paracetamol with codeine (30 mg per os). Blood samples were collected at the following intervals: 2-5, 22-26, or 45-47 hours following fentanyl patch application. The severity of pain experienced by the patient was assessed thrice daily using a visual analogue scale. The study period was 46 days. Large patient-to-patient variations in pharmacokinetic parameters occurred, although intraindividual variability was limited. A mean bioavailability of 78% was estimated; the total clearance averaged 41 L/h. From 25 to 100 mug/h fentanyl delivery rate, the pharmacokinetics was linear. At the 2 highest doses, an increase of total clearance was observed (>60 L/h). For the whole group, transdermal fentanyl treatment provided good to excellent pain relief in the majority of patients. 相似文献
150.
London GM Marchais SJ Guérin AP Métivier F 《Current opinion in nephrology and hypertension》2005,14(6):525-531
PURPOSE OF REVIEW: Arterial calcification in chronic kidney disease (CKD) is associated with increased cardiovascular risk. The mechanisms responsible for arterial calcification include alterations of mineral metabolism and expression of mineral-regulating proteins. RECENT FINDINGS: Arterial calcification is similar to bone formation, involving differentiation of vascular smooth muscle cells (VSMCs) into phenotypically distinct osteoblast-like cells. Elevated phosphate and/or calcium trigger a concentration-dependent increase of calcium precipitates in VSMC in vitro. The calcification is initiated by VSMC release of membrane-bound matrix vesicles and formation of apoptotic bodies. The presence of serum prevents these changes, indicating the presence of calcification inhibitors. Arterial calcification occurs in two sites: the tunica intima and tunica media. Intimal calcification is a marker of atherosclerotic disease and is associated with arterial stenotic lesions. Medial calcification influences outcome by promoting arterial stiffening whose principal consequences are left-ventricular hypertrophy and altered coronary perfusion. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in CKD patients. Age, duration of dialysis, smoking and diabetes are risk factors for the development of arterial calcification in end-stage renal disease. Oversuppression of parathyroid hormone and low bone turnover potentiate the development of arterial calcification. SUMMARY: Arterial disease in CKD patients is characterized by extensive calcification. Evidence has accumulated pointing to the active and regulated nature of the calcification process. Elevated phosphate and calcium may stimulate sodium-dependent phosphate cotransport involving osteoblast-like changes in cellular gene expression. Arterial calcification is responsible for stiffening of the arteries with increased left-ventricular afterload and abnormal coronary perfusion as the principal clinical consequences. 相似文献