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951.
Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells 总被引:3,自引:0,他引:3
Yuan TC Veeramani S Lin FF Kondrikou D Zelivianski S Igawa T Karan D Batra SK Lin MF 《Endocrine-related cancer》2006,13(1):151-167
Neuroendocrine (NE) cells are the minor cell populations in normal prostate epithelial compartments. During prostate carcinogenesis, the number of NE cells in malignant lesions increases, correlating with its tumorigenicity and hormone-refractory growth. It is thus proposed that cancerous NE cells promote prostate cancer (PCa) cell progression and its androgen-independent proliferation, although the origin of the cancerous NE cells is not clear. To investigate the role of cancerous NE cells in prostate carcinogenesis, we characterized three NE subclone cell lines-NE-1.3, NE-1.8 and NE-1.9, which were transdifferentiated from androgen-sensitive human PCa LNCaP cells by culturing in an androgen-depleted environment, resembling clinical androgen-ablation therapy. These subclone cells acquire many features of NE cells seen in clinical prostate carcinomas, for example exhibiting a neuronal morphology and expressing multiple NE markers, including neuron-specific enolase, chromogranin B, neurotensin, parathyroid hormone-related peptide, and to a lesser degree for chromogranin A, while lacking androgen receptor (AR) or prostate specific antigen (PSA) expression. These cells represent terminally differentiated stable cells because after 3 months of re-culturing in a medium containing androgenic activity, they still retained the NE phenotype and expressed NE markers. Despite these NE cells having a slow growth rate, they readily developed xenograft tumors. Furthermore, media conditioned by these NE cells exhibited a stimulatory effect on proliferation and PSA secretion by LNCaP cells in androgen-deprived conditions. Additionally, we found that receptor protein tyrosine phosphatase alpha plays a role in upregulating multiple NE markers and acquiring the NE phenotype. These NE cells thus represent cancerous NE cells and could serve as a useful cell model system for investigating the role of cancerous NE cells in hormone-refractory proliferation of PCa cells. 相似文献
952.
Gabrilovich DI 《Expert opinion on biological therapy》2006,6(8):823-832
Mutations in the p53 gene are the most frequent genetic alterations in human tumours, occurring in approximately 50% of all cancers. The p53 protein is pivotal in maintaining genetic integrity after DNA damage, and alterations in the p53 pathway, including mutations in the p53 gene, greatly increase the probability of tumour formation. Gene therapy using adenoviral p53 has emerged as a novel treatment option, with the potential to be safe and effective in a wide range of cancer types. INGN 201 (Ad5CMV-p53, Advexin), a replication-impaired adenoviral vector that carries the p53 gene, has been evaluated in both preclinical and clinical trials. Results show that Advexin is a well-tolerated and efficacious treatment for numerous cancers, both as monotherapy and in combination with radiation and/or chemotherapy agents. In addition, there is now data to support the use of Advexin in cancer immunotherapy. 相似文献
953.
Veprintsev DB Freund SM Andreeva A Rutledge SE Tidow H Cañadillas JM Blair CM Fersht AR 《Proceedings of the National Academy of Sciences of the United States of America》2006,103(7):2115-2119
The tumor suppressor p53 consists of four 393-residue chains, each of which has two natively unfolded (N- and C-terminal) and two folded (core and tetramerization) domains. Their structural organization is poorly characterized as the protein tends to aggregate, has defied crystallization, and is at the limits of NMR studies. We first stabilized the protein by mutation to make it more suitable for extended study and then acquired NMR spectra on full-length protein and various combinations of shorter domain constructs. The NMR spectrum (15N,1H transverse relaxation optimized spectroscopy) of full-length p53 was close to that expected from the sum of the spectra of isolated individual domains. However, patterns of changes in chemical shifts revealed unexpected interactions between the core domains. We used the NMR data as constraints in docking algorithms and found a previously uncharacterized self-complementary surface for the association of core domains into dimers within the tetrameric complex. Binding to DNA requires about a 70 degrees rotation to break those subunit interactions and form the known protein:protein interface in the p53-DNA complex. We verified the interactions by the effects of mutation on DNA binding. Spectroscopic, biophysical, and mutational data conspired to give a picture of the p53 tetramer as a dimer of loosely tethered core dimers of appropriate symmetry to be poised to bind target DNA. 相似文献
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956.
