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排序方式: 共有3719条查询结果,搜索用时 62 毫秒
91.
92.
AP Krapcho E Menta A Oliva R Di Domenico L Fiocchi ME Maresch CE Gallagher MP Hacker G Beggiolin FC Giuliani G Pezzoni S Spinelli 《Canadian Metallurgical Quarterly》1998,41(27):5429-5444
The synthesis and antitumor evaluation of 2, 5-disubstituted-indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-aza-APs) are described. The key intermediates in the synthesis are benz[g]isoquinoline-5,10-diones which are substituted at positions 6 and 9 with groups of different nucleofugacity for SNAr displacements. The initial displacement of fluoride by a substituted hydrazine leads to the pyrazole analogues. Substitution of the remaining leaving group by an amine or BOC-protected amines leads to the 9-aza-APs 12. These analogues were converted into their maleate or hydrochloride salts 13. In two cases, namely, 13x and 13z, sidearm buildup was also employed in the synthetic pathway. In vitro evaluation of 9-aza-APs against the human colon tumor cell line LoVo uncovered for most of the compounds a cytotoxic potency lower than that of DuP-941 or mitoxantrone and comparable to that of doxorubicin. Only analogues 13c, 13n, and 13ff were as cytotoxic as DuP-941. Interestingly, while DuP-941 was highly cross-resistant in the LoVo cell line resistant to doxorubicin (LoVo/Dx), the 9-aza-APs carrying a distal lipophilic tertiary amine moiety in both chains were capable of overcoming the MDR resistance induced in this cell line. The 9-aza-APs show outstanding in vivo antitumor activity against both systemic P388 murine leukemia and MX-1 human mammary carcinoma transplanted in nude mice. At their optimal dosages, congeners 13a-c, 13f, 13n, 13q, 13x, and 13dd were highly effective against P388 leukemia with T/C% of 200-381, while the T/C% value of DuP-941 was 147. In the MX-1 tumor model, 24 compounds elicited percentages of tumor weight inhibitions (TWI) ranging from 50% to 99%. Congeners 13d, 13k, 13l, 13x, 13z, and 13ee emerged as the most effective ones, with TWI% 96, simliar to that of DuP-941 (TWI% = 95). On the basis of their efficacy profile in additional experimental tumors and lack of cardiotoxicity in preclinical models, two congeners have surfaced as potential clinical candidates. 相似文献
93.
ME Richardson 《Canadian Metallurgical Quarterly》1998,185(7):324-327
It is probably true to say that the masticatory apparatus attracts proportionally greater attention than any other part of the body. Evidence that this is so is provided, not only by the degree of specialisation within the dental profession, but by the frequency with which references to teeth and dentistry crop up in literature. Generations of biographers, novelists, poets, playwrights and essayists have written about their dental experiences and included the dentition in describing the facial appearance of characters, factual and fictional. The literary extracts in this article, culled from an extensive collection, refer to orthodontics. They provide a fascinating insight into the patient's perspective on that speciality and make entertaining reading. 相似文献
94.
The interaction of pancreatic triglyceride lipase and colipase at an oil-water interface is required for efficient digestion of dietary fats and provides a model system for the interaction of proteins at biological membranes. Colipase has two important surfaces, a hydrophilic surface that interacts with lipase and a hydrophobic surface that presumably interacts with substrate. To begin our investigations into the role of the hydrophobic surface in the function of colipase, we replaced three neighboring tyrosine residues at positions 55, 58, and 59 in the hydrophobic surface with aspartic acid. Two of the three residues, Tyr55 and Tyr59, influenced the activity of colipase. Introducing aspartic acid at either position decreased the activity with long-chain triglycerides, but not with a short-chain triglyceride. Decreased ability of the mutants to anchor lipase to long-chain triglycerides did not explain the altered activity of the mutants. A mutant containing aspartic acid at positions 55 and 59 had no activity with any substrate and did not anchor lipase to either short- or long-chain triglycerides. These results identify the two tyrosine residues that interact with substrate and suggest that the hydrophobicity of the surface containing these tyrosines influences colipase function and the substrate selectivity of pancreatic triglyceride lipase. 相似文献
95.
Y Yamada EM Webber I Kirillova JJ Peschon N Fausto 《Canadian Metallurgical Quarterly》1998,28(4):959-970
We used KO mice lacking either TNF receptor 1 (TNFR-1) or receptor 2 (TNFR-2) to determine whether signaling at the start of liver regeneration after partial hepatectomy (PH) involves only one or both TNF receptors and to analyze in more detail the abnormalities caused by lack of TNFR-1 receptor, which is required for the initiation of liver regeneration. Lack of TNFR-2 had little effect on NF-kappaB and STAT3 binding, and no effect in interleukin-6 production after PH, but caused a delay in AP-1 and C/EBP binding and in the expression of c-jun and c-myc messenger RNA (mRNA). In contrast to mice lacking TNFR-1, which had deficient hepatocyte DNA synthesis and massive lipid accumulation in hepatocytes, TNFR-2 KO mice had normal liver structure and similar levels of hepatocyte DNA replication as those of wild type mice. We conclude that TNFR-1, but not TNFR-2, is necessary for liver regeneration, and that NF-kappaB and STAT3 binding are activated by signals transduced by TNFR-1. Inhibition of AP-1 and C/EBP binding and in the expression of c-jun and c-myc mRNA in the first 4 hours after PH, as well as the apparent lack of Fos in AP-1 complexes, had no effect on the timing or extent of DNA replication. 相似文献
96.
