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991.
Sanders JM Ghosh S Chan JM Meints G Wang H Raker AM Song Y Colantino A Burzynska A Kafarski P Morita CT Oldfield E 《Journal of medicinal chemistry》2004,47(2):375-384
gammadelta T cells are the first line of defense against many infectious organisms and are also involved in tumor cell surveillance and killing. They are stimulated by a broad range of small, phosphorus-containing antigens (phosphoantigens) as well as by the bisphosphonates commonly used in bone resorption therapy, such as pamidronate and risedronate. Here, we report the activation of gammadelta T cells by a broad range of bisphosphonates and develop a pharmacophore model for gammadelta T cell activation, in addition to using a comparative molecular similarity index analysis (CoMSIA) approach to make quantitative relationships between gammadelta T cell activation by bisphosphonates and their three-dimensional structures. The CoMSIA analyses yielded R(2) values of approximately 0.8-0.9 and q(2) values of approximately 0.5-0.6 for a training set of 45 compounds. Using an external test set, the activities (IC(50) values) of 16 compounds were predicted within a factor of 4.5, on average. The CoMSIA fields consisted of approximately 40% hydrophobic, approximately 40% electrostatic, and approximately 20% steric interactions. Since bisphosphonates are known to be potent, nanomolar inhibitors of the mevalonate/isoprene pathway enzyme farnesyl pyrophosphate synthase (FPPS), we also compared the pharmacophores for gammadelta T cell activation with those for FPPS inhibition, using the Catalyst program. The pharmacophores for gammadelta T cell activation and FPPS inhibition both consisted of two negative ionizable groups, a positive charge feature and an endocyclic carbon feature, all having very similar spatial dispositions. In addition, the CoMSIA fields were quite similar to those found for FPPS inhibition by bisphosphonates. The activities of the bisphosphonates in gammadelta T cell activation were highly correlated with their activities in FPPS inhibition: R = 0.88, p = 0.002, versus a human recombinant FPPS (N = 9 compounds); R = 0.82, p < 0.0001, for an expressed Leishmania major FPPS (N = 45 compounds). The bisphosphonate gammadelta T cell activation pharmacophore differs considerably, however, from that reported previously for gammadelta T cell activation by phosphoantigens (Gossman, W.; Oldfield, E. J. Med. Chem. 2002, 45, 4868-4874), suggesting different primary targets for the two classes of compounds. The ability to quite accurately predict the activity of bisphosphonates as gammadelta T cell activators by using 3D QSAR techniques can be expected to help facilitate the design of additional bisphosphonates for potential use in immunotherapy. 相似文献
992.
New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia 总被引:4,自引:0,他引:4
Cannabis consumption may induce psychotic states in normal individuals, worsen psychotic symptoms of schizophrenic patients, and may facilitate precipitation of schizophrenia in vulnerable individuals. Recent studies provide additional biological and genetic evidence for the cannabinoid hypothesis of schizophrenia. Examinations using [3H]CP-55940 or [3H]SR141716A revealed that the density of CB1 receptors, a central type of cannabinoid receptor, is increased in subregions of the prefrontal cortex in schizophrenia. Anandamide, an endogenous cannabinoid, is also increased in the CSF in schizophrenia. A genetic study revealed that the CNR1 gene, which encodes CB1 receptors, is associated with schizophrenia, especially the hebephrenic type. Individuals with a 9-repeat allele of an AAT-repeat polymorphism of the gene may have a 2.3-fold higher susceptibility to schizophrenia. Recent findings consistently indicate that hyperactivity of the central cannabinoid system is involved in the pathogenesis of schizophrenia or the neural mechanisms of negative symptoms. 相似文献
993.
