全文获取类型
收费全文 | 597篇 |
免费 | 18篇 |
专业分类
耳鼻咽喉 | 5篇 |
儿科学 | 12篇 |
妇产科学 | 7篇 |
基础医学 | 67篇 |
口腔科学 | 29篇 |
临床医学 | 37篇 |
内科学 | 94篇 |
皮肤病学 | 12篇 |
神经病学 | 82篇 |
特种医学 | 12篇 |
外科学 | 60篇 |
综合类 | 11篇 |
一般理论 | 1篇 |
预防医学 | 51篇 |
眼科学 | 5篇 |
药学 | 84篇 |
中国医学 | 7篇 |
肿瘤学 | 39篇 |
出版年
2022年 | 3篇 |
2021年 | 18篇 |
2020年 | 6篇 |
2019年 | 5篇 |
2018年 | 12篇 |
2017年 | 11篇 |
2016年 | 12篇 |
2015年 | 13篇 |
2014年 | 9篇 |
2013年 | 27篇 |
2012年 | 39篇 |
2011年 | 48篇 |
2010年 | 37篇 |
2009年 | 24篇 |
2008年 | 24篇 |
2007年 | 33篇 |
2006年 | 18篇 |
2005年 | 20篇 |
2004年 | 23篇 |
2003年 | 20篇 |
2002年 | 14篇 |
2001年 | 12篇 |
2000年 | 15篇 |
1999年 | 8篇 |
1998年 | 7篇 |
1997年 | 6篇 |
1996年 | 4篇 |
1994年 | 5篇 |
1993年 | 3篇 |
1992年 | 9篇 |
1991年 | 6篇 |
1990年 | 9篇 |
1989年 | 9篇 |
1988年 | 7篇 |
1987年 | 11篇 |
1986年 | 15篇 |
1985年 | 8篇 |
1984年 | 6篇 |
1983年 | 6篇 |
1982年 | 7篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 6篇 |
1977年 | 4篇 |
1976年 | 3篇 |
1975年 | 4篇 |
1973年 | 5篇 |
1971年 | 3篇 |
1917年 | 4篇 |
1916年 | 2篇 |
排序方式: 共有615条查询结果,搜索用时 31 毫秒
101.
Background
Human TNF-related apoptotic-inducing ligand (TRAIL) has been used successfully for targeted therapy of almost all cancers. Leukemia is the most common type of cancer in children, and despite the advances in therapeutic strategies, the survival rate in leukemia cases is very low. Overexpression of interleukin 2 receptor (IL2R) in hematological malignancies has been utilized to target leukemia. Here, we report an immunotoxin fusion construct of human IL2α and TRAIL for targeting leukemia.Aim
Our aim was to develop an immunotoxin to target CD25+ leukemic cells.Methods
Recombinant fusion construct comprising human IL2α and TRAIL114–281 was cloned, expressed and purified. Surface expression levels of IL2α and TRAIL receptors (CD25 and DR5 respectively) were compared in four leukemic cell lines and patient-derived peripheral blood mononuclear cells (PBMCs). Efficacy of immunotoxins was tested in cell lines and PBMCs by cell viability assay and compared with receptor expression.Results
The efficacy of IL2-TRAIL was higher than TRAIL alone and showed an IC50 ranging from 0.2-0.8 μM in cell lines. IL2-TRAIL induced cell death in PBMCs from leukemic patients in vitro, which was proportional to CD25 expression. Out of 34 leukemic samples, 24 samples were susceptible to immunotoxin-mediated cytotoxicity. The efficacy of IL2-TRAIL (87.5 %) was significantly high compared to TRAIL protein (29 %) in both myeloid and lymphoid leukemic patient samples. IL2-TRAIL fusion protein was highly specific for CD25+ leukemia and showed 100 % efficacy in lymphocytic leukemia [acute lymphoblastic leukemia and chronic lymphocytic leukemia] that overexpressed CD25.
102.
Salt loading increases urinary excretion of linoleic acid diols and triols in healthy human subjects
Dreisbach AW Rice JC Japa S Newman JW Sigel A Gill RS Hess AE Cemo AC Fonseca JP Hammock BD Lertora JJ Hamm LL 《Hypertension》2008,51(3):755-761
Increased dietary linoleic acid has been associated with reduced blood pressure in clinical and animal studies possibly mediated by prostaglandins. Urinary linoleate and prostaglandin metabolite excretion were investigated in subjects exposed to a salt-loading/salt-depletion regimen. Twelve healthy subjects were recruited from the New Orleans population (before Hurricaine Katrina) and admitted to the Tulane-Louisiana State University-Charity Hospital General Clinical Research Center after a 5-day outpatient lead-in phase on a 160-mmol sodium diet. On inpatient day 1, the subjects were maintained on the 160-mmol sodium diet, and a 24-hour urine specimen was collected. On day 2, the subjects received 2 L of IV normal saline over 4 hours and continued on a 160-mmol Na(+) diet (total: 460 mmol of sodium). Two 12-hour urine collections were obtained. On day 3, the subjects received three 40-mg oral doses of furosemide, two 12-hour urine collections were obtained, and the subjects were given a 10-mmol sodium diet. Urinary oxidized lipids were measured by high-performance liquid chromatography-tandem quadrupole mass spectroscopy. The excretion of the urinary linoleate metabolites, dihydroxyoctadecamonoenoic acids, and trihydroxyoctadecamonoenoic acids increased significantly during intravenous salt loading as compared with day 1 and the salt-depleted periods. The urinary excretion of 6-keto- prostaglandin F1alpha was unaffected by salt loading but was dramatically increased 7- to 10-fold by salt depletion. Prostaglandin E2 excretion was positively correlated with sodium excretion. The salt-stimulated production of linoleic acid diols and triols may inhibit tubular sodium reabsorption, thereby assisting in the excretion of the sodium load. 相似文献
103.