ME McCarty EA Grossi C Cutting CD Prevel R Elluru BL Eppley 《Canadian Metallurgical Quarterly》1995,16(7):476-481
In order to improve the understanding of the role of sympathetic nerve degeneration in reimplantation failure, the hindlimbs of eight rats (Group I) underwent near-complete amputation. The soft tissues of the hindlimb were transected at the proximal thigh with the femoral artery, vein and femur left intact. The femoral vessels were clamped and guanethidine was infused into a branch of the femoral artery of the right leg of each animal, while saline was injected into the left leg. The clamps were removed after 15 minutes. A baseline preoperative injection of radiolabeled microspheres was made, and subsequent injections at 6, 12, 18, and 24 hours postoperation. Twelve rats (Group II) were then used to assess the amount of arterial-venous shunting preoperatively (n = 6) and at 18 hours postoperation (n = 6), by venous sampling. Blood flow to both limbs increased postoperation, but there was significantly more flow in the guanethidine treated limb at 18 and 24 hours postoperation. The amount of shunting was approximately 50% in both limbs at 18 hours, as compared to 10% preoperation. These results highlight the potential benefit of guanethidine and other sympathetic blocking agents in reimplantation to increase blood flow, decrease tissue ischemia and increase anastomotic patency rates. They also suggest that sympathetic nerve degeneration did not affect the volume of arterial-venous shunting in this model, but the difference in blood flow was likely due to arteriolar vasospasm. Further study is needed to elucidate the clinical significance of sympathetic nerve degeneration in reimplantation failure. 相似文献
97.
ME D?schel 《Canadian Metallurgical Quarterly》1995,49(10):677-679
98.
ME Bertrand V Legrand J Boland E Fleck J Bonnier H Emmanuelson M Vrolix L Missault S Chierchia M Casaccia L Niccoli A Oto C White M Webb-Peploe E Van Belle EP McFadden 《Canadian Metallurgical Quarterly》1998,98(16):1597-1603
BACKGROUND: Dual therapy with ticlopidine and aspirin has been shown to be as effective as or more effective than conventional anticoagulation in patients with an optimal result after implantation of intracoronary metallic stents. However, the safety and efficacy of antiplatelet therapy alone in an unselected population has not been evaluated. METHODS: Patients were randomized to conventional anticoagulation or to treatment with antiplatelet therapy alone. Indications for stenting were classified as elective (decided before the procedure) or unplanned (to salvage failed angioplasty or to optimize the results of balloon angioplasty). After stenting, patients received aspirin and either ticlopidine or conventional anticoagulation (heparin or oral anticoagulant). The primary end point was the occurrence of bleeding or peripheral vascular complications; secondary end points were cardiac events (death, infarction, or stent occlusion) and duration of hospitalization. RESULTS: In 13 centers, 236 patients were randomized to anticoagulation and 249 to antiplatelet therapy. Stenting was elective in 58% of patients and unplanned in 42%. Stent implantation was successfully achieved in 99% of patients. A primary end point occurred in 33 patients (13.5%) in the antiplatelet group and 48 patients (21%) in the anticoagulation group (odds ratio=0.6 [95% CI 0.36 to 0.98], P=0.03). Major cardiac-related events in electively stented patients were less common (odds ratio=0.23 [95% CI 0.05 to 0.91], P=0.01) in the antiplatelet group (3 of 123, 2.4%) than the anticoagulation group (11 of 111, 9.9%). Hospital stay was significantly shorter in the antiplatelet group (4.3+/-3.6 versus 6. 4+/-3.7 days, P=0.0001). CONCLUSIONS: Antiplatelet therapy after coronary stenting significantly reduced rates of bleeding and subacute stent occlusion compared with conventional anticoagulation. 相似文献
99.
100.
ME Stefanek 《Canadian Metallurgical Quarterly》1995,7(6):527-530
Over the past year, increasing research attention has been devoted to the issue of women at increased risk of developing breast cancer. These articles focus on a range of issues from recruiting high-risk women into breast cancer trials to recommendations for assessment and counseling women with a family history of breast cancer. In addition, continuing research attention has focused on quality of life, symptom management, and articles related to physician-patient communication. This review summarizes and critiques publications in these areas, and it includes articles reviewing the status of research in psychosocial oncology. 相似文献