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61.
Yasmine Asses Vincent Leroux Safia Tairi‐Kellou Rosanna Dono Flavio Maina Bernard Maigret 《Chemical biology & drug design》2009,74(6):560-570
The receptor tyrosine kinase c‐Met have multiple roles during cancer development and is currently considered as an important target for molecularly targeted therapies. Structural knowledge of how compounds interact on c‐Met catalytic site could guide structure‐based drug design strategies towards more effective and selective anticancer drug candidates. However, although 17 crystal structures of c‐Met complexed with adenosine triphosphate (ATP)‐competitive kinase inhibitors are publicly available (August 2009), there are still open questions regarding the prediction of ligand binding modes. We have applied molecular modeling and molecular mechanics to analyze the distribution of ligands interaction energy on c‐Met residues, and deduced a new model of the active site allowing for an unambiguous identification of ligand binding modes. We demonstrate that the binding of known ligands on the c‐Met catalytic site involves seven identified structurally‐distinct areas. Five of these match the generic kinase ATP binding site model built by Novartis scientists in the 1990s, while the two others are distinct allosteric regions that can be exploited by second generation kinase inhibitors such as Gleevec. We show here that c‐Met can accept both such kinds of allosteric inhibitors, a very unusual feature in the kinase family that opens new grounds for highly specific drug design. 相似文献
62.
Muhammad Tariq Afaq Motiwala Syed Umer Ali Mehmood Riaz Safia Awan Jaweed Akhter 《BMC medical education》2010,10(1):53
Background
Ward rounds form an integral part of Internal Medicine teaching. This study aimed to determine the trainees' opinions regarding various aspects of their ward rounds, including how well they cover their learning needs, how they would like the rounds to be conducted, and differences of opinion between medical students and postgraduates. 相似文献63.
64.
Safety of furosemide administration in an elderly woman recovered from thiazide-induced hyponatremia
BackgroundElderly women are at risk to develop severe hyponatremia after thiazide but not loop diuretic administration. In patients with previous thiazide-induced hyponatremia, the risk for recurrent hyponatremia after furosemide has not been established.MethodsIn order to determine how both diuretics affect water metabolism, we here compare the effects of a rechallenge with either amiloride-hydrochlorothiazide fixed association (AmHTZ; amiloride chlorhydrate 5 mg + hydrochlorothiazide 50 mg; Moduretic?) or furosemide (F; 40 mg; Lasix?) on water excretion in a 79 year old woman who was previously admitted for severe symptomatic hyponatremia secondary to a 5 days course of AmHTZ for systolic hypertension. After correction of initial hydromineral disturbances, a standard oral water load (WL; 20 mL per kg body weight) was administered before, during and after AmHTZ or F challenges.ResultsHyponatremia developed after AmHTZ but not after F challenge. A negative free water clearance (CH2O) was only observed during AmHTZ (? 0.39 mL/min), while maximal CH2O during F was 3.17 mL/min. Based on the results obtained during WL, the calculated maximal daily electrolyte free water clearance ability was only 888 mL after AmHTZ but 10,166 mL after F therapy. Taking into account a measured mean daily water intake of 1830 mL, severe hyponatremia could be predicted to occur after a few days treatment with AmHTZ. In comparison, F appears to be safer, without risk of hyponatremia, during an equivalent period of time.ConclusionsWe here showed that F may be administered to a patient with previous AmHTZ induced hyponatremia without risk for recurrent hyponatremia. 相似文献
65.
A 36-year-old woman presented with multiple yellowish cutaneous cysts of 5 years duration, over the scalp, trunk and upper limbs. She had pachyonychia, keratoderma of hands and feet, eyebrows which stood straight out and a single cafe-au-lait macule. 相似文献
66.
