全文获取类型
收费全文 | 15311篇 |
免费 | 1209篇 |
国内免费 | 54篇 |
专业分类
耳鼻咽喉 | 208篇 |
儿科学 | 322篇 |
妇产科学 | 248篇 |
基础医学 | 1905篇 |
口腔科学 | 430篇 |
临床医学 | 1531篇 |
内科学 | 3572篇 |
皮肤病学 | 188篇 |
神经病学 | 1175篇 |
特种医学 | 636篇 |
外科学 | 2293篇 |
综合类 | 315篇 |
一般理论 | 16篇 |
预防医学 | 1161篇 |
眼科学 | 502篇 |
药学 | 1054篇 |
中国医学 | 38篇 |
肿瘤学 | 980篇 |
出版年
2022年 | 81篇 |
2021年 | 193篇 |
2020年 | 96篇 |
2019年 | 191篇 |
2018年 | 215篇 |
2017年 | 167篇 |
2016年 | 205篇 |
2015年 | 251篇 |
2014年 | 397篇 |
2013年 | 666篇 |
2012年 | 822篇 |
2011年 | 898篇 |
2010年 | 491篇 |
2009年 | 472篇 |
2008年 | 876篇 |
2007年 | 994篇 |
2006年 | 1015篇 |
2005年 | 985篇 |
2004年 | 1043篇 |
2003年 | 960篇 |
2002年 | 968篇 |
2001年 | 137篇 |
2000年 | 92篇 |
1999年 | 168篇 |
1998年 | 230篇 |
1997年 | 205篇 |
1996年 | 182篇 |
1995年 | 195篇 |
1994年 | 145篇 |
1993年 | 157篇 |
1992年 | 89篇 |
1991年 | 92篇 |
1990年 | 96篇 |
1989年 | 95篇 |
1988年 | 99篇 |
1987年 | 79篇 |
1986年 | 86篇 |
1985年 | 110篇 |
1984年 | 167篇 |
1983年 | 147篇 |
1982年 | 217篇 |
1981年 | 218篇 |
1980年 | 164篇 |
1979年 | 90篇 |
1978年 | 113篇 |
1977年 | 143篇 |
1976年 | 136篇 |
1975年 | 121篇 |
1974年 | 94篇 |
1973年 | 90篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
991.
Isolation, structure, absolute stereochemistry, and HIV-1 integrase inhibitory activity of integrasone, a novel fungal polyketide 总被引:2,自引:0,他引:2
Herath KB Jayasuriya H Bills GF Polishook JD Dombrowski AW Guan Z Felock PJ Hazuda DJ Singh SB 《Journal of natural products》2004,67(5):872-874
HIV-1 integrase is a critical enzyme for replication of HIV, and its inhibition is one of the most promising new drug targets for anti-retroviral therapy with potentially significant advantages over existing therapies. In this Note, the isolation, structure elucidation, and absolute stereochemistry of integrasone, a novel polyketide, derived from an unidentified sterile mycelium have been described. This bicyclic dihydroxy epoxide lactone inhibited the strand transfer reaction of HIV-1 integrase with an IC(50) of 41 microM. 相似文献
992.
BACKGROUND: To redirect cytotoxic T cells to target a broad range of adenocarcinomas, the authors constructed a novel, recombinant, bispecific antibody, E3Bi, directed at the tumor-associated antigen, epithelial cell adhesion molecule (EpCAM), and the CD3 receptor on T cells. METHODS: T cells were prepared from healthy blood donors. The cytotoxicity of activated T cells (ATC) redirected to tumor cells by E3Bi was measured with in vitro (51)Cr release assays. In vivo studies were performed in a severe combined immunodeficient (SCID)/Beige mouse xenograft model. Tumor-bearing mice were treated with low doses (1 mg/kg) or high doses (10 mg/kg) of E3Bi along with ATC (2 x 10(9) cells/kg), and treatment efficacy was evaluated both by ex vivo tumor cell survival assay after in vivo treatments and by in vivo tumor growth delay studies. RESULTS: In vitro, targeting the EpCAM-overexpressing human tumor cell lines with E3Bi increased specific cytotoxicity of ATC by > 70% at an effector-to-target ratio of 2.5 (P < 0.001); this cytotoxicity was abolished competitively in the presence of an anti-EpCAM monoclonal antibody. In contrast, E3Bi did not enhance ATC cytotoxicity toward the low EpCAM-expressing tumor cell line. In ex vivo tumor cytotoxicity assays, a significant reduction in tumor cell survival (40% with low-dose E3Bi; 90% with high-dose E3Bi) was observed in E3Bi/ATC-treated mice compared with control mice that were treated with ATC only. In addition, SCID/Beige mice xenografted with LS174T tumors demonstrated a significant tumor growth delay (P = 0.0139) after receiving E3Bi/ATC/interleukin 2 (IL-2) compared with mice that received ATC/IL-2 alone. CONCLUSIONS: E3Bi specifically and very efficiently redirected T cells to destroy EpCAM-overexpressing tumors both in vitro and in an animal model. These results suggest a therapeutic utility for E3Bi in the treatment of adenocarcinomas. 相似文献
993.
