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《Clinical Lymphoma, Myeloma & Leukemia》2020,20(3):184-189
BackgroundSystemic AL amyloidosis (AL) is a rare disease in which clonal immunoglobulin light chains produced by monoclonal plasma cells circulate and misfold, resulting in direct toxicity and fibrillar deposition of amyloid in numerous tissues. Early mortality from cardiac damage remains high. As depth of organ response carries a prognostic significance, combining anti-plasma cell and anti-amyloid therapies might hold the key to achieving long lasting responses. We report a series of patients who received 2 monoclonal antibodies, anti-CD38 and anti-amyloid, simultaneously.Materials and MethodsWe describe the characteristics and outcomes of 19 patients who received daratumumab (anti-CD38) on progression with front-line therapy for AL, 9 of whom were on concurrent dual monoclonal antibody treatment with daratumumab and NEOD001 (anti-amyloid), and also provide data on the schedule, safety, and tolerability of intravenous infusions of these monoclonal antibodies.ResultsThe 9 patients who received treatment with dual monoclonal antibodies achieved a high rate (100%) of hematologic response in a median of 33 days. There was no significant toxicity to dual monoclonal antibody therapy. Seven of the 8 met criteria for cardiac response, achieved in less than 3 months of combined therapy. Ten patients who received daratumumab alone also had high rates of hematologic and organ responses.ConclusionsMonoclonal antibodies with distinctly different targets can be safely combined in patients with AL and cardiac involvement. Patients experienced high rates of hematologic and cardiac response with combined anti-CD38 and anti-amyloid monoclonal antibody therapies. Further study of this combined approach is warranted. 相似文献
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摘 要 目的:建立原料药HSSYO 001 3S细菌内毒素检查方法。方法: 以二甲亚砜(DMSO)溶解HSSYO 001 3S,用适量细菌内毒素检查用水(BET水)稀释后,离心取上清液,按中国药典2015年版四部通则11431检查凝胶法,对HSSYO 001 3S进行细菌内毒素检查的方法学研究。结果:HSSYO 001 3S加助溶剂并以BET水稀释至1 mg·m-1 ,经离心后取上清液稀释4倍及以上时对鲎试剂凝集反应无干扰作用。结论:HSSYO 001 3S可采用细菌内毒素检查法控制其质量。 相似文献
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Neil Smith Nicola Longo Keith Levert Keith Hyland Nenad Blau 《Molecular genetics and metabolism》2019,126(4):406-412
Tetrahydrobiopterin (BH4) is the natural cofactor of aromatic amino acid hydroxylases and essential for degradation of phenylalanine and synthesis of catecholamines and serotonin. It can be synthesized either de novo from GTP or through the salvage pathway from sepiapterin. Sepiapterin, a natural precursor of BH4, is a more stable molecule and is transported more efficiently across cellular membranes, thus having potentially significant advantage over BH4 as a pharmacological agent for diseases associated with BH4-deficient conditions.We report the results of a first-in-humans, randomized, double-blind, placebo-controlled, dose-ranging, Phase I clinical trial in 83 healthy volunteers of CNSA-001, a novel formulation of sepiapterin. Single oral doses of 2.5–80 mg/kg CNSA-001 caused dose-related increases in plasma sepiapterin (mean Cmax 0.58–2.92 ng/mL) and BH4 (mean Cmax 57–312 ng/mL). Maximum plasma concentrations were achieved in about 1–2 h (sepiapterin) or about 4 h (BH4) after CNSA-001 oral intake.Increases in plasma BH4 were substantially larger in absolute terms and on a dose-for-dose basis following treatment with CNSA-001 vs. sapropterin dihydrochloride, a synthetic form of BH4. The pharmacokinetics of plasma sepiapterin and BH4 were similar before and after seven days of repeat daily dosing with CNSA-001 at 5, 20 or 60 mg/kg indicating little or no drug accumulation. Oral administration of CNSA-001 resulted in higher concentrations of sepiapterin in fasted vs. fed subjects, but overall BH4 plasma exposure following CNSA-001 intake increased by 1.7–1.8-fold in fed subjects. CNSA-001 was well tolerated, with no clear dose-relationship for adverse events (AE), no serious AE and no study discontinuations for AE. These data indicate that CNSA-001 is rapidly and efficiently converted to BH4 in humans supporting further clinical evaluation of CNSA-001 for the management of PKU, primary BH4 deficiencies and other diseases associated with deficient BH4 metabolism. 相似文献
5.
