全文获取类型
收费全文 | 608篇 |
免费 | 26篇 |
国内免费 | 25篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 29篇 |
妇产科学 | 7篇 |
基础医学 | 52篇 |
口腔科学 | 8篇 |
临床医学 | 73篇 |
内科学 | 85篇 |
皮肤病学 | 8篇 |
神经病学 | 44篇 |
特种医学 | 49篇 |
外科学 | 52篇 |
综合类 | 42篇 |
预防医学 | 12篇 |
眼科学 | 5篇 |
药学 | 143篇 |
肿瘤学 | 49篇 |
出版年
2022年 | 3篇 |
2021年 | 2篇 |
2020年 | 5篇 |
2019年 | 4篇 |
2018年 | 6篇 |
2017年 | 6篇 |
2016年 | 4篇 |
2015年 | 9篇 |
2014年 | 10篇 |
2013年 | 17篇 |
2012年 | 9篇 |
2011年 | 10篇 |
2010年 | 22篇 |
2009年 | 19篇 |
2008年 | 17篇 |
2007年 | 37篇 |
2006年 | 23篇 |
2005年 | 27篇 |
2004年 | 24篇 |
2003年 | 23篇 |
2002年 | 28篇 |
2001年 | 30篇 |
2000年 | 19篇 |
1999年 | 19篇 |
1998年 | 29篇 |
1997年 | 22篇 |
1996年 | 24篇 |
1995年 | 11篇 |
1994年 | 19篇 |
1993年 | 12篇 |
1992年 | 10篇 |
1991年 | 16篇 |
1990年 | 10篇 |
1989年 | 11篇 |
1988年 | 16篇 |
1987年 | 10篇 |
1986年 | 17篇 |
1985年 | 9篇 |
1984年 | 7篇 |
1983年 | 6篇 |
1982年 | 8篇 |
1981年 | 8篇 |
1980年 | 7篇 |
1979年 | 2篇 |
1978年 | 10篇 |
1977年 | 4篇 |
1976年 | 11篇 |
1975年 | 5篇 |
1974年 | 1篇 |
1968年 | 1篇 |
排序方式: 共有659条查询结果,搜索用时 6 毫秒
11.
1. Replacement of a threonine by a lysine at position 373 in the C-terminal portion of the third intracellular loop of the human alpha2A-adrenergic receptor (alpha2A AR) has been reported to generate a constitutively active mutant receptor in analogy with similar mutations in the alpha1B and beta2 AR (Ren et al., 1993). In the present study, the mutant Thr373Lys alpha2A AR receptor was investigated by measuring the formation of inositol phosphates in either the absence or presence of mouse G(alpha)15 protein in Cos-7 cells. 2. Increased affinity, potency and/or efficacy for the agonists [(-)-adrenaline, UK 14304, clonidine, guanabenz and oxymetazoline] was observed, consistent with a precoupled mutant alpha2A AR: G-protein state. The basal inositol phosphates response was similar at the wild-type (wt) and mutant alpha2A AR, but was enhanced at the mutant alpha2A AR upon co-expression with the mouse G(alpha)15 protein. This enhanced response could not be attenuated in the presence of any of the tested alpha2 AR antagonists (10 microM), suggesting that inverse agonist activity did not occur at the mutant alpha2A AR. 3. Ligands that so far have been identified as antagonists at the wt alpha2A AR demonstrated either no intrinsic activity (MK 912, WB 4101, RS 15385, RX 811059 and RX 821002) or positive efficacy [Emax, % vs. 1 microM UK 14304: dexefaroxan (27+/-7), idazoxan (34+/-9), atipamezole (27+/-4), BRL 44408 (59+/-5) and SKF 86466 (54+/-9)] at the mutant alpha2A AR, but only in the presence of the mouse G(alpha)15 protein. The ligand potencies corresponded with their respective pKi values at the mutant alpha2A AR receptor. 4. The partial agonist effect of SKF 86466 was resistant to pertussis toxin treatment (100 ng ml(-1)) and not affected by co-expression of the rat G(alpha)i1 protein. It was virtually absent in the presence of 10 microM RS 15385. SKF 86466 was without intrinsic activity upon co-expression of the mouse G(alpha)q protein. 5. Some putative alpha2 AR antagonists exerted a partial agonist activity that was highly dependent on the presence of specific G-protein alpha-subunits, suggesting that these ligands cause selective G-protein activation at the mutant alpha2A AR. 相似文献
12.
