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991.
992.
Hoefnagel LD Moelans CB Meijer SL van Slooten HJ Wesseling P Wesseling J Westenend PJ Bart J Seldenrijk CA Nagtegaal ID Oudejans J van der Valk P van Gils CH van der Wall E van Diest PJ 《Cancer》2012,118(20):4929-4935
BACKGROUND:
Changes in the receptor profile of primary breast cancers to their metastases (receptor conversion) have been described for the estrogen receptor α (ERα) and progesterone receptor (PR). The purpose of this study was to evaluate the impact of receptor conversion for ERα and PR on survival in a large group of distant non‐bone breast cancer metastases.METHODS:
Receptor conversion was studied by immunohistochemistry in a group of 233 metastatic breast cancer patients. Kaplan‐Meier overall survival curves were plotted, and differences between the curves were analyzed by log‐rank analysis. The additional prognostic value of conversion to established prognosticators was studied by Cox regression.RESULTS:
Overall survival of patients showing conversion from positive to negative ERα or PR, or from negative to positive ERα or PR, or remaining receptor negative was comparable, and significantly worse than patients remaining receptor positive. ERα or PR receptor conversion from positive in the primary breast tumor to negative in distant metastases has independent negative prognostic value.CONCLUSIONS:
ERα or PR receptor conversion from positive in the primary breast cancer to negative in distant metastases has negative prognostic value. Cancer 2012. © 2012 American Cancer Society. 相似文献993.
994.
Nanos-Webb A Jabbour NA Multani AS Wingate H Oumata N Galons H Joseph B Meijer L Hunt KK Keyomarsi K 《Breast cancer research and treatment》2012,132(2):575-588
Low molecular weight cyclin E (LMW-E) plays an important oncogenic role in breast cancer. LMW-E, which is not found in normal
tissue, can promote the formation of aggressive tumors and can lead to increased genomic instability and tumorigenesis. Additionally,
breast cancer patients whose tumors express LMW-E have a very poor prognosis. Therefore, we investigated LMW-E as a potential
specific target for treatment either alone or in combination therapy. We hypothesized that because LMW-E binds to CDK2 more
efficiently than full length cyclin E, resulting in increased activity, CDK inhibitors could be used to target tumors with
LMW-E bound to CDK2. To test the hypothesis, an inducible full length and LMW-E MCF7-Tet-On system was established. Cyclin
E (full length (EL) or LMW-E) is only expressed upon induction of the transgene. The doubling times of cells were unchanged
when the transgenes were induced. However, upon induction, the kinase activity associated with LMW-E was much higher than
that in the EL induced cells or any of the uninduced cells. Additionally only the LMW-E induced cells underwent chromosome
aberrations and increased polyploidy. By examining changes in proliferation and survival in cells with induced full length
and LMW-E, CDK inhibitors alone were determined to be insufficient to specifically inhibit LMW-E expressing cells. However,
in combination with Doxorubicin, the CDK inhibitor, Roscovitine (Seliciclib, CYC202), synergistically led to increased cell
death in LMW-E expressing cells. Clinically, the combination of CDK inhibitors and chemotherapy such as Doxorubicin provides
a viable personalized treatment strategy for those breast cancer patients whose tumors express the LMW-E. 相似文献
995.
996.
van Oosterwijk JG Herpers B Meijer D Briaire-de Bruijn IH Cleton-Jansen AM Gelderblom H van de Water B Bovée JV 《Annals of oncology》2012,23(6):1617-1626
BackgroundChondrosarcomas are malignant cartilage-forming tumors notorious for their resistance to conventional chemo- and radiotherapy. Postulated explanations describe the inaccessibility due to abundant hyaline cartilaginous matrix, presence of multidrug resistance (MDR) pumps, and expression of anti-apoptotic BCL-2 family members.Materials and methodsWe studied the sensitivity of chondrosarcoma cell lines (SW1353, CH2879, JJ012, OUMS27) and two primary cultures for doxorubicin and cisplatin. We examined the role of extracellular matrix using three-dimensional (3D) pellet models and MDR pump activity using fluorescence-activated cell sorter analysis. The role of BCL-2 family members was investigated using the BH3 mimetic ABT-737.ResultsChondrosarcoma cells showed highest resistance to cisplatin. 3D cell pellets, morphologically strongly resembling chondrosarcoma in vivo, confirmed nuclear incorporation of doxorubicin. MDR pump activity was heterogeneous among cultures. Chondrosarcoma cells responded to ABT-737 and combination with doxorubicin led to complete loss of cell viability and apoptosis with cytochrome C release.ConclusionsDespite MDR pump activity and abundance of hyaline cartilaginous matrix, doxorubicin is able to accumulate in the cell nuclei. By repairing the apoptotic machinery, we were able to sensitize chondrosarcoma cells to doxorubicin and cisplatin, indicating an important role for BCL-2 family members in chemoresistance and a promising new treatment strategy for inoperable chondrosarcoma. 相似文献
997.