Cigarette smoking, metabolic activation and carcinogenesis 总被引:2,自引:0,他引:2
Epidemiologically, it has been suggested that cigarette smoking is closely associated with an increased risk of cancers in various organs such as the lung, oropharynx, stomach, pancreas, liver and colon. Nevertheless, influences of cigarette smoking on experimental tumorigenesis in organs other than the respiratory tract remain to be elucidated. In our experimental studies, it has been shown that cigarette smoke exposure induces hepatic CYP enzymes, especially CYP1A2, in both rats and hamsters, and S9 fraction from their livers exposed to cigarette smoke specifically increases the mutagenicity in Ames assay of various heterocyclic amines (HCAs) contained in cigarette smoke and cooked food, which is in good agreement with the fact that HCAs are principally activated by CYP1A2 to proximate carcinogens. In fact, cigarette smoke exposure enhanced liver carcinogenesis in rats induced by 2-amino-3, 8-dimethylimidazo[4, 5-f]quinoxaline (MeIQx), a major HCA. Furthermore, in our recent study, it was also shown that cigarette smoke exposure induces hepatic CYP2A8 in hamsters, which is homologous to CYP2A6 in human, and hepatic S9 fraction exposed to cigarette smoke increases the mutagenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco specific nitrosamine, which is in line with the fact that NNK is metabolically activated by CYP2A6. Keeping these data, the aim of this review is to discuss any relevancy of modulated metabolic activation by cigarette smoking to cancer risk in human. 相似文献
994.
Sakata J Inoue J Ohi H Kosugi-Okano H Mishima Y Hatakeyama K Niwa O Kominami R 《Carcinogenesis》2004,25(6):1069-1075
Mouse thymic lymphomas induced by gamma-irradiation exhibited homozygous deletions of the Rit1/Bcl11b tumor suppressor gene on chromosome 12 at high frequencies. Internal deletions of one allele were frequently accompanied by loss of the other allele. In order to elucidate the mechanism of these internal deletions, the sites of breakage and rejoining were examined by PCR mapping and sequencing. The 5' site of the deletions clustered within an approximately 5 kb region of intron 1 and the 3' site was confined to a site in intron 3. These sites contained P and/or N nucleotides and cryptic sequences recognizable by the RAG1/2 recombinase in the vicinity. This suggests that the Rit1 intragenic deletions were generated by endogenous illegitimate V(D)J recombinase activity and such aberrant recombination was also detected by nested PCR of DNA from the thymus of unirradiated mice but not of RAG2-deficient mice. A rough estimate indicated that there reside as many as 10(3)-10(4) thymocytes having Rit1 deletions, assuming the presence of 10(8) thymocytes in the thymus of unirradiated mice. Moreover, the recombination frequency was not affected by gamma-irradiation. These results show no effect of radiation on Rit1 mutations and suggest an indirect mechanism for its role in lymphomagenesis. 相似文献
995.
996.
CA125 expression in epithelioid sarcoma 总被引:9,自引:0,他引:9
Kato H Hatori M Kokubun S Watanabe M Smith RA Hotta T Ogose A Morita T Murakami T Aiba S 《Japanese journal of clinical oncology》2004,34(3):149-154
OBJECTIVE: There has been no report on useful immunohistological markers for epithelioid sarcoma (ES) so far. The purpose of this study is to evaluate the positivity and specificity of CA125 as a marker for the correct diagnosis of ES. METHODS: This study was performed in 11 patients with ES (nine men and two women; distal type: 10 cases; proximal type: one case), 78 patients with other soft tissue tumors and nine with benign granulomas. The other soft tissue tumors consisted of six synovial sarcomas, six clear cell sarcomas, eight leiomyosarcomas, six rhabdomyosarcomas, five malignant peripheral nerve sheath tumors, ten malignant fibrous histiocytomas, 17 desmoid tumors, 14 liposarcomas, six squamous cell carcinomas (cutaneous SCC of the distal extremities), two rheumatoid nodules and seven foreign body granulomas. Immunohistochemical analysis for CA125 was performed for these 89 soft tissue tumors and nine granulomas using a labeled streptavidin biotin method. Immunohistochemical analysis of epithelial membrane antigen, cytokeratin, carcinoembrionic antigen, vimentin and CD34 was performed only for the 11 ES patients. RESULTS: CA125 was strongly expressed in 10 out of the 11 ES patients. EMA, cytokeratin and vimentin were also positive in all the cases. CEA was positive in two of the 11 patients. Immunohistochemical study in six ES patients showed expression of CD 34. The other 78 soft tissue tumors and nine granulomas did not express CA125. CONCLUSION: This study clearly revealed the specificity and positivity of CA125 in ES. These data indicate that CA125 may be a useful tumor marker for diagnosing ES. 相似文献
997.
