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991.
992.
FG Njoroge AG Taveras J Kelly S Remiszewski AK Mallams R Wolin A Afonso AB Cooper DF Rane YT Liu J Wong B Vibulbhan P Pinto J Deskus CS Alvarez J del Rosario M Connolly J Wang J Desai RR Rossman WR Bishop R Patton L Wang P Kirschmeier AK Ganguly 《Canadian Metallurgical Quarterly》1998,41(24):4890-4902
We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials. 相似文献
993.
K Bunting JB Cooper MO Badasso IJ Tickle M Newton SP Wood Y Zhang D Young 《Canadian Metallurgical Quarterly》1998,251(3):795-803
We have refined the X-ray structures of two site-directed mutants of the iron-dependent superoxide dismutase (SOD) from Mycobacterium tuberculosis. These mutations which affect residue 145 in the enzyme (H145Q and H145E) were designed to alter its metal-ion specificity. This residue is either Gln or His in homologous SOD enzymes and has previously been shown to play a role in active-site interactions since its side-chain helps to coordinate the metal ion via a solvent molecule which is thought to be a hydroxide ion. The mutations were based on the observation that in the closely homologous manganese dependent SOD from Mycobacterium leprae, the only significant difference from the M. tuberculosis SOD within 10 A of the metal-binding site is the substitution of Gln for His at position 145. Hence an H145Q mutant of the M. tuberculosis (TB) SOD was engineered to investigate this residue's role in metal ion dependence and an isosteric H145E mutant was also expressed. The X-ray structures of the H145Q and H145E mutants have been solved at resolutions of 4.0 A and 2.5 A, respectively, confirming that neither mutation has any gross effects on the conformation of the enzyme or the structure of the active site. The residue substitutions are accommodated in the enzyme's three-dimensional structure by small local conformational changes. Peroxide inhibition experiments and atomic absorption spectroscopy establish surprisingly the H145E mutant SOD has manganese bound to it whereas the H145Q mutant SOD retains iron as the active-site metal. This alteration in metal specificity may reflect on the preference of manganese ions for anionic ligands. 相似文献
994.
P Cooper 《Canadian Metallurgical Quarterly》1998,7(20):1232-1235
The use of moisture-retentive dressings (dressings that are capable of maintaining a warm moist environment) has been shown to provide the optimal environment for wound healing, accelerating the healing process and promoting tissue growth. TenderWet, produced by Paul Hartmann, is an innovative dressing that not only provides a moist warm environment but also incorporates the unique properties of Ringer's solution which actively cleanses (debrides) the wound. 相似文献
995.
996.
Peter Cooper 《Coloration Technology》1991,107(11):384-386
Pollution control has never been as rigorous as it is today and many manufacturers claim that they are swimming as hard as they can simply to stay above water. Peter Cooper considers the threats of ‘green’ legislation facing dyers and finishers and assesses what benefits can be derived from tighter effluent consent limits. 相似文献
997.
Golden perch Macquaria ambigua (Percichthyidae) and silver perch Bidyanus bidyanus (Terapontidae) are two potamodromous fish species of the Murray‐Darling river system in southeastern Australia. Ageing of these species using thin sections of the sagittal otoliths and validation with known‐age fish revealed: they live for over 26 years; male and female silver perch reach maturity at 3 and 5 years respectively; male and female golden perch reach maturity at 2 and 4 years respectively; both species exhibit sexual dimorphism with larger females; and growth varies (L∞ silver perch 331–397 mm, golden perch 354–502 mm) among interconnected river systems. Longevity and opportunistic growth are characteristics that are well suited to the semi‐arid and temperate hydrology of this river system. A flood‐recruitment model for these two species, consistent with the ‘flood‐pulse concept’, has previously been assumed to be the main mechanism of recruitment. The model appeared appropriate for this large, low‐gradient river system with productive floodplains. However, in the middle reaches of the Murray River we found that golden perch recruitment was strong in non‐flood years and poor in flood years, and silver perch recruited in all years. These data do not preclude golden perch recruiting during floods as well, because downstream larval drift may have resulted in strong year‐classes being swept downstream of the sampling area during high flows. However, the recruitment models for these species need to be re‐evaluated to include within‐channel flows. Importantly, these flows can be manipulated by river regulation, unlike large floods, and therefore there is potential to enhance recruitment. Copyright © 2003 John Wiley & Sons, Ltd. 相似文献
998.
H Date A Matsumura JK Manchester JM Cooper OH Lowry JD Cooper 《Canadian Metallurgical Quarterly》1993,105(3):492-501
Adult human liver microsomes supplemented with NADPH catalyzed the regioselective N-oxygenation of the aliphatic tertiary amine and S-oxidation of the phenothiazine sulfur atom of several 10-(N,N-dimethylaminoalkyl)phenothiazines. In addition, (+)- and (-)-4-bromophenyl-1,3-oxathiolane were converted to the corresponding S-oxides in the presence of NADPH and adult human liver microsomes. The (+) and (-) enantiomers of 4-bromophenyl-1,3-oxathiolane were converted to the S-oxides with low and high stereoselectivity, respectively. Studies on the biochemical mechanism for N-oxygenation of 10-(N,N-dimethylaminoalkyl)phenothiazines suggested that this reaction was catalyzed by the flavin-containing monooxygenase (form II), although cytochrome P-450 2D6 may also have contributed to N-oxide formation. S-Oxidation of chlorpromazine was catalyzed mainly by cytochrome P-450 3A. S-Oxidation of 10-(N,N-dimethylaminoalkyl)phenothiazines was catalyzed by a number of cytochromes P-450, including cytochromes P-450 2A6, 2C8, and 2D6. S-Oxygenation of (+)-4-bromophenyl-1,3-oxathiolane produced a mixture of the cis- and trans diastereomers in a process probably dependent on both hepatic monooxygenase systems. (-)-4-Bromophenyl-1,3-oxathiolane was converted almost exclusively to the trans-S-oxide in a process likely dependent on the adult human liver flavin-containing monooxygenase (form II). Development of regio- and stereochemical probes of adult human liver flavin-containing monooxygenase (form II) and cytochromes P-450 activity may be useful for eventual in vitro-in vivo correlations, but may require approaches quite distinct from that currently used for animal monooxygenases. 相似文献
999.
B R Cooper J A Jankowski D J Leszczyszyn R M Wightman J W Jorgenson 《Analytical chemistry》1992,64(6):691-694
A microcolumn liquid chromatographic method for the determination of norepinephrine and epinephrine in single bovine adrenomedullary cells is described. A single cell is isolated from a culture plate, (3,4-dihydroxybenzyl)amine is added as an internal standard, and the cell is lysed with perchloric acid. After centrifugation, the supernatant is injected directly into a 42 or 50 microns Inner diameter C18 reversed-phase column operated with electrochemical detection. Detection limits for norepinephrine and epinephrine were 46 and 75 amol, respectively. Of the 22 cells examined, 8 contained predominantly norepinephrine, 10 contained predominantly epinephrine, and at least 4 cells contained significant amounts of each. On average, a single cell contained approximately 150 fmol of catecholamine. 相似文献
1000.
TC Blochberger C Cooper D Peretz J Tatzelt OH Griffith MA Baldwin SB Prusiner 《Canadian Metallurgical Quarterly》1997,10(12):1465-1473
BACKGROUND: Personnel working in neonatal intensive care units frequently face difficult ethical problems related to the initiation, maintenance or withdrawal of life support therapies. AIM: To assess the importance of ethical issues in the clinical decision making of health care providers in neonatal intensive care units. MATERIAL AND METHODS: A questionnaire based on five clinical vignettes that assessed judgments about quality of life, impact of parent's opinions and decision making in emergency situations and with different degrees of certainty, was designed. Eleven neonatologists and 20 nurses and midwives specialized in neonatology anonymously answered this questionnaire. RESULTS: There was a great inter individual variability in therapeutic approaches in cases with a bad vital and neurological prognosis. In cases of medical emergencies with uncertain diagnoses, bad vital prognosis but neurological indemnity, most professionals coincided in delivering all possible therapeutic options. Parent's opinions had a great impact in medical decisions, except when there was neurological indemnity. CONCLUSIONS: The specific responsibilities of the different agents in medical decision making must be delimited. Parents do not have absolute rights over their offspring and physicians must reject useless therapies. 相似文献