994.
This study updates our experience with hepatic artery infusion chemotherapy for colorectal liver metastases at the Lahey Clinic. It compares surgical versus percutaneous catheter methods, employing an external pump. The surgical series (SS) consisted of 58 patients (1970-1995) treated with floxuridine (FUDR), 20 mg/d for 4 to 5 weeks (modified in 1985; 2-week cycles). Percutaneous series (PS) consisted of 42 patients (1976-1995) treated with fluorouracil (5-FU), 20 mg/d for 10 days followed by a floxuridine (FUDR) schedule as with SS. Analysis consisted of tumor response, survival, and toxicity data between the two methods. Response rates showed no significant difference, SS (34%) and PS (48%) (P = 0.22). There were no significant differences in survival from treatment until death in SS (n = 58) of 13 months versus PS (n = 42) of 10.6 months (P = 0.39), from diagnosis until death, SS being 28.4 months versus PS of 26.4 months (P = 0.71) and from metastases until death, SS being 17.4 months versus PS of 22.2 months (P = 0.35). Hepatic toxicity was similar, but there was increased bone marrow toxicity, mucositis, and diarrhea for the PS. Response rates are similar for both our SS and PS and to that reported in recently randomized surgical trials. Hepatic artery infusion chemotherapy with FUDR by percutaneous catheter placement may be as effective as surgical catheter placement for colorectal liver metastases, but further study is needed. 相似文献
995.
SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization 总被引:2,自引:0,他引:2
Ismail IH Mårtensson S Moshinsky D Rice A Tang C Howlett A McMahon G Hammarsten O 《Oncogene》2004,23(4):873-882
Loss of the DNA-dependent protein kinase (DNA-PK) results in increased sensitivity to ionizing radiation due to inefficient repair of DNA double-strand breaks. Overexpression of DNA-PK in tumor cells conversely results in resistance to ionizing radiation. It is therefore possible that inhibition of DNA-PK will enhance the preferential killing of tumor cells by radiotherapy. Available inhibitors of DNA-PK, like wortmannin, are cytotoxic and stop the cell cycle because they inhibit phoshatidylinositol-3-kinases at 100-fold lower concentrations required to inhibit DNA-PK. In an effort to develop a specific DNA-PK inhibitor, we have characterized SU11752, from a three-substituted indolin-2-ones library. SU11752 and wortmannin were equally potent inhibitors of DNA-PK. In contrast, inhibition of the phoshatidylinositol-3-kinase p110gamma required 500-fold higher concentration of SU11752. Thus, SU11752 was a more selective inhibitor of DNA-PK than wortmannin. Inhibition kinetics and a direct assay for ATP binding showed that SU11752 inhibited DNA-PK by competing with ATP. SU11752 inhibited DNA double-strand break repair in cells and gave rise to a five-fold sensitization to ionizing radiation. At concentrations of SU11752 that inhibited DNA repair, cell cycle progression was still normal and ATM kinase activity was not inhibited. We conclude that SU11752 defines a new class of drugs that may serve as a starting point for the development of specific DNA-PK inhibitors. 相似文献
996.
997.
998.
Johnstone AM Faber P Andrew R Gibney ER Elia M Lobley G Stubbs RJ Walker BR 《European journal of endocrinology / European Federation of Endocrine Societies》2004,150(2):185-194
OBJECTIVES: Obesity is associated with increased inactivation of cortisol by hepatic A-ring 5alpha- and 5beta-reductases, impaired hepatic regeneration of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), but increased subcutaneous adipose 11HSD1 activity enhancing local cortisol levels in fat. Cause and effect between obesity and abnormal cortisol metabolism is untested. DESIGN: Acute weight loss was induced by very low calorie diet (VLCD) or starvation in obese men. METHODS: Otherwise healthy males (aged 20-55 years; body mass index (BMI) 30-40 kg/m2) were studied after 6 days on a weight maintenance diet; then after either 6 days of starvation (n=6) or 3 weeks of VLCD (2.55 MJ; n=6); then after 1 week of weight maintenance; and finally after 2 weeks of being allowed to feed ad libitum. Plasma samples were obtained from indwelling cannulae at 0930 h and 1815 h and a 24 h urine collection was completed for analysis of cortisol metabolites by gas chromatography/mass spectrometry. RESULTS: Data are mean+/-S.E.M. BMI fell (kg/m3) from 34.8+/-0.8 at baseline to 31.8+/-1.4 on VLCD and 32.7+/-1.1 on starvation. Starvation caused a rise in plasma cortisol (at 0930 h from 143+/-17 to 216+/-11 nM, P<0.001) but no change in total urinary cortisol metabolites. VLCD did not alter plasma cortisol and markedly reduced cortisol metabolite excretion (from 15.8+/-1.1 mg/day at baseline to 7.0+/-1.1 mg/day, P<0.001). Relative excretion of 5alpha-reduced cortisol metabolites fell on both diets, but there were no changes in cortisol/cortisone metabolite ratios reflecting 11HSD activities. CONCLUSIONS: Weight loss with VLCD in obesity reverses up-regulation of hepatic A-ring reductases and normalises cortisol production rate; in contrast, starvation produces acute stress and further activation of cortisol secretion. We suggest that activation of cortisol secretion is not an irreversible intrinsic abnormality in obese patients, and speculate that dietary content has an important influence on the neuroendocrine response to weight loss. 相似文献
999.
Leyden J Bergfeld W Drake L Dunlap F Goldman MP Gottlieb AB Heffernan MP Hickman JG Hordinsky M Jarrett M Kang S Lucky A Peck G Phillips T Rapaport M Roberts J Savin R Sawaya ME Shalita A Shavin J Shaw JC Stein L Stewart D Strauss J Swinehart J Swinyer L Thiboutot D Washenik K Weinstein G Whiting D Pappas F Sanchez M Terranella L Waldstreicher J 《Journal of the American Academy of Dermatology》2004,50(3):443-447
Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function. 相似文献
1000.
Ringel TM Heidrich A Jacob CP Pfuhlmann B Stoeber G Fallgatter AJ 《Psychiatry research》2004,125(3):237-245
The dual click P50 paradigm has been established as a neurophysiological method to detect gating mechanisms. Studies of schizophrenic patients have shown that an insufficient reduction of the P50 amplitude after the second relative to the first stimulus indicates a deficient sensory gating mechanism. The aim of this study was to compare the P50 responses in the dual click paradigm of healthy volunteers to those of patients with different psychotic disorders, especially with regard to psychopathology and nosology according to ICD-10 and DSM-IV and to the classification system of Leonhard. A total of 34 patients and 12 healthy volunteers were investigated electrophysiologically while they performed the P50 dual click experiment. Patients with prominent negative symptoms and without perceptual abnormalities and patients with a hebephrenic subtype of schizophrenia showed less suppression in the dual click P50 paradigm than did healthy controls. Patients with brief/acute and transient psychotic disorders or cycloid psychoses did not differ from healthy volunteers with regard to suppression in the dual click P50 paradigm. No striking influence of gender, age, duration of disease and present medication was found. The findings confirm the lack of sensory gating measured by the dual click P50 paradigms in some but not all patients with schizophrenia. Both subtype of schizophrenia and current form of psychopathology appear to be related to the presence or absence of abnormal sensory gating. 相似文献