High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia
Sokolenko AP Iyevleva AG Preobrazhenskaya EV Mitiushkina NV Abysheva SN Suspitsin EN Kuligina ESh Gorodnova TV Pfeifer W Togo AV Turkevich EA Ivantsov AO Voskresenskiy DV Dolmatov GD Bit-Sava EM Matsko DE Semiglazov VF Fichtner I Larionov AA Kuznetsov SG Antoniou AC Imyanitov EN 《International journal of cancer. Journal international du cancer》2012,130(12):2867-2873
The BLM gene belongs to the RecQ helicase family and has been implicated in the maintenance of genomic stability. Its homozygous germline inactivation causes Bloom syndrome, a severe genetic disorder characterized by growth retardation, impaired fertility and highly elevated cancer risk. We hypothesized that BLM is a candidate gene for breast cancer (BC) predisposition. Sequencing of its entire coding region in 95 genetically enriched Russian BC patients identified two heterozygous carriers of the c.1642 C>T (Q548X) mutation. The extended study revealed this allele in 17/1,498 (1.1%) BC cases vs. 2/1,093 (0.2%) healthy women (p = 0.004). There was a suggestion that BLM mutations were more common in patients reporting first-degree family history of BC (6/251 (2.4%) vs. 11/1,247 (0.9%), p = 0.05), early-onset cases (12/762 (1.6%) vs. 5/736 (0.7%), p = 0.14) and women with bilateral appearance of the disease (2/122 (1.6%) vs. 15/1376 (1.1%), p = 0.64). None of the BLM-associated BC exhibited somatic loss of heterozygosity at the BLM gene locus. This study demonstrates that BLM Q548X allele is recurrent in Slavic subjects and may be associated with BC risk. 相似文献
957.
Soloviev D Lewis D Honess D Aboagye E 《European journal of cancer (Oxford, England : 1990)》2012,48(4):416-424
The paradigm of drug development is shifting towards early use of imaging biomarkers as surrogate end-points in clinical trials. Quantitative Imaging in Cancer: Connecting Cellular Processes (QuIC-ConCePT) is an initiative to qualify complementary imaging biomarkers (IB) of proliferation, cell death and tumour heterogeneity as possible tools in early phase clinical trials to help pharmaceutical developers in 'go, no-go' decisions early in the process of drug development. One of the IBs is [(18)F]3'-deoxy-3'-fluorothymidine with Positron Emission Tomography (FLT-PET). We review results of recent clinical trials using FLT-PET for monitoring tumour response to drug treatment and discuss the potential and the possible pitfalls of using this IB as a surrogate end-point in early phase clinical trials for assessing tumour response to drug treatment. From first human trial results it seems that the degree of FLT accumulation in tumours is governed not only by the tumour proliferation rate but also by other factors. Nevertheless FLT-PET could potentially be used as a negative predictor of tumour response to chemotherapy, and hence evaluation of this IB is granted in multi-centre clinical trials. 相似文献
958.
Dmitry O Traktuev Zoya I Tsokolaeva Alexander A Shevelev Konstantin A Talitskiy Victoria V Stepanova Brian H Johnstone Tahmina M Rahmat-Zade Alexander N Kapustin Vsevolod A Tkachuk Keith L March Yelena V Parfyonova 《Molecular therapy》2007,15(11):1939-1946
Urokinase plasminogen activator (uPA) is required for both endogenous and vascular endothelial growth factor (VEGF)-augmented angiogenesis in normal tissues, leading us to hypothesize that uPA augmentation by gene transfer might promote angiogenesis in ischemic tissues. Overexpression of uPA was studied in rat myocardial infarction (MI) and mouse hind limb ischemia models and compared with VEGF overexpression effects. Animals were divided into control and three experimental groups (n = 6), receiving intramuscular injections of plasmids as follows: (i) control (empty vector or expressing beta-galactosidase); (ii) uPA; (iii) VEGF(165); (iv) a 1:1 mixture of uPA and VEGF(165). The capillary densities in both ischemic models were greater (P < 0.05) in tissues treated with uPA, VEGF, or a combination of both than in controls. Infarct size was reduced in hearts from uPA and VEGF experimental groups compared with controls (P < 0.05). Local overexpression of uPA induced a marked increase in the number of macrophages and myofibroblasts present within infarcts. Hind limb blood flow was greater in all experimental groups by day 10 (P < 0.05). Overall, the effects of uPA and VEGF were uniformly comparable. Additional analysis revealed association of local edema with VEGF but not with uPA treatment. This study established that uPA gene therapy effectively induces functionally significant angiogenesis in models of acute MI and hind limb ischemia. 相似文献
959.
960.