The activity state of G proteins is involved in the ligands' maximal responses that can be produced by activating the 5-HT1A receptor (Pauwels et al., 1997). The present study investigated the ligand responses at the recombinant h 5-HT1A receptor (RC: 2.1.5HT.01A) as mediated by the Galpha(o) protein. Therefore, a fusion protein was constructed between the 5-HT1A receptor and a pertussis toxin resistant rat Galpha(o)Cys351Gly mutant protein to define its pharmacological properties at a receptor: Galpha(o) protein density ratio of 1. Pertussis toxin treatment (100 ng/ml) affected neither the expression of the 5-HT1A receptor fusion protein as measured by [3H] MPPF (3.0+/-0.7 pmol/mg protein) nor the 5-HT-mediated [35S]GTPgammaS binding response (146+/-34 fmol/mg protein) in Cos-7 cells. 8-OH-DPAT (Emax: 55+/-7%) and buspirone (Emax: 22+/-4%) yielded partial agonist activity as compared to 5-HT, whereas WAY 100635 acted as a competitive antagonist (pK(B): 9.75+/-0.17). The magnitude of the 8-OH-DPAT response (Emax, %) was highly dependent on the nature of the amino acid 351 in the C-terminus of the Galpha(o) protein: Ile351 (93+/-4) > Cys351 (79+/-3) > Gly351 (55+/-7). The Emax values (%) of buspirone displayed the following gradient: 69+/-5 approximately/= 62+/-8 > 22+/-4. For comparison, maximal responses of 8-OH-DPAT and buspirone were enhanced versus 5-HT upon co-expression of the 5-HT1A receptor with the respective Galpha(o) proteins, probably due to an altered receptor: Galpha(o) protein density ratio. In conclusion, residue 351 of the rat Galpha(o) protein is involved in determining the magnitude of 5-HT1A receptor activation that ligands can produce at these receptors. Moreover, the fusion protein approach allows quantitative comparisons of the intrinsic activities of ligands between one single receptor subtype with different Galpha protein subtypes. 相似文献
13.
Petrus J. Pauwels Thierry Wurch Christiane Palmier Francis C. Colpaert 《Naunyn-Schmiedeberg's archives of pharmacology》1996,354(2):136-144
5-Hydroxytryptamine (serotonin, 5-HT), essentially known as a neurotransmitter and vasoactive agent, also functions as a mitogen in various cell types through several different second messenger systems. Stimulation of cloned human 5-HT1D receptor sites by sumatriptan in stably transfected rat C6-glial/5-HT1D cells promotes cell growth (Pauwels et al. (1996) Naunyn-Schmiedeberg's Arch Pharmacol 353:144–156). In the present study, the pharmacology of this growth response was investigated using a broad series of 5-HT receptor ligands. The data were compared with the responses obtained by measuring inhibition of forskolin-stimulated cAMP formation. 5-HT (EC50: 25 nM) promoted cell growth of C6-glial/5-HT1D cells, and this in contrast to the absence of any measurable effect in pcDNA3-plasmid transfected and non-transfected C6-glial cells. The 5-HT effect could be mimicked by the following compounds (EC50 in nM): zolmitriptan (0.41), 2-methyl-4-(5-methyl[1,2,4] oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127,935; 0.86), naratriptan (0.92), metergoline (1.9), sumatriptan (2.9), (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-y)]ethylamine (MK-462; 3.0), and R(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R(+)-8-OH-DPAT; 30.7). These EC50-values correspond to the compounds binding affinities at the human 5-HT1D receptor site and, with the exception of GR 127,935 and metergoline, also to the EC50-values found by measuring over 5 min inhibition of forskolin (100 M)-stimulated cAMP formation. Prolonged exposure of GR 127,935 (3 h) and metergoline (30 min) to cells yielded EC50 values in the cAMP assay more close to those measured in the mitogenic response. The growth response to sumatriptan, 5-HT, GR 127,935 and metergoline was blocked by the apparently silent antagonists methiothepin, ritanserin and ketanserin with potencies similar to blockade of inhibition of stimulated CAMP formation. The 8-OH-DPAT effect also is likely mediated by 5-HT1D receptors; stereoselectivity was found with its enantiomers at this receptor site and the effect was blocked by ketanserin (1 M) but not by spiperone (1 M). Micromolar concentrations of the 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydro)-4-pyridil-5-pyrrolo[3, 2-b]pyril-5-one (CP 93,129) and of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced cell growth with a potency that accorded with the affinity of these compounds for the human 5-HT1D receptor site. These effects were sensitive to ketanserin (1 M) antagonism, but not to blockade by -adrenergic blockers and the 5-HT2 receptor antagonist 2-anilino-N-[2-(3-chlorophenoxy)-propyl] acetamidine hydroiodide (BW 501-C-67). The findings suggest that 5-HT1A, 5-HT1B and 5-HT2 receptors are not implicated in 5-HT-stimulated C6-glial/5-HT1D cell growth. In conclusion, human 5-HT1D receptors are involved in the growth of C6-glial/5-HT1D cells. This cellular response is highly sensitive to the intrinsic activity of compounds at 5-HT1D receptors. 相似文献
14.