Morita S Toi M Kobayashi T Ito Y Hozumi Y Ohno S Iwata H Sakamoto J 《Japanese journal of clinical oncology》2004,34(2):104-106
A phase I clinical trial was started in order to determine the recommended doses of capecitabine and epirubicin, when administered in combination with a fixed dose of cyclophosphamide (600 mg/m(2) day 1 q3 weeks) in patients with inoperable or recurrent breast cancer. This study consists of five dose levels with combinations of three levels of epirubicin (75, 90 and 100 mg/m(2) day 1 q3 weeks) and three levels of capecitabine (1255, 1657 and 1800 mg/m(2)/day consecutive administration for 2 weeks followed by 1 week of rest). Dose escalation and de-escalation decisions are based on a continual reassessment method (CRM). We conducted a survey of the clinical oncologists participating in this trial to determine the dose escalation/de-escalation rule, including a prior distribution for model parameters used in the CRM. 相似文献
998.
Masai K Iwashita Y Tominaga M Hirano S Shibata K Matsumoto T Sasaki A Ohta M Kitano S 《Gan to kagaku ryoho. Cancer & chemotherapy》2004,31(8):1261-1263
Chemokines represent a large family of polypeptide signaling molecules that are notable for their role in chemotaxis, leukocyte homing, and directional migration. Recent observations have indicated that the expression of chemokine receptors on cancer cells may play a role in tumor progression and metastasis. In this study, the expression of mRNA for chemokine receptors in various human tumor cell lines was analyzed by multiplex-polymerase chain reaction (M-PCR). Strong expression of CCR6 mRNA in 3 of 3 hepatoma cell lines was observed. In the 3 pancreatic cancer cell lines, no specific expression of chemokine receptors was observed. Raji (lymphoma cell line) strongly expressed CCR7 and CXCR4. We further investigated CCR6 mRNA expression in these cell lines by real-time quantitative-PCR. Similar results were obtained by both the PCR methods. Because human liver constitutively express liver and activation-regulated chemokine (specific ligand for CCR6), hepatoma cells may selectively root and spread in the liver. Strong CCR7 and CXCR4 expressions in the lymphoma cell may explain the organ specificity of lymphoma for lymphoid organs as well. These findings probably indicate that some cancer cells have organ specificity via expression of chemokine receptors. 相似文献
999.
Kudo M Chung H Osaki Y Kasugai H Oka H Seki T 《Gan to kagaku ryoho. Cancer & chemotherapy》2004,31(13):2100-2104
It is well known that prognosis of patients with hepatocellular carcinoma (HCC) depends not only cancer spread, but also on liver disease stage. The Japan Integrated Staging (JIS) scoring system, which combines TNM stage and Child-Pugh stage, is superior to CLIP Score in the discriminatory ability of the prognosis in 3,934 patients with HCC. Therefore, it is also useful in the comparison of the treatment results between treatment modalities or between institutions. It is thus recommended that the JIS score be used in the comparison of treatment results of patients with HCC. 相似文献
1000.
Akagi Y Hashimoto Y Takiyama W Mukaida H Murakami Y Ito K 《Gan to kagaku ryoho. Cancer & chemotherapy》2004,31(12):1993-1997
We reported concurrent chemoradiation for postoperative recurrent esophageal cancer patients with lymph node metastases and a pulmonary metastasis. From October 2001 to January 2004, we treated 6 consecutive patients with radiation and concurrent chemotherapy using daily low-doses of CDDP and UFT-E. Of the 6 patients, 4 (67%) had a complete response and 2 (33%) a partial response, yielding an overall response rate of 100% (6/6). Five patients are now alive without cancers, and 1 patient died with cancer. Concurrent chemoradiation using daily low-doses of CDDP and UFT-E is feasible and seems to offer good results for recurrent esophageal cancer patients. 相似文献