The N-terminus of a novel isoform of human iASPP is required for its cytoplasmic localization 总被引:11,自引:0,他引:11
Slee EA Gillotin S Bergamaschi D Royer C Llanos S Ali S Jin B Trigiante G Lu X 《Oncogene》2004,23(56):9007-9016
ASPP1 and ASPP2 are both proteins that interact with p53 and enhance its ability to induce apoptosis by selectively elevating the expression of proapoptotic p53-responsive genes. iASPP(RAI) is a third member of the family that is the most conserved inhibitor of p53-mediated apoptosis. Here, we have described iASPP, a longer form of iASPP(RAI), which at 828 amino acids is more than twice the size of iASPP(RAI). Using two antibodies that recognize both iASPP and iASPP(RAI), we report that this longer form of iASPP is the predominant form of the molecule expressed in cells. Like iASPP(RAI), iASPP also binds to p53 and inhibits apoptosis induced by p53 overexpression. However, whereas iASPP(RAI) is predominantly nuclear, the N-terminus of iASPP is entirely cytoplasmic, and the longer iASPP is located in both the cytoplasm and the nucleus. The effect upon subcellular localization of the longer N-terminus of iASPP means that this new, longer form of the molecule may be subject to greater regulation and provides another layer in the control of p53-induced apoptosis. 相似文献
67.
Banes-Berceli AK Ogobi S Tawfik A Patel B Shirley A Pollock DM Fulton D Marrero MB 《Vascular pharmacology》2005,43(5):310-319
Endothelin-1 (ET-1) and JAK2 are both implicated in diabetic complications. Therefore, we investigated whether ET-1 differentially activates JAK2 under conditions of normal (5 mM) and high (25 mM) glucose. We tested the hypothesis that reactive oxygen species mediate the activation of JAK2 in response to ET-1. In rat aortic vascular smooth muscle cells (VSMC), ET-1 (10 (- 7) M, 5 min) stimulated the activation of JAK2, which was further enhanced under high glucose conditions. Allopurinol (xanthine oxidase inhibitor, 1 microM) and l-NAME (nitric oxide synthase inhibitor, 1 mM) had no effect on ET-1-induced JAK2 activation, while apocynin (NAD(P)H oxidase inhibitor 100 microM) resulted in a significant inhibition of ET-1-induced JAK2 and MAPK activation. Overexpression of SOD did not inhibit ET-1-induced activation of JAK2, but catalase (50 units/mL) treatment resulted in complete inhibition. In vivo administration of apocynin (1.5 mM) resulted in a significant decrease ( 50%), while the ETA receptor antagonist ABT-627 completely inhibited phosphorylation of JAK2 in aortae from STZ-induced diabetic rats. Additionally, DHE staining of aortic sections was significantly reduced in diabetic rats treated with ABT-627. These data suggest that in VSMC, ET-1 via the ETA receptor, utilizes NAD(P)H oxidase to activate JAK2. 相似文献
68.
An aminopeptidase of human leukocyte lysosomes was partially purified by chromatography on SP-Sephadex, Sephadex G-200 and QAE-Sephadex. By QAE-Sephadex and isoelecric focusing it showed microheterogeneity, focusing at pH 3.7 and 4.1. By gel filtration its molecular weight was estimated to be approx. 200,000. The enzyme had leucine amino peptidase activity and pharmacological assays indicated that it converted lysyl- or methionyl-lysylbradykinin to bradykinin. Conversion of lysyl-bradykinin to bradykinin could be confirmed also by chromatography on CM-cellulose. When the neutrophil-derived enzyme acted on methionyl-lysyl-bradykinin it increased its effect of enhancing vascular permeability, when injected intradermally into guinea pigs. Thus the enzyme may play a role in neutrophil leukocyte-mediated vascular phenomena of the inflammatory reaction.Supported by the Ontario Heart Foundation and the Medical Research Council of Canada (MT-1251). 相似文献
69.
70.
Safia Wasi Thomas Santowski Shelley A. Murray Roger A. Perrault and Peter Gill 《Vox sanguinis》1991,60(2):82-87
The Canadian Red Cross Blood Services have been harvesting plasma from whole blood by plasmapheresis procedure for the last 10 years. To date, we have performed approximately 230,000 procedures. To determine whether this procedure is a health hazard to an individual, a donor safety program was established in 1979 at the National Reference Laboratory. Serum levels of total protein, albumin, and immunoglobulins are monitored at intervals set by the Bureau of Biologics, Health and Welfare Canada. In this communication, we present a 10-year evaluation of this program. A comparison of the protein concentration distributions between first-time and long-term plasmapheresis donors showed no significant differences. Therefore, we have demonstrated that the donors are not at risk as the result of changes in the measured plasma protein levels following plasmapheresis procedure as performed over the last 10 years at The Canadian Red Cross Blood Services. 相似文献