全文获取类型
收费全文 | 5280篇 |
免费 | 371篇 |
国内免费 | 12篇 |
专业分类
耳鼻咽喉 | 31篇 |
儿科学 | 160篇 |
妇产科学 | 97篇 |
基础医学 | 1033篇 |
口腔科学 | 65篇 |
临床医学 | 424篇 |
内科学 | 1071篇 |
皮肤病学 | 149篇 |
神经病学 | 548篇 |
特种医学 | 141篇 |
外科学 | 444篇 |
综合类 | 15篇 |
一般理论 | 1篇 |
预防医学 | 460篇 |
眼科学 | 82篇 |
药学 | 349篇 |
中国医学 | 4篇 |
肿瘤学 | 589篇 |
出版年
2023年 | 28篇 |
2022年 | 48篇 |
2021年 | 86篇 |
2020年 | 55篇 |
2019年 | 120篇 |
2018年 | 127篇 |
2017年 | 82篇 |
2016年 | 104篇 |
2015年 | 137篇 |
2014年 | 164篇 |
2013年 | 245篇 |
2012年 | 389篇 |
2011年 | 407篇 |
2010年 | 201篇 |
2009年 | 236篇 |
2008年 | 375篇 |
2007年 | 393篇 |
2006年 | 396篇 |
2005年 | 378篇 |
2004年 | 412篇 |
2003年 | 343篇 |
2002年 | 329篇 |
2001年 | 46篇 |
2000年 | 32篇 |
1999年 | 55篇 |
1998年 | 80篇 |
1997年 | 46篇 |
1996年 | 48篇 |
1995年 | 57篇 |
1994年 | 36篇 |
1993年 | 28篇 |
1992年 | 15篇 |
1991年 | 22篇 |
1990年 | 16篇 |
1989年 | 14篇 |
1988年 | 6篇 |
1987年 | 8篇 |
1986年 | 9篇 |
1985年 | 8篇 |
1984年 | 9篇 |
1983年 | 10篇 |
1982年 | 9篇 |
1981年 | 11篇 |
1980年 | 9篇 |
1979年 | 6篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 5篇 |
1970年 | 2篇 |
1957年 | 2篇 |
排序方式: 共有5663条查询结果,搜索用时 15 毫秒
961.
de Kruijf P Lim HD Roumen L Renjaän VA Zhao J Webb ML Auld DS Wijkmans JC Zaman GJ Smit MJ de Graaf C Leurs R 《Molecular pharmacology》2011,80(6):1108-1118
We have shown previously that different chemical classes of small-molecule antagonists of the human chemokine CXCR2 receptor interact with distinct binding sites of the receptor. Although an intracellular binding site for diarylurea CXCR2 antagonists, such as N-(2-bromophenyl)-N'-(7-cyano-1H-benzotriazol-4-yl)urea (SB265610), and thiazolopyrimidine compounds was recently mapped by mutagenesis studies, we now report on an imidazolylpyrimidine antagonist binding pocket in the transmembrane domain of CXCR2. Using different CXCR2 orthologs, chimeric proteins, site-directed mutagenesis, and in silico modeling, we have elucidated the binding mode of this antagonist. Our in silico-guided mutagenesis studies indicate that the ligand binding cavity for imidazolylpyrimidine compounds in CXCR2 is located between transmembrane (TM) helices 3 (Phe130(3.36)), 5 (Ser217(5.44), Phe220(5.47)), and 6 (Asn268(6.52), Leu271(6.55)) and suggest that these antagonists enter CXCR2 via the TM5-TM6 interface. It is noteworthy that the same interface is postulated as the ligand entry channel in the opsin receptor and is occupied by lipid molecules in the recently solved crystal structure of the CXCR4 chemokine receptor, suggesting a general ligand entrance mechanism for nonpolar ligands to G protein-coupled receptors. The identification of a novel allosteric binding cavity in the TM domain of CXCR2, in addition to the previously identified intracellular binding site, shows the diversity in ligand recognition mechanisms by this receptor and offers new opportunities for the structure-based design of small allosteric modulators of CXCR2 in the future. 相似文献
962.
