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131.
SR Turner JW Strohbach RA Tommasi PA Aristoff PD Johnson HI Skulnick LA Dolak EP Seest PK Tomich MJ Bohanon MM Horng JC Lynn KT Chong RR Hinshaw KD Watenpaugh MN Janakiraman S Thaisrivongs 《Canadian Metallurgical Quarterly》1998,41(18):3467-3476
A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide substitution within the dihydropyrone template provided a series of highly potent HIV protease inhibitors, with structure-activity relationships described in this paper. Crystallographic studies provided further information on important binding interactions responsible for high enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease with a Ki value of 8 pM and shows an IC90 value of 100 nM in antiviral cell culture. Clinical trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway. 相似文献
132.
城市垃圾气化熔融焚烧技术因能有效地抑止二恶英和重金属生成而日益受到重视。首先从热力学角度建立了城市垃圾气化熔融工艺临界热值的计算模型,具体分析了垃圾中水份、灰份和有机成份的变化对临界热值的影响。结果表明:随着空气预热从25C提高到250C,垃圾临界热值从8.7MJ/kg减少6.4MJ/kg,而垃圾中灰份过高也不利于气化熔融工艺。继而从气-固反应器的角度比较了回转窑、流化床和炼钢高炉作为基础炉型的气化熔融工艺的技术特点和适用条件,为国内未来垃圾气化熔融工艺的选择提供了参考。图6表2参14 相似文献
133.
J Longstreth FR de Gruijl ML Kripke S Abseck F Arnold HI Slaper G Velders Y Takizawa JC van der Leun 《Canadian Metallurgical Quarterly》1998,46(1-3):20-39
The health risks associated with ozone depletion will principally be those due to increased ultraviolet B (UV-B) radiation in the environment, i.e., increased damage to the eyes, the immune system, and the skin. Some new risks may also be introduced with the increased use of alternatives to the ozone-depleting substances (ODSs). Quantitative risk estimates are available for some of the UV-B-associated effects, e.g., cataract and skin cancer; however, the data are insufficient to develop similar estimates for effects such as immunosuppression and the toxicity of alternatives. Ocular damage from UV exposures includes effects on the cornea, lens, iris, and associated epithelial and conjunctival tissues. The most common acute ocular effect of environmental ultraviolet radiation (UVR) is photokeratitis. Also known as snowblindness in skiers, this condition also occurs in other outdoor recreationists. Chronic eye conditions likely to increase with ozone depletion include cataract, squamous cell carcinoma, ocular melanoma, and a variety of corneal/conjunctival effects, e.g., pterygium and pinguecula. Suppression of local (at the site of UV exposure) and systemic (at a distant, unexposed site) immune responses to a variety of antigens has been demonstrated in both humans and animals exposed to UV-B. In experiments with animals these effects have been shown to worsen the course/outcome of some infectious diseases and cancers. There is reasonably good evidence that such immunosuppression plays a role in human carcinogenesis; however, the implications of such immunosuppression for human infectious diseases are still unknown. In light-skinned populations, exposure to solar UVR appears to be the most important environmental risk factor for basal and squamous cell carcinomas and cutaneous melanoma. Originally it was believed that total accumulated exposure to UVR was the most important environmental factor in determining risk for these tumors. Recent information now suggests that only squamous cell carcinoma risk is related to total exposure. In the cases of both basal cell carcinoma and melanoma, new information suggests that increases in risk are tied to early exposures (before about age 15), particularly those leading to severe sunburns. Testing of a number of the chlorofluorocarbon (CFC) alternatives indicates that most of these chemicals have low acute toxicity, and low to moderate chronic toxicity. Some chemicals that were originally proposed as alternatives have been dropped from consideration because these tests raised concerns about toxicity and/or manufacturing difficulties. In one instance, high accidental occupational exposure was associated with liver damage, underlining the need for care in the use of these substitutes. Recent quantitative risk estimates have been developed for cataract, melanoma, and all skin cancers combined. These estimates indicate that under the Montreal Adjustments, cataract and skin-cancer incidence will peak mid-century at additional incidences of just under 3 per 100,000 and about 7 per 100,000, respectively. 相似文献
134.
TH Burkey FJ Ehlert Y Hosohata RM Quock S Cowell K Hosohata E Varga D Stropova X Li C Slate H Nagase F Porreca VJ Hruby WR Roeske HI Yamamura 《Canadian Metallurgical Quarterly》1998,62(17-18):1531-1536
Delta-opioid receptor-selective drugs may provide an alternative to mu-opioid-selective drugs currently used for the relief of pain. To develop improved delta-opioid receptor-selective drugs, better measures of drug activity are necessary. In this review we suggest that efficacy calculations provide a superior measure of drug activity as compared to dissociation constants and drug potencies in functional assays. Efficacy, as discussed in this review, is defined as a quantitative measurement of the ability of a drug to stimulate second messenger systems or measurable functional responses in cells or tissues under standard conditions. Efficacy values will allow medicinal chemists to understand the contributions of both the coupling efficiency and dissociation constant to drug potencies in the development of new delta-opioid receptor-selective drugs. 相似文献
135.