Bosch LJ Oort FA Neerincx M Khalid-de Bakker CA Terhaar sive Droste JS Melotte V Jonkers DM Masclee AA Mongera S Grooteclaes M Louwagie J van Criekinge W Coupé VM Mulder CJ van Engeland M Carvalho B Meijer GA 《Cancer prevention research (Philadelphia, Pa.)》2012,5(3):464-472
Using a bioinformatics-based strategy, we set out to identify hypermethylated genes that could serve as biomarkers for early detection of colorectal cancer (CRC) in stool. In addition, the complementary value to a Fecal Immunochemical Test (FIT) was evaluated. Candidate genes were selected by applying cluster alignment and computational analysis of promoter regions to microarray-expression data of colorectal adenomas and carcinomas. DNA methylation was measured by quantitative methylation-specific PCR on 34 normal colon mucosa, 71 advanced adenoma, and 64 CRC tissues. The performance as biomarker was tested in whole stool samples from in total 193 subjects, including 19 with advanced adenoma and 66 with CRC. For a large proportion of these series, methylation data for GATA4 and OSMR were available for comparison. The complementary value to FIT was measured in stool subsamples from 92 subjects including 44 with advanced adenoma or CRC. Phosphatase and Actin Regulator 3 (PHACTR3) was identified as a novel hypermethylated gene showing more than 70-fold increased DNA methylation levels in advanced neoplasia compared with normal colon mucosa. In a stool training set, PHACTR3 methylation showed a sensitivity of 55% (95% CI: 33-75) for CRC and a specificity of 95% (95% CI: 87-98). In a stool validation set, sensitivity reached 66% (95% CI: 50-79) for CRC and 32% (95% CI: 14-57) for advanced adenomas at a specificity of 100% (95% CI: 86-100). Adding PHACTR3 methylation to FIT increased sensitivity for CRC up to 15%. PHACTR3 is a new hypermethylated gene in CRC with a good performance in stool DNA testing and has complementary value to FIT. 相似文献
998.
Bosch LJ Mongera S Sive Droste JS Oort FA van Turenhout ST Penning MT Louwagie J Mulder CJ van Engeland M Carvalho B Meijer GA 《Cellular oncology (Dordrecht)》2012,35(4):309-315
Background
Stool-based molecular tests hold large potential for improving colorectal cancer screening. Here, we investigated the analytical sensitivity of a DNA methylation assay on partial stool samples, and estimated the DNA degradation in stool over time. In addition, we explored the detection of DNA methylation in fecal immunochemical test (FIT) fluid.Materials and Methods
Partial stool samples of colonoscopy-negative individuals were homogenized with stool homogenization buffer, spiked with different numbers of HCT116 colon cancer cells and kept at room temperature for 0, 24, 48, 72 and 144?h before DNA isolation. Analytical sensitivity was determined by the lowest number of cells that yielded positive test results by DNA methylation or mutation analysis. DNA methylation in FIT fluid was measured in 11 CRC patients and 20 control subjects.Results
The analytical sensitivity for detecting DNA methylation was 3000 cells per gram stool, compared to 60000 cells per gram stool for detection of DNA mutations in the same stool samples. No degradation up to 72?h was noted when a conservation buffer was used. DNA methylation was detected in 4/11 CRC FIT samples and in none of the 20 control FIT samples.Conclusions
Methylation based stool DNA testing showed a high analytical sensitivity for tumor DNA in partial stool samples, which was hardly influenced by DNA degradation over time, provided an adequate buffer was used. The feasibility of detecting DNA methylation in FIT fluid demonstrates the opportunity to combine testing for occult blood with DNA methylation in the same collection device. 相似文献999.
1000.
Sustained survival of xenografted human neural stem/progenitor cells in experimental brain trauma despite discontinuation of immunosuppression 总被引:3,自引:0,他引:3
Wennersten A Holmin S Al Nimer F Meijer X Wahlberg LU Mathiesen T 《Experimental neurology》2006,199(2):339-347
Neural stem cells have emerged as a promising therapeutic tool in CNS disease and injuries. In the clinical setting, cultured human neural stem/progenitor cells (hNSC) are an attractive possibility for transplantation to the damaged brain. However, transplantation of hNSC requires toxic immunosuppressive treatment to avoid rejection. The aim of the current study was to evaluate if shortening the duration of immunosuppression by cyclosporin A would affect hNSC survival and differentiation after transplantation to the site of a focal brain injury in the rat. hNSC were xenografted to the hippocampus and the medial limit of an experimentally induced cortical contusion. The animals received immunosuppression for either 6 or 3 weeks or no immunosuppression. The status of the grafted human cells was analysed by immunohistochemistry. No statistically significant differences were observed between the two immunosuppressed groups regarding graft survival, migration or proliferation at 6 weeks post-transplantation. In contrast, the graft survival was extremely poor in the non-immunosuppressed group. Furthermore, the expression of the differentiation markers nestin, neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) in the transplanted cells did not differ significantly between the two immunosuppressed groups. Moreover, a fourth group of eight animals that were immunosuppressed for 3 weeks were allowed to survive for 6 months. Five of these rats demonstrated robust graft survival in the hippocampus and scattered cells in the cortex. This study demonstrates the importance of immunosuppression but also the possibility of shortening immunosuppression without impacting on the phenotype of the grafted hNSC. 相似文献