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71.
RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability 总被引:4,自引:0,他引:4
Heikkinen K Rapakko K Karppinen SM Erkko H Knuutila S Lundán T Mannermaa A Børresen-Dale AL Borg A Barkardottir RB Petrini J Winqvist R 《Carcinogenesis》2006,27(8):1593-1599
The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer. 相似文献
72.
Camps J Armengol G del Rey J Lozano JJ Vauhkonen H Prat E Egozcue J Sumoy L Knuutila S Miró R 《Carcinogenesis》2006,27(3):419-428
Genomic copy number changes are frequently found in cancers and they have been demonstrated to contribute to carcinogenesis; and it is widely accepted that tumors with microsatellite instability (MSI) are genetically stable and mostly diploid. In the present study we compared the copy number alterations and the gene-expression profiles of microsatellite stable (MSS) and MSI colorectal tumors. A total number of 31 fresh-frozen primary tumors (16 MSS and 15 MSI) were used. Twenty-eight samples (15 MSS and 13 MSI) were analyzed with metaphase comparative genomic hybridization (CGH), nine of which plus one additional sample (4 MSS and 6 MSI) were further analyzed by cDNA-based array-CGH. Gene expression analysis was performed with six samples [3 MSS and 3 MSI, four of these used in metaphase CGH (mCGH) analysis] to identify differentially expressed genes possibly located in the lost or amplified regions found by CGH, stressing the biological significance of copy number changes. Metaphase and array-CGH analysis of two colon cancer cell lines (HTC116 and SW480, reported as MSI and MSS archetypes) gave comparable results. Alterations found by mCGH in MSS tumors were +20, +8q, -8p and -18q. Interestingly, 1p22, 4q26 and 15q21 were found deleted preferentially in MSS tumors, while 22q13 was found gained in MSI tumors. The regions of alterations identified by array-CGH were gains at 8q24, 16q24.3 and 20q13, and the loss of 5q21, appearing in the both types of tumors. Gene expression analysis revealed genes with specific associations with the copy number changes of the corresponding genomic regions. As a conclusion, colorectal cancer is a heterogeneous disease, demonstrated by the genomic profiles of individual samples. However, our data shows that copy number changes do not occur exclusively in the MSS phenotypes. 相似文献
73.
74.
Sakari Sekine Takeshi Watanabe Hirosato Tanaka 《Journal of clinical laboratory analysis》1995,9(3):193-195
A novel homogeneous enzyme immunoassay has been developed that takes advantage of the observation that the activity of a bacterial chitinase could be enhanced by the binding of a ligand conjugate of a monoclonal antibody to the enzyme (L-MAbchi). The enhancement was suppressed by an antiligand antibody (AbL). Free ligand molecules competed for AbL combining with L-MAbchi, and the suppression of the enhancement was reduced. Thus the concentration of free ligand could be estimated. Biotin was used as a ligand in this model experiment. When this monoclonal antibody was conjugated with a ligand (e.g., biotin), we furthermore found that the enhancement could be suppressed by an antiligand antibody (AbL). When free ligand molecules are added to the system, competition with L-MAbchi results to reduce the suppression of enhancement.©1995 wiley-Liss, inc. 相似文献
75.
Lindahl U Li JP Kusche-Gullberg M Salmivirta M Alaranta S Veromaa T Emeis J Roberts I Taylor C Oreste P Zoppetti G Naggi A Torri G Casu B 《Journal of medicinal chemistry》2005,48(2):349-352
Heparin remains a major drug in prevention of thromboembolic disease. Concerns related to its animal source have prompted search for heparin analogues. The anticoagulant activity of heparin depends on a specific pentasaccharide sequence that binds antithrombin. We report the generation of a product with antithrombin-binding, anticoagulant, and antithrombotic properties similar to those of heparin, through combined chemical and enzymatic modification of a bacterial (E. coli K5) polysaccharide. The process is readily applicable to large-scale production. 相似文献
76.
Mattila P Joenväärä S Renkonen J Toppila-Salmi S Renkonen R 《Clinical and translational allergy》2011,1(1):5
ABSTRACT: The objective of this review is to focus on putative modified epithelial functions related to allergy. The dysregulation of the epithelial barrier might result in the allergen uptake, which could be the primary defect in the pathogenesis of allergic reaction. We review the literature of the role of respiratory epithelium as an active barrier, how allergens are transported through it and how it senses the hostile environmental allergens and other dangerous stimuli. 相似文献
77.
78.
Vauhkonen H Vauhkonen M Sajantila A Sipponen P Knuutila S 《Cancer Genetics and Cytogenetics》2006,167(2):150-154
Genomic instability can be divided into 2 categories: chromosomal instability (CIN) and microsatellite instability (MSI). CIN has been linked to aneuploidy and chromosomal aberrations, and high-level loss of heterozygosity (LOH-H) has been suggested to be an indicator of CIN. High-level MSI (MSI-H), which results from nonfunctional mismatch repair, has previously been suggested to be mutually exclusive with CIN. Four MSI-H and three LOH-H primary gastric tumors of intestinal histology were used for copy number analysis by array-based comparative genomic hybridization (aCGH) with 13,000 cDNA targets. The MSI-H group showed fewer gains (0-12, average 4.5) and losses (0-10, average 2.5) per tumor as compared to the LOH-H group (9-15 gains, average 11.6 and 1-6 losses, average 4). Two MSI-H tumors did not show any copy number changes and one showed only gains of whole chromosomes. The most common alterations were gains of 20q (5/7 samples), 1q, 8, and 10p (3/7 samples) and losses of 1p and 5p (3/7 samples). The minimal amplified regions in 1q and 20q were localized to 1q21.1 approximately q21.2, 1q21.3, 20q11.2, 20q13.12, and 20q13.3 approximately qter. No copy number change was found to be specific for MSI-H or LOH-H. The results suggest that the LOH-H phenotype revealed by microsatellite analysis predicts reliably copy number abnormalities on aCGH and that a subset of MSI-H and all LOH-H tumors share the CIN phenotype. 相似文献
79.
80.
Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors 总被引:5,自引:0,他引:5 下载免费PDF全文
Lehtonen R Kiuru M Vanharanta S Sjöberg J Aaltonen LM Aittomäki K Arola J Butzow R Eng C Husgafvel-Pursiainen K Isola J Järvinen H Koivisto P Mecklin JP Peltomäki P Salovaara R Wasenius VM Karhu A Launonen V Nupponen NN Aaltonen LA 《The American journal of pathology》2004,164(1):17-22
Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer. 相似文献