Low doses of benzodiazepines produce state-dependence (StD) of food-rewarded lever pressing in rats, and it has been hypothesized that the changes of memory states that can thus be studied constitute the mechanism whereby benzodiazepines cause their characteristic psychopharmacological actions such as anxiolysis, apparent memory loss and dependence. Non-benzodiazepine CNS agents such as NMDA antagonists also produce StD in this procedure, suggesting that the StD hypothesis of psychopharmacological drug action can be expanded to include agents other than benzodiazepines. For this expansion to be possible, however, it must be shown that the StD mechanism operates in a specific manner. The present experiments examined whether varying the extent of food deprivation affects any of a number of quantitative features of chlordiazepoxide (CDP)-induced StD of food-rewarded lever pressing in rats. The data indicate that the CDP doses required to generate StD in both drug-to-saline and dose-to-dose transfer tests, are considerably lower in relatively sated as opposed to more deprived animals; little or no difference was found in tests assaying saline-to-drug transfer. The data add behavioural to available pharmacological evidence supporting the hypothesis that changes of memory state constitute the mechanism whereby CNS agents such as benzodiazepines and NMDA antagonists cause their characteristic psychopharmacological actions. Some directions for future research are identified to explore further the pharmacological and behavioural specificity of drug-produced StD. 相似文献
15.
Arif JM; Gairola CG; Glauert HP; Kelloff GJ; Lubet RA; Gupta RC 《Carcinogenesis》1998,19(8):1515-1517
The present study investigated the effects of dietary oltipraz on cigarette
smoke-related lipophilic DNA adduct formation. Female Sprague- Dawley rats
were exposed daily to sidestream cigarette smoke in a whole- body exposure
chamber 6 h/day for 4 consecutive weeks. One group of rats was maintained
on control diet while another group received the same diet supplemented
with either a low (167 p.p.m.) or high (500 p.p.m.) dose of oltipraz,
starting 1 week prior to initiation of smoke exposure until the end of the
experiment. Analysis of lipophilic DNA adducts by the nuclease P1-mediated
32P-post-labeling showed up to five smoke-related adducts. Adduct no. 5
predominated in both the lung and the heart while adduct nos 3 and 2
predominated in the trachea and bladder, respectively. Quantitative
analysis revealed that the total adduct level was the highest in lungs
(270+/-68 adducts/10(10) nucleotides), followed by trachea (196+/-48
adducts/10(10) nucleotides), heart (141+/-22 adducts/10(10) nucleotides)
and bladder (85+/-16 adducts/10(10) nucleotides). High dose oltipraz
treatment reduced the adduct levels in lungs and bladder by >60%, while
the reduction in lungs in the low-dose group was approximately 35%. In
trachea, the effect of low and high dietary oltipraz on smoke DNA adduction
was equivocal, while smoke-related DNA adducts in the heart were minimally
inhibited by high-dose oltipraz. In a repeat experiment that employed a
3-fold lower dose of cigarette smoke, oltipraz (500 p.p.m.) was found to
inhibit the formation of DNA adducts in rat lungs and trachea by 80 and
65%, respectively. These data clearly demonstrate a high efficacy of
oltipraz in inhibiting the formation of cigarette smoke-induced DNA adducts
in the target tissues.
相似文献
16.
Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid 总被引:1,自引:0,他引:1
Anna Kruczynski Francis Colpaert Jean-Pierre Tarayre Pierre Mouillard Jacques Fahy Bridget T. Hill 《Cancer chemotherapy and pharmacology》1998,41(6):437-447
Vinflunine, or 20′,20′-difluoro-3′,4′-dihydrovino‐relbine, is a novel Vinca alkaloid obtained by hemisynthesis using superacidic chemistry. The most impressive structural modification of this vinorelbine
derivative was the selective introduction of two fluorine atoms at the 20′ position, a part of the molecule previously inaccessible
by classic chemistry. The antitumor activity of vinflunine was evaluated against a range of transplantable murine and human
tumors. Vinflunine exhibited marked activity against murine P388 leukemia grafted i.v. when given i.p. in single or multiple
doses according to various schedules or in single i.v. or p.o. doses. Increases in life span achieved with vinflunine, as
assessed by T/C ratios, ranged from 200% to 457% and proved markedly superior to those of 129–186% obtained with the other
Vinca alkaloids tested. Against s.c.-implanted B16 melanoma, multiple i.p. administration of vinflunine proved active in terms
of both survival prolongation and tumor growth inhibition, with optimal T/C values and relative areas under the tumor growth
curves (rAUC) being 24% and 36%, respectively. The extent of this activity was superior to that noted for vinorelbine under
the same experimental conditions. Growth inhibition of human tumor xenografts LX-1 (lung) and MX-1 (breast) was also observed
following four weekly i.p. injections of vinflunine as reflected by optimal T/C values of 23% and 26%, respectively, and significant
differences in the rAUCs noted for treated versus control animals. It was also noticeable that vinflunine induced considerably
more prolonged inhibitory effects on tumor growth than did vinorelbine. These results demonstrate that vinflunine is well
tolerated and is definitively active against a range of experimental animal tumor models. Vinflunine activity has been documented
in terms of both survival prolongation and tumor growth inhibition, with definite superiority over vinorelbine being shown
in each tumor model evaluated.
Received: 13 July 1997 / Accepted: 21 October 1997 相似文献
17.
Mutation of the p53 tumor suppressor gene in spontaneously occurring osteosarcomas of the dog 总被引:8,自引:0,他引:8
Inactivation of the p53 tumor suppressor gene has been implicated in the
pathogenesis of numerous human cancers, including osteosarcomas.
Appendicular osteosarcomas of the dog appear to be a good model for their
human equivalent with regard to biologic behavior, epidemiology and
histopathology. We individually screened exons 5-8 of the p53 gene for
mutations in 15 canine appendicular osteosarcomas using 'Cold' SSCP to
compare the role of this gene in human and canine osteosarcoma
tumorigenesis. Seven of the tumors (47%) exhibited point mutations, with
one tumor possessing two mutations within different exons. Of these, seven
were missense mutations and the eighth was a 'silent' mutation potentially
affecting the exon 6-7 splicing region. Five of the missense mutations were
located in highly conserved regions IV and V, while another corresponded
with the highly conserved codon 220 mutational hotspot located outside the
conserved domains. The locations and types of mutations were nearly
identical to those reported in human cancer. These findings provide strong
evidence of the involvement of p53 mutations in the development of canine
appendicular osteosarcomas. Canine osteosarcomas appear to be a promising
model for their human equivalent on a clinical, pathologic, and molecular
level.
相似文献
18.
Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. 总被引:11,自引:0,他引:11
Ilse Van der Auwera Gert G Van den Eynden Cecile G Colpaert Steven J Van Laere Peter van Dam Eric A Van Marck Luc Y Dirix Peter B Vermeulen 《Clinical cancer research》2005,11(21):7637-7642
PURPOSE: At the time of diagnosis, metastatic dissemination of tumor cells via the lymphatic system has occurred in nearly all patients with inflammatory breast cancer (IBC). The objective of this study was twofold: (a) to determine which is the most suitable marker of lymph vessels in primary breast tumors and (b) to compare histomorphometric lymph vessel variables in IBC and non-IBC. EXPERIMENTAL DESIGN: Serial sections of 10 IBCs and 10 non-IBCs were immunostained for D2-40, LYVE-1, podoplanin, and PROX-1. Relative lymph vessel area, lymph vessel perimeters, and counts and lymphatic endothelial cell proliferation (LECP) were then measured in D2-40/Ki-67 double-immunostained sections of 10 normal breast tissues, 29 IBCs, and 56 non-IBCs. RESULTS: D2-40 was the most suitable antibody for staining peritumoral and intratumoral lymph vessels. D2-40-stained intratumoral lymph vessels were present in 80% of non-IBCs and 82.8% of IBCs (P = 0.76). In non-IBC, lymph vessels located in the tumor parenchyma were smaller and less numerous than those at the tumor periphery (P < 0.0001) whereas in IBC, intratumoral and peritumoral variables were not significantly different. The mean relative tumor area occupied by lymph vessels was larger in IBC than in non-IBC (P = 0.01). LECP at the tumor periphery was higher in IBC than in non-IBC: median LECP was 5.74% in IBC versus 1.83% in non-IBC (P = 0.005). CONCLUSIONS: The high LECP in IBC suggests that lymphangiogenesis contributes to the extensive lymphatic spread of IBC. 相似文献
19.
20.
Benoit D Decruyenaere J Depuydt P Colpaert K 《Lancet》2004,363(9403):170; author reply 170-170; author reply 171