全文获取类型
收费全文 | 1359篇 |
免费 | 213篇 |
国内免费 | 11篇 |
专业分类
耳鼻咽喉 | 11篇 |
儿科学 | 12篇 |
妇产科学 | 14篇 |
基础医学 | 340篇 |
口腔科学 | 52篇 |
临床医学 | 81篇 |
内科学 | 296篇 |
皮肤病学 | 58篇 |
神经病学 | 61篇 |
特种医学 | 7篇 |
外国民族医学 | 1篇 |
外科学 | 175篇 |
综合类 | 71篇 |
预防医学 | 15篇 |
眼科学 | 26篇 |
药学 | 129篇 |
中国医学 | 61篇 |
肿瘤学 | 173篇 |
出版年
2024年 | 3篇 |
2023年 | 8篇 |
2022年 | 9篇 |
2021年 | 18篇 |
2020年 | 33篇 |
2019年 | 69篇 |
2018年 | 61篇 |
2017年 | 72篇 |
2016年 | 67篇 |
2015年 | 76篇 |
2014年 | 147篇 |
2013年 | 109篇 |
2012年 | 87篇 |
2011年 | 123篇 |
2010年 | 87篇 |
2009年 | 96篇 |
2008年 | 86篇 |
2007年 | 69篇 |
2006年 | 64篇 |
2005年 | 62篇 |
2004年 | 73篇 |
2003年 | 50篇 |
2002年 | 50篇 |
2001年 | 24篇 |
2000年 | 11篇 |
1999年 | 10篇 |
1998年 | 6篇 |
1997年 | 4篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1993年 | 1篇 |
1992年 | 2篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1986年 | 1篇 |
排序方式: 共有1583条查询结果,搜索用时 15 毫秒
1.
Signaling by the transforming growth factor-β (TGF-β) superfamily is important in the regulation of hematopoiesis and is dysregulated in myelodysplastic syndromes (MDS), contributing to ineffective hematopoiesis and clinical cytopenias. TGF-β, activins and growth differentiation factors exert inhibitory effects on red cell formation by activating canonical SMAD2/3 pathway signaling. SMAD2/3 overactivation is seen in numerous subtypes of MDS. Furthermore, reduced levels of inhibitory SMAD7 are 相似文献
References
- 1.Valcarcel D, Verma A, Platzbecker U, et al. Phase 2 Study of Monotherapy Galunisertib (LY2157299 Monohydrate) in Very Low-, Low-, and Intermediate-Risk Patients with Myelodysplastic Syndromes. Blood. 2015;126:1669.
- 2.Suragani RN, Cawley SM, Li R, Wallner S, et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia. Blood. 2014 Jun 19;123(25):3864-72.
- 3.Dussiot M, Maciel TT, Fricot A, et al. Nat Med. 2014 Apr;20(4):398-407.
- 4.
2.
Roberto V.P. Ribeiro Mitesh V. Badiwala Danny Ramzy Laura C. Tumiati Vivek Rao 《The Journal of thoracic and cardiovascular surgery》2019,157(2):615-625.e1
Objective
Hypertonic saline (HTS) has potent immune and vascular effects. We assessed recipient pretreatment with HTS on allograft function in a porcine model of heart transplantation and hypothesized that HTS infusion would limit endothelial and left ventricular (LV) dysfunction following transplantation.Methods
Heart transplants were performed after 6 hours of cold ischemic storage. Recipient pigs were randomized to treatment with or without HTS (7.5% NaCl) before cardiopulmonary bypass (CPB). Using a myograft apparatus, coronary artery endothelial-dependent (Edep) and -independent (Eind) relaxation was assessed. LV performance was determined using pressure-volume loop analysis. Pulmonary interleukin (IL)-2, IL-6, and tumor necrosis factor (TNF)-α expression was measured.Results
Weaning from CPB and LV performance after transplantation were improved in HTS-treated animals. Successful weaning from CPB was greater in the HTS-treated hearts (8 of 8 vs 2 of 8; P < .05). Mean LV functional recovery was improved in the HTS-treated animals, as assessed by preload recruitable stroke work (65 ± 10% vs 27 ± 10%; P < .001) and end-systolic elastance (55 ± 7% vs 37 ± 4%; P < .001). Treatment with HTS resulted in improved Edep (mean maximum elastance [Emax], 56 ± 5% vs 37 ± 7%; P < .001) and Eind (mean Emax%, 77 ± 6% vs 52 ± 4%; P < .001) vasorelaxation compared with control. Pulmonary expression of IL-2, IL-6, and TNF-α increased following transplantation, whereas HTS therapy attenuated IL production (P < .001). Transplantation increased plasma TNF-α levels and LV TNF-α expression, whereas HTS prevented this up-regulation (P < .001).Conclusions
Recipient HTS pretreatment preserves allograft vasomotor and LV function, and HTS therapy limits CPB-induced injury. HTS may be a novel recipient intervention to prevent graft dysfunction. 相似文献3.