Claire S Reader Sabari Vallath Colin W Steele Syed Haider Adam Brentnall Ami Desai Kate M Moore Nigel B Jamieson David Chang Peter Bailey Aldo Scarpa Rita Lawlor Claude Chelala Stephen M Keyse Andrew Biankin Jennifer P Morton TR Jeffry Evans Simon T Barry Owen J Sansom Hemant M Kocher John F Marshall 《The Journal of pathology》2019,249(3):332-342
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Aim
To be able to calculate the potential of organ donation from deceased donors in a single hospital, region, and country, it is necessary to develop a useful stratification system for all hospitals taking into account their characteristics in having or not having departments crucial for donor identification and recruitment, such as an intensive care unit (ICU or neurology and neurosurgery departments), number of beds, and patient profiles (pediatric vs adult).Materials and Methods
There are 1032 hospitals in Poland, and 388 have facilities and tools to confirm death according to neurological criteria. These hospitals with the potential of deceased donation were characterized accordingly to the criteria presented above.Results
The largest group of institutions were first-degree referral hospitals having ICUs only for adults (161 hospitals), followed by hospitals with ICU and stroke departments for adults (76), then hospitals for adults with ICU and neurological department with no stroke beds (25), and hospitals for adults with second-degree referral and with ICU, stroke departments, and neurosurgery. In the case of pediatric patients and possible pediatric organ donation, the largest group consisted of 5 hospitals with pediatric ICU, pediatric neurology, and pediatric neurosurgery units. The remaining hospitals were unique in the country range.An exemplary analysis of 1 of the 40 stratified groups (19 out of 388 hospitals) showed that differences in actual activity in the donation process between similar hospitals are significant (from 0 to 62 donations in a 3-year period).Conclusion
We believe the results of this study are fundamental for the calculation of potential donation in the country. Our thesis is that hospitals from the same group should have the same potential and should be active in donation process on the same level. Formal comparative analysis of historical data on donor referral from active and nonactive hospitals will allow us to estimate the lost numbers of possible donations and will help focus efforts to improve transplantation systems. 相似文献8.
S. Benjamens S.P. Berger A.W.J.M. Glaudemans J.S.F. Sanders R.A. Pol R.H.J.A. Slart 《Transplantation reviews (Orlando, Fla.)》2018,32(2):102-109
Background
Clinicians use several diagnostic modalities to recognize post-transplant complications, such as acute tubular necrosis, acute rejection, urologic and vascular complications. Currently, there is no consensus about the best procedural approach to evaluate post-transplant renal dysfunction. Renal needle-biopsy is often required, however, this is invasive and may lead to sample errors and complications, and most clinicians prefer using one of the noninvasive diagnostic modalities.Methods
A systematic literature search was performed using PubMed, EMBASE, the Cochrane Library, MEDLINE (OvidSP), Web of Science, and Google Scholar to identify relevant articles. This review provides a literature overview of the technical aspects, new developments and clinical value of renal scintigraphy (RS), after kidney transplantation. Additionally, the advantages and limitations of RS in comparison to other diagnostic modalities are addressed. The study protocol is registered with PROSPERO, protocol number CRD42017078391.Results
A total of 32 studies were included. Studies were categorized in the following groups: tracer pharmacokinetics; acute rejection and acute tubular necrosis; vascular complications; urological complications; postoperative fluid collections; early transplant outcomes; one-year transplant outcomes.Conclusions
Several studies have described the use of RS for the diagnosis of acute rejection, however, differentiating between rejection and acute tubular necrosis remains difficult. For the diagnosis of vascular complications, RS has been described as an alternative for invasive procedures. For urologic complications, studies support the use of RS in combination with routine ultrasonography (US) surveillance. For the diagnosis of postoperative fluid collections, RS provides information to differentiate lymphoceles and urinomas. Altogether, RS should be considered in case of non-acute complications, and if US provides insufficient results. 相似文献9.
Elodie Montaudon Rania El Botty Sophie Vacher Olivier Das Adnan Naguez Sophie Chateau-Joubert Damien Treguer Ludmilla de Plater Leïla Zemoura Fariba Nmati Andr Nicolas Alain Chapelier Alain Livartowski Stefano Cairo Catherine Daniel Marie Brevet Elisabetta Marangoni Didier Meseure Sergio Roman-Roman Ivan Bieche Nicolas Girard Didier Decaudin 《Oncotarget》2021,12(8):859
Significant rational is available for specific targeting of PI3K/AKT/mTOR pathway in the treatment of non-small cell lung cancer (NSCLC). However, almost all clinical trials that have evaluated Pi3K pathway-based monotherapies/combinations did not observe an improvement of patient’s outcome. The aim of our study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus. An in vivo study showed high efficacy of RAD001 in NSCLC Patient-Derived Xenografts (PDXs). When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., PLK1, CXCR4, and AXL. We have then focused our study on the combination of RAD001 + Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an in vitro study. Pharmacodynamics study demonstrated that this synergy was due to (1) tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and (2) decrease of the Carbonic Anhydrase 9 (CAIX) protein that could not correct intracellular acidosis. In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients. 相似文献
10.
Association of RAD51 and XRCC2 Gene Polymorphisms with Cervical Cancer Risk in the Bangladeshi Women 下载免费PDF全文
Sanjida Chowdhury IvySamia ShabnazMohammad ShahriarSarah JafrinTutun Das AkaMd. Abdul AzizMohammad Safiqul Islam 《Asian Pacific journal of cancer prevention》2021,22(7):2099-2107
Objective: Alterations in common DNA repair genes (RAD51 and XRCC2) may lead to cervical cancer (CC) development. In the present study, we analyzed the association between RAD51 rs1801320 and XRCC2 rs3218536 polymorphisms and CC. Methods: Variants were selected based on their associations with some cancers in several ethnicities and the risk allele frequency (>0.05) in different populations. The variants were detected using the PCR-RFLP method. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were determined by logistic regression models. Result: Significantly increased risk (p <0.05) were detected for both SNPs with CC (rs1801320- GC vs. GG: aOR=2.21, 95% CI=1.43-3.42; CC vs. GG: aOR=4.48, 95% CI=1.76-11.42; dominant model: aOR=2.49, 95% CI=1.65-3.76; recessive model: aOR=3.52, 95% CI=1.40-8.88; allele model: OR=2.30, 95% CI=1.63-3.26, and rs3218536- GA vs. GG: aOR=2.77, 95% CI=1.85-4.17; AA vs. GG: aOR=5.86, 95% CI=2.08-16.50; dominant model: aOR=2.97, 95% CI=1.99-4.42; recessive model: aOR=3.56, 95% CI=1.30-9.73; and allele model: aOR=2.21, 95% CI=1.62-3.00). Besides, older patients (>60 years) with rs1801320 showed significantly reduced risk (OR=0.53, 95% CI=0.29-0.96, p=0.04) but with rs3218536 depicted significantly increased risk (aOR=2.44, 95% CI=1.20-4.96, p=0.01) for CC. Conclusion: This study indicates an association of rs1801320 and rs3218536 polymorphisms with CC and confirms that patients older than 60 years are more likely to develop CC for rs3218536 polymorphism. 相似文献