BACKGROUND: Neuroblastomas (NBs) exhibit a wide variety of clinical behavior. It is important to determine the biology of NB before treatment is instituted. METHODS: One hundred six NBs detected clinically (clinical NBs) were classified according to immunohistochemical expression of the Ha-ras and trk A genes. Association of the two-gene expression with patient outcome was examined retrospectively, and the possibility of prognostic prediction was evaluated. The profile of the expression of the two genes in 85 NBs detected through mass screening (mass NBs) was compared with that in clinical NBs. RESULTS: Ha-rasltrk A expression in clinical NBs was associated with disease free survival, even when the NBs had no amplification of the N-myc gene. Multivariate analysis demonstrated that the expression of Ha-rasl/trk A was a significant prognostic factor that was independent of stage, age at diagnosis, and N-myc amplification. Favorable outcomes of patients with advanced NB were distinguished by high Ha-ras and high trk A expression, and unfavorable outcomes were distinguished by low Ha-ras and low trk A expression. A profile of the two genes in mass NBs was different from that in clinical NBs. Greater than 50% of the mass NBs were detected as localized tumors with high Ha-ras and high trk A expression. The mass screening detected NBs with favorable and unfavorable biology. CONCLUSIONS: The expression of Ha-ras and trk A is an excellent predictor of both favorable and unfavorable biology in NBs. The information it provides can be important in determining the appropriate therapeutic intervention for each patient. 相似文献
136.
GW Mathern JK Pretorius D Mendoza A Lozada HI Kornblum 《Canadian Metallurgical Quarterly》1998,54(6):734-753
There is considerable controversy whether aberrant fascia dentata (FD) mossy fiber sprouting is an epiphenomena related to neuronal loss or a pathologic abnormality responsible for spontaneous limbic seizures. If mossy fiber sprouting contributes to seizures, then reorganized axon circuits should alter postsynaptic glutamate receptor properties. In the pilocarpine-status rat model, this study determined if changes in alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and n-methyl-D-aspartic acid (NMDA) receptor subunit mRNA levels correlated with mossy fiber sprouting. Sprague-Dawley rats were injected with pilocarpine (320 mg/kg; i.p.) and maintained in status epilepticus for 6 to 8 hours (pilocarpine-status). Rats were killed during the: (1) latent phase after neuronal loss but before spontaneous limbic seizures (day 11 poststatus; n = 7); (2) early seizure phase after their first seizures (day 25; n = 7); and (3) chronic seizure phase after many seizures (day 85; n = 9). Hippocampi were studied for neuron counts, inner molecular layer (IML) neo-Timm's staining, and GluR1-3 and NMDAR1-2b mRNA levels. Compared with controls, pilocarpine-status rats in the: (1) latent phase showed increased FD GluR3, NMDAR1, and NMDAR2b; greater CA4 and CA1 NMDAR1; and decreased subiculum GluR1 hybridization densities; (2) early seizure phase showed increased FD GluR3, increased CA1 NMDAR1, and decreased subiculum NMDAR2b densities; and (3) chronic seizure phase showed increased FD GluR2; increased FD and CA4 GluR3; decreased CA1 GluR2; and decreased subiculum GluR1, GluR2, NMDAR1, and NMDAR2b levels. In multivariate analyses, greater IML neo-Timm's staining: (1) positively correlated with FD GluR3 and NMDAR1 and (2) negatively correlated with CA1 and subiculum GluR1 and GluR2 mRNA levels. These results indicate that: (1) hippocampal AMPA and NMDA receptor subunit mRNA levels changed as rats progressed from the latent to chronic seizure phase and (2) certain subunit alterations correlated with mossy fiber sprouting. Our findings support the hypothesis that aberrant axon circuitry alters postsynaptic hippocampal glutamate receptor subunit stoichiometry; this may contribute to limbic epileptogenesis. 相似文献
137.
138.
Gligor V.D. Haigh T. Kemmerer D. Landwehr C.E. Lipner S. McLean J. 《Security & Privacy, IEEE》2006,4(1):62-69
This paper gives insights into how the threat's evolving nature, the current information technology environment, and various market forces are combining to yield new security challenges and likely new technology paths for the future. 相似文献
139.
S Liao J Alfaro-Lopez MD Shenderovich K Hosohata J Lin X Li D Stropova P Davis KA Jernigan F Porreca HI Yamamura VJ Hruby 《Canadian Metallurgical Quarterly》1998,41(24):4767-4776
On the basis of the structure-activity relationships of delta-opioid-selective peptide ligands and on a model of the proposed bioactive conformation for a potent and selective, conformationally constrained delta-opioid peptide ligand [(2S, 3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the delta-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand binding assays and in vitro bioassays. The new non-peptide ligands use piperazine as a template to present the most important pharmacophore groups, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of the D-Pen residues in DPDPE, which has been found to be extremely important for increasing the binding affinity and selectivity of these non-peptide ligands for the delta-opioid receptor over the mu-opioid receptor. Compound 6f (SL-3111) showed 8 nM binding affinity and over 2000-fold selectivity for the delta-opioid receptor over the mu-opioid receptor. Both enantiomers of SL-3111 were separated, and the (-)-isomer was shown to be the compound with the highest affinity for the delta-opioid receptor found in our study (IC50 = 4.1 nM), with a selectivity very similar to that observed for the racemic compound. The phenol hydroxyl group of SL-3111 turned out to be essential to maintain high affinity for the delta-opioid receptor, which also was observed in the case of the delta-opioid-selective peptide ligand DPDPE. Binding studies of SL-3111 and [p-ClPhe4]DPDPE on the cloned wild-type and mutated human delta-opioid receptors suggested that the new non-peptide ligand has a binding profile similar to that of DPDPE but different from that of (+)-4-[((alphaR)-alpha(2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80), another delta-opioid-selective non-peptide ligand. 相似文献
140.