《Biomaterials》2015
Tenocytes represent a valuable source of cells for the purposes of tendon tissue engineering and regenerative medicine and as such, should possess a high degree of tenogenic differentiation prior to their use in vivo in order to achieve maximal efficacy. In the current report, we identify an efficient means by which to maintain differentiated tenocytes in vitro by employing the hanging drop technique in combination with defined growth media supplements. Equine tenocytes retained a more differentiated state when cultured as scaffold-free microtissue spheroids in low serum-containing medium supplemented with l-ascorbic acid 2-phosphate, insulin and transforming growth factor (TGF)-β1. This was made evident by significant increases in the expression levels of pro-tenogenic markers collagen type I (COL1A2), collagen type III (COL3A1), scleraxis (SCX) and tenomodulin (TNMD), as well as by enhanced levels of collagen type I and tenomodulin protein. Furthermore, tenocytes cultured under these conditions demonstrated a typical spindle-like morphology and when embedded in collagen gels, became highly aligned with respect to the orientation of the collagen structure following their migration out from the microtissue spheroids. Our findings therefore provide evidence to support the use of a biomimetic microtissue approach to culturing tenocytes and that in combination with the defined growth media described, can improve their differentiation status and functional repopulation of collagen matrix. 相似文献
4.
P. MORSING A. STENBERG D. CASELLAS A. MIMRAN C. MÜLLER-SUUR C. THORUP L. HOLM A. E. G. PERSSON 《Acta physiologica (Oxford, England)》1992,146(3):393-398
Atrial natriuretic peptide (ANP), injected at physiological concentrations, is known to induce both natriuresis and diuresis. It has been suggested by some investigators that these changes result from an increasing glomerular filtration rate (GFR), but others have been unable to demonstrate an increased GFR. The tubuloglomerular feedback (TGF) mechanism is an important regulator of GFR, and the sensitivity of TGF is decreased during ANP administration. Furthermore, resetting of TGF is, in most instances, related to changes in renal interstitial hydrostatic and oncotic pressures. It is also known that ANP may increase capillary permeability which may change renal interstitial pressure. The present study was performed to examine renal interstitial pressures and the TGF mechanism during ANP infusion. In accordance with previous studies, TGF sensitivity was found to be decreased. The tubular flow rate which elicited half the maximal drop in stop-flow pressure (Psf) was increased from 18.5 to 25.7 nl min-1. In contrast, ANP infusion resulted in a decreased interstitial hydrostatic pressure and an increased interstitial oncotic pressure. From previous experiments, such changes in interstitial pressures would be expected to increase TGF sensitivity. The changes in interstitial pressure cannot, therefore, directly explain the resetting of the feedback mechanism. In conclusion, the present paper shows a decreased renal net interstial pressure after intravenous administration of ANP. 相似文献
5.
Prime SS Eveson JW Stone AM Huntley SP Davies M Paterson IC Robinson CM 《The Journal of pathology》2004,203(4):927-932
This study examined the behaviour of nine human malignant oral keratinocyte cell lines following orthotopic transplantation to the floor of the mouth of athymic mice. Tumourigenesis, local spread, and metastatic dissemination were correlated with known cellular responses to transforming growth factor-beta 1 (TGF-beta 1). Six of nine cell lines were tumourigenic; four of these cell lines showed local spread which was characterized by vascular and bone invasion. Metastatic spread was uncommon, with only 9% of animals with primary tumours developing metastases and these were almost exclusively found in the regional lymph nodes; there was one pulmonary metastasis and no liver deposits. Tumour cell behaviour did not reflect the clinical stage of the original tumours. Cell lines that were resistant to TGF-beta 1-induced growth inhibition were more likely to form primary tumours, exhibit local spread, and metastasize than cells that were growth-inhibited by the ligand. The data demonstrate that tumourigenicity and tumour behaviour in this orthotopic mouse model varied between cell lines and that the pattern of local invasion and metastasis was similar to that seen in human oral cancer. Furthermore, cell lines that were refractory to the growth inhibitory effects of TGF-beta 1 behaved more aggressively than cells that underwent ligand-induced cell-cycle arrest. 相似文献
6.