Agrawal DK Saikia D Tiwari R Ojha S Shanker K Kumar JK Gupta AK Tandon S Negi AS Khanuja SP 《Planta medica》2008,74(15):1828-1831
Demethoxycurcumin, isolated from the rhizomes of Curcuma longa, was found to possess antitubercular activity against Mycobacterium tuberculosis H (37)Rv strain at 200 microg/mL. Derivatisation of this active principle yielded a potent agent 6, exhibiting considerable activity with a minimum inhibitory concentration (MIC) value of 7.8 microg/mL. H (37)Rv:Mycobacterium tuberculosis H (37)Rv strain MIC:minimum inhibitory concentration. 相似文献
104.
105.
106.
Sharad B. Murdande Michael J. Pikal Ravi M. Shanker Robin H. Bogner 《Journal of pharmaceutical sciences》2011,100(10):4349-4356
A method is described for screening compounds that inhibit crystallization in solution to enable more accurate measurement of amorphous drug solubility. Three polymers [polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose acetate succinate (HPMCAS)] were screened for their ability to inhibit the crystallization of neat amorphous drugs during measurement of solubility of the amorphous form in water. Among the polymers evaluated, HPMCAS was found to be most promising. The use of HPMCAS provided an “apparent solubility” of amorphous drugs that was closer to the theoretically calculated values. With danazol, agreement was essentially quantitative, and for griseofulvin and iopanoic acid, agreement was within a factor of two; these maximum concentrations were sustained for a period of 40–90 xsmin. Dynamic light scattering of filtered samples (0.22 µ) revealed the presence of colloidal drug–polymer assemblies in solution (100–150 nm). The supernatant resulting from this centrifugation gradually decreased in concentration, but remained supersaturated with respect to crystalline drug for several hours. Thus, HPMCAS has been shown to be a useful additive in dissolution media to allow a more accurate determination of the solubility of fast crystallizing neat amorphous drugs, at least for the drugs studied, and it should also serve to retard crystallization in vivo and therefore, facilitate improved bioavailability. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4349–4356, 2011 相似文献
107.
Huang Y Lin L Shanker A Malhotra A Yang L Dikov MM Carbone DP 《Cancer research》2011,71(19):6122-6131
Deficiencies in immune function that accumulate during cancer immunoediting lead to a progressive escape from host immunosurveillance. Therapies that correct or overcome these defects could have a powerful impact on cancer management, but current knowledge of the types and mechanisms of immune escape is still incomplete. Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth. Conversely, tumor growth led to inhibition of Delta family ligand signaling through Notch in the hematopoietic environment, resulting in suppressed T-cell function. Overall, our findings uncover a novel mechanism of tumoral immune escape and suggest that a soluble multivalent form of DLL1 may offer a generalized therapeutic intervention to stimulate T-cell immunity and suppress tumor growth. 相似文献
108.
Roychowdhury S Iyer MK Robinson DR Lonigro RJ Wu YM Cao X Kalyana-Sundaram S Sam L Balbin OA Quist MJ Barrette T Everett J Siddiqui J Kunju LP Navone N Araujo JC Troncoso P Logothetis CJ Innis JW Smith DC Lao CD Kim SY Roberts JS Gruber SB Pienta KJ Talpaz M Chinnaiyan AM 《Science translational medicine》2011,3(111):111ra121
109.
Sharma HS 《Journal of neural transmission (Vienna, Austria : 1996)》2011,118(1):155-176
Spinal cord injury (SCI) is a devastating disease that leads to permanent disability of victims for which no suitable therapeutic
intervention has been achieved so far. Thus, exploration of novel therapeutic agents and nano-drug delivery to enhance neuroprotection
after SCI is the need of the hour. Previous research on SCI is largely focused to improve neurological manifestations of the
disease while ignoring spinal cord pathological changes. Recent studies from our laboratory have shown that pathological recovery
of SCI appears to be well correlated with the improvement of sensory motor functions. Thus, efforts should be made to reduce
or minimize spinal cord cell pathology to achieve functional and cellular recovery to enhance the quality of lives of the
victims. While treating spinal cord disease, recovery of both neuronal and non-neuronal cells, e.g., endothelia and glial
cells are also necessary to maintain a healthy spinal cord function after trauma. This review focuses effects of novel therapeutic
strategies on the role of spinal cord microvascular reactions and endothelia cell functions, i.e., blood–spinal cord barrier
(BSCB) in SCI and repair mechanisms. Thus, new therapeutic approach to minimize spinal cord pathology after trauma using antibodies
to various neurotransmitters and/or drug delivery to the cord directly by topical application to maintain strong localized
effects on the injured cells are discussed. In addition, the use of nanowired drugs to affect remote areas of the cord after
their application on the injured spinal cord in thwarting the injury process rapidly and to enhance the neuroprotective effects
of the parent compounds are also described in the light of current knowledge and our own investigations. It appears that local
treatment with new therapeutic agents and nanowired drugs after SCI are needed to enhance neurorepair leading to improved
spinal cord cellular functions and the sensory motor performances. 相似文献
110.
Near-infrared laser (785-nm)-excited Raman spectra from a red blood cell, optically trapped using the same laser beam, show significant changes as a function of trapping duration even at trapping power level of a few milliwatts. These changes in the Raman spectra and the bright-field images of the trapped cell, which show a gradual accumulation of the cell mass at the trap focus, suggest photoinduced aggregation of intracellular heme. The possible role of photoinduced protein denaturation and hemichrome formation in the observed aggregation of heme is discussed. 相似文献