Breast cancer is the second most frequent cancer in Sub-Saharan African women with an incidence of 15-53 per 100,000 women. Using PubMed, we reviewed all the articles published on this topic between 1989 and 2009. Breast cancer is usually diagnosed in women younger than in developed countries (mean age: 42-53 years), with later stages (III or IV, i.e. with axillary nodes and distant metastases). Reported tumors are mostly invasive ductal carcinomas with aggressive characteristics: grade III histoprognosis, absence of hormonal receptors or HER2 expression. According to the new breast cancer classification, nearly half of these tumors should be classified as triple negative. However, studies are rare and require confirmation. In conclusion, data on epidemiology and biology of breast cancer in Sub-Saharan African women are still scarce and need more extensive studies. In these countries, the pattern of breast cancer will likely change in the future, according to the evolution of lifestyle namely urbanisation. There is a great need for commitment of research and clinical resources in Sub-Saharan Africa in order to develop specific strategies. 相似文献
963.
van Luijn MM van den Ancker W Chamuleau ME Zevenbergen A Westers TM Ossenkoppele GJ van Ham SM van de Loosdrecht AA 《Cancer research》2011,71(7):2507-2517
Immune escape in cancer poses a substantial obstacle to successful cancer immunotherapy. Multiple defects in HLA class I antigen presentation exist in cancer that may contribute to immune escape, but less is known about roles for HLA class II antigen presentation. On class II(+) leukemic blasts, the presence of class II-associated invariant chain peptide (CLIP) is known to be correlated with poor survival in acute myeloid leukemia (AML). In this study, we evaluated the functional significance of CLIP expression on leukemic blasts of AML patients. CD4(+) T cells from patients were cocultured with autologous CLIP(-) and CLIP(+) primary leukemic blasts and analyzed for several functional parameters by flow cytometry. Increased HLA-DR and IFN-γ expression was observed for CD4(+) T cells stimulated with CLIP(-) leukemic blasts, in contrast to CLIP(+) leukemic blasts, which indicated an activation and polarization of the CD4(+) T cells toward T-helper 1 cells. In addition, CLIP(-) leukemic blasts induced greater outgrowth of effector memory CD4(+) T cells (with HLA-DR-restricted T-cell receptor Vβ repertoires) that were associated with better leukemia-specific reactivity than with CLIP(+) leukemic blasts. Our findings offer a clinical rationale to downmodulate CLIP on leukemic blasts as a strategy to degrade immune escape and improve leukemia-specific T-cell immunity in AML patients. 相似文献
964.
Decrausaz L Domingos-Pereira S Duc M Bobst M Romero P Schiller JT Jichlinski P Nardelli-Haefliger D 《International journal of cancer. Journal international du cancer》2011,129(3):762-772
Cervical cancer is a public health concern as it represents the second cause of cancer death in women worldwide. High-risk human papillomaviruses (HPV) are the etiologic agents, and HPV E6 and/or E7 oncogene-specific therapeutic vaccines are under development to treat HPV-related lesions in women. Whether the use of mucosal routes of immunization may be preferable for inducing cell-mediated immune responses able to eradicate genital tumors is still debated because of the uniqueness of the female genital mucosa (GM) and the limited experimentation. Here, we compared the protective activity resulting from immunization of mice via intranasal (i.n.), intravaginal (IVAG) or subcutaneous (s.c.) routes with an adjuvanted HPV type 16 E7 polypeptide vaccine. Our data show that s.c. and i.n. immunizations elicited similar frequencies and avidity of TetE71CD81 and E7-specific Interferon-gamma-secreting cells in the GM, whereas slightly lower immune responses were induced by IVAG immunization. In a novel orthotopic murine model, both s.c. and i.n. immunizations allowed for complete long-term protection against genital E7-expressing tumor challenge. However, only s.c. immunization induced complete regression of already established genital tumors. This suggests that the higher E7-specific systemic response observed after s.c. immunization may contribute to the regression of growing genital tumors, whereas local immune responses may be sufficient to impede genital challenges. Thus, our data show that for an efficiently adjuvanted protein-based vaccine, parenteral vaccination route is superior to mucosal vaccination route for inducing regression of established genital tumors in a murine model of HPV-associated genital cancer. 相似文献
965.
966.
Clozel M 《Science translational medicine》2011,3(67):67cm2
To continue to improve life expectancy and quality of life, the discovery of innovative therapies should be among the prime goals of the life sciences. The large majority of the drugs that are discovered and successfully developed to the point of being used by patients come from the drug industry, but publications from this sector are rare among life sciences research publications. Publications in the field of pharmaceutical drug discovery should take into account the confidentiality inherent to the protection of the intellectual property rights of a discovery, but they are fundamentally important because they can enhance scientific knowledge, improve the care and safety of patients, provide information for prescribers, and educate the public about the pharmaceutical industry. 相似文献
967.
Mark E. Schmidt Peter de Boer Randolph Andrews Martine Neyens Stefaan Rossenu Demiana William Falteos Erik Mannaert 《Psychopharmacology》2012,224(4):549-557
Rationale
JNJ-37822681 is a highly selective, fast dissociating dopamine D2-receptor antagonist being developed for the treatment of schizophrenia. A single dose [11C]raclopride positron emission tomography (PET) imaging study had yielded an estimated clinical dose range. Receptor occupancy at steady state was explored to test the validity of the single-dose estimates during chronic treatment.Objectives
The aims of this study are to characterize single and multiple dose pharmacokinetics and obtain striatal D2-receptor occupancies to predict doses for efficacy studies and assess the safety and tolerability of JNJ-37822681.Methods
An open-label single- and multiple-dose study with 10?mg JNJ-37822681 (twice daily for 13 doses) was performed in 12 healthy men. Twenty [11C]raclopride PET scans (up to 60?h after the last dose) from 11 subjects were used to estimate D2-receptor occupancy. A direct effect O max model was applied to explore the relationship between JNJ-37822681 plasma concentration and striatal D2-receptor occupancy.Results
Steady state was reached after 4?C5?days of twice daily dosing. JNJ-37822681 plasma concentrations of 3.17 to 63.0?ng/mL resulted in D2 occupancies of 0?% to 62?%. The concentration leading to 50?% occupancy was 18.5?ng/mL (coefficient of variation 3.9?%) after single dose and 26.0?ng/mL (8.2?%) at steady state. JNJ-37822681 was well tolerated.Conclusions
Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30?mg JNJ-37822681 twice daily could be suitable for these studies. 相似文献968.
Céline René Damien Paulet Emmanuelle Girodon Catherine Costa Guy Lalau Julie Leclerc Fa?za Cabet-Bey Thierry Bienvenu Martine Blayau Albert Iron Hervé Mittre Delphine Feldmann Caroline Guittard Mireille Claustres Marie des Georges 《European journal of human genetics : EJHG》2011,19(1):36-42
Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, 26 patients (5 having CF, 10 CBAVD (congenital bilateral absence of the vas deferens) and 11 with CF-like symptoms) and 14 healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from >2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution, give several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD. 相似文献
969.
970.
Vesikari T Karvonen A Borrow R Kitchin N Baudin M Thomas S Fiquet A 《Clinical and Vaccine Immunology : CVI》2011,18(5):878-884
RotaTeq (Merck & Co. Inc./Sanofi Pasteur MSD) is a three-dose, oral pentavalent rotavirus vaccine for the immunization of infants from 6 weeks of age for the prevention of rotavirus gastroenteritis. The primary objective of the present trial was to demonstrate that RotaTeq can be coadministered with meningococcal serogroup C conjugate vaccine (MenCC; NeisVac-C; Baxter Healthcare) to healthy infants without impairing the protective immune responses to MenCC. This was an open-label, randomized, comparative study conducted in Finland. The study was designed to assess concomitant versus sequential administration of RotaTeq and MenCC on the immune response to both vaccines. Healthy infants (n = 247), aged 6 to 7 weeks, were recruited. Coadministration of MenCC with RotaTeq was noninferior to sequential administration for the seroprotection rate against meningococcal serogroup C (the proportion of infants with a serum bactericidal antibody titer using baby rabbit complement of ≥ 8 was 100% in both groups). The other responses to MenCC (titer of ≥ 1:128, ≥ 4-fold increase in titer, and geometric mean titers [GMTs]) and the responses to RotaTeq (IgA and SNA response to G1 to G4 and P1A[8], GMTs, and ≥ 3-fold increase in titer) were comparable between groups, including a ≥ 3-fold IgA increase in >96% of the infants in both groups. Concomitant administration of the first doses of MenCC, diphtheria and tetanus toxoids and acellular pertussis vaccine, inactivated poliovirus vaccine, and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV-Hib), and RotaTeq was associated with a higher rate of vomiting and diarrhea than concomitant administration of MenCC and DTaP-IPV-Hib, but that was not observed after the second concomitant administration. The convenience of concomitant administration of RotaTeq and MenCC may, however, outweigh the additive effect of mostly mild adverse events reported after the individual administration of each vaccine. These results support the coadministration of RotaTeq and MenCC. 相似文献