Swirski FK Gajewska BU Robbins CS D'Sa A Johnson JR Pouladi MA Inman MD Stämpfli MR 《European journal of immunology》2004,34(9):2375-2386
We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) breaks tolerance induction. The objective of this study was to determine whether GM-CSF breaks established inhalation tolerance. To induce tolerance, BALB/c mice were exposed to aerosolized ovalbumin (OVA) for 10 consecutive days. A control group was exposed to saline. Subsequently, tolerant and control animals were exposed to OVA in a GM-CSF-enriched airway microenvironment. Tolerant animals, unlike control animals, did not develop airway and peripheral blood eosinophilia, had diminished levels of OVA-specific IgE, and reduced airway hyper-responsiveness. While tolerant animals did not express IL-4, IL-5 and IL-13, levels of the regulatory cytokines IL-10, IFN-gamma and transfoming growth factor (TGF)-beta were similar between tolerant and non-tolerant animals. Lung CD4+ T cells were activated according to CD69, CD25 and T1/ST2 expression, but systemic responses characterized by splenocyte proliferation and Th2 effector function were dramatically reduced. Concurrent expression of GM-CSF and decorin, a natural inhibitor of TGF-beta, reversed eosinophilic unresponsiveness. Our study suggests that the breakdown of tolerance and, by extension, the emergence of eosinophilic inflammation, requires two signals: one that triggers sensitization and one that interferes with negative regulation. Moreover, our study shows that dysregulated expression of an extracellular matrix protein may break established tolerance and lead to eosinophilic airway inflammation. 相似文献
7.
Yi Wang Zhiyou Zhou Yang Liu Zimin Wang Yifan Kang 《Journal of orthopaedic research》2021,39(1):204-218
To investigate the effect of inhibiting transforming growth factor‐β (TGF‐β1)/Smad2/3 signaling on rotator cuff (RC) healing. A bilateral supraspinatus tendon detachment‐repair model of Sprague‐Dawley (SD) rats was utilized. A total of 120 SD rats were randomly assigned to six groups and each group received the subacromial injection of normal saline, empty vectors, or lentiviral vectors containing small interfering RNA against TGF‐β1, Smad2, Smad3 at the bone‐tendon junction. Biomechanical and histological analyses were performed to evaluate bone‐tendon junction healing quality at 8 weeks after repair. Histologically, scar healing was found in all surgical groups. Animals with inhibited Smad3 exhibited better bone‐tendon junction structures with higher density, parallel orientation, and collagen fiber continuity than other surgical group animals. Immunohistochemistry revealed that the protein expression level of collagen I in animals with inhibited Smad3 was more prominent compared with all other surgical groups. Biomechanically, Animals with inhibited Smad3 showed better results in the maximum load at 4, 6, and 8 weeks after surgery compared with other surgical groups. Besides, C3H10T1/2 (Smad3?) cells increased TT‐D6 cell migration and tendon‐associated genes expression (scleraxis, tenascin C, collagen I) in coculture system. We conclude that inhibition of Smad3 promotes RC tendon healing in the rat supraspinatus model. 相似文献
8.
Victor Villar Jelena Kocić Juan F. Santibanez 《International journal of cancer. Journal international du cancer》2010,127(1):77-85
TGF‐β1 is a potent inductor of malignance in cancer cells. TGF‐β1 stimulates the expression of extracellular matrix degrading proteases, cell migration and it is also involved in the epithelial‐mesenchymal transition (EMT). In the present work, we analyzed the role of Spred2 in the urokinase‐type plasminogen activator (uPA) stimulation, EMT and cell migration by TGF‐β1. We found that both the expression of mRNA and the protein level of Spred2 were lower in transformed keratinocytes PDV compared with immortalized keratinocytes MCA‐3D. The transient ectopic expression of Spred2 in PDV cells inhibited the TGF‐β1‐transactivated SRE‐Luc reporter which is related with the ERK1,2 signal. The stable ectopic expression of Spred2 in PDV cells (SP cells) led to the loss of ERK 1,2 activation by TGF‐β1, although Smad2 activation was not affected, and the knockdown of Spred2 enhanced the activation of ERK1,2 signal by TGF‐β1. The increment of uPA expression induced by TGF‐β1 was suppressed in SP cells. In contrast, the stimulus on PAI‐1 expression was not affected and comparable to parental PDV cells. SP cells under TGF‐β1 treatment were unable to display the EMT, since the overexpression of Spred2 abolished the TGF‐β1‐induced disruption of the E‐cadherin cell to cell interactions, reorganization of the actin cytoskