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Hansen TV Ejlertsen B Albrechtsen A Bergsten E Bjerregaard P Hansen T Myrhøj T Nielsen PB Timmermans-Wielenga V Andersen MK Jønson L Nielsen FC 《Breast cancer research and treatment》2009,115(1):69-76
Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations
in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC)
database. The mutation changes a conserved cysteine 39 to a glycine in the Zn2+ site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the families had members with
ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all
13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit, representing almost ~2% of the
total Greenlandic Inuit population, showed that the frequency of the mutation was 1.0%. We conclude that the BRCA1 nucleotide 234 T > G is a common Greenlandic Inuit founder mutation. The relative high frequency in the general population,
together with the ease of screening and possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic
Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
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Hansen Tv Jønson L Albrechtsen A Andersen MK Ejlertsen B Nielsen FC 《Breast cancer research and treatment》2009,115(2):315-323
BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0–36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian cancer patients in whom a deleterious mutation in BRCA1 and BRCA2 was not detected by sequencing using the multiplex ligation-dependent probe amplification (MLPA) assay. We identified 15
patients with 7 different genomic rearrangements, including a BRCA1 exon 5–7 deletion with a novel breakpoint, a BRCA1 exon 13 duplication, a BRCA1 exon 17–19 deletion, a BRCA1 exon 3–16 deletion, and a BRCA2 exon 20 deletion with a novel breakpoint as well as two novel BRCA1 exon 17–18 and BRCA1 exon 19 deletions. The large rearrangements in BRCA1 and BRCA2 accounted for 9.2% (15/163) of all BRCA1 and BRCA2 mutations in East Denmark. Nine patients had the exon 3–16 deletion in BRCA1. By SNP analysis we find that the patients share a 5 Mb fragment of chromosome 17, including BRCA1, indicating that the exon 3–16 deletion represents a Danish founder mutation.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
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997.
Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells 总被引:1,自引:0,他引:1
Konecny GE Venkatesan N Yang G Dering J Ginther C Finn R Rahmeh M Fejzo MS Toft D Jiang SW Slamon DJ Podratz KC 《British journal of cancer》2008,98(6):1076-1084
In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib. 相似文献
998.
Background: The frequency of asymptomatic central line-associated thromboses is high and well recognized among children with cancer, while the long-term consequences are mainly unknown. Aim: In a cross-sectional study, we evaluated clinical and radiological venous outcome in children with previous long-standing intravascular catheters. Methods: The study enrolled 71 children previously treated for malignant or haematological diseases, 4-180 (median 37) mo after removal of their central lines. Inclusion criteria were a prior central line in a jugular vein for a minimum of 6 mo and no previous history of thrombosis. The children had clinical examination for post-thrombotic syndrome (PTS) and Doppler ultrasonography of the central neck veins. Twelve children had additional venous magnetic resonance imaging (MRI). But no kind of venography was performed in the remaining. Results: We observed mild PTS with increased superficial collaterals in four children (6%), but no cases of more severe PTS. None complained of symptoms related to venous late effects. By ultrasonography, post-thrombotic venous alterations were detected in 17 children (24%), and five of these had complete occlusion of the veins. The sensitivity for pathologically increased collaterals to identify occlusive thrombosis was 0.6, while the specificity was 0.98. Occlusive venous thromboembolism was associated with the total number of central venous lines (CVLs; p=0.002), previous severe CVL-associated infections (p=0.001) and duration of central line in place (p=0.042).
Conclusion: In spite of no prior history of thrombosis, children with previous long-term jugular lines frequently had local thrombotic sequelae, while clinical symptoms of PTS were rare. 相似文献
Conclusion: In spite of no prior history of thrombosis, children with previous long-term jugular lines frequently had local thrombotic sequelae, while clinical symptoms of PTS were rare. 相似文献
999.
Dolphins are well known for their complex social and foraging behaviours. Direct underwater observations of wild dolphin feeding behaviour however are rare. At mass spawning aggregations of giant cuttlefish (Sepia apama) in the Upper Spencer Gulf in South Australia, a wild female Indo-Pacific bottlenose dolphin (Tursiops aduncus) was observed and recorded repeatedly catching, killing and preparing cuttlefish for consumption using a specific and ordered sequence of behaviours. Cuttlefish were herded to a sand substrate, pinned to the seafloor, killed by downward thrust, raised mid-water and beaten by the dolphin with its snout until the ink was released and drained. The deceased cuttlefish was then returned to the seafloor, inverted and forced along the sand substrate in order to strip the thin dorsal layer of skin off the mantle, thus releasing the buoyant calcareous cuttlebone. This stepped behavioural sequence significantly improves prey quality through 1) removal of the ink (with constituent melanin and tyrosine), and 2) the calcareous cuttlebone. Observations of foraging dolphin pods from above-water at this site (including the surfacing of intact clean cuttlebones) suggest that some or all of this prey handling sequence may be used widely by dolphins in the region. Aspects of the unique mass spawning aggregations of giant cuttlefish in this region of South Australia may have contributed to the evolution of this behaviour through both high abundances of spawning and weakened post-spawning cuttlefish in a small area (>10,000 animals on several kilometres of narrow rocky reef), as well as potential long-term and regular visitation by dolphin pods to this site. 相似文献
1000.
Rubab Agha Krogh Finn Friis Lauszus Eigil Guttorm Kjeld Rasmussen 《Archives of gynecology and obstetrics》2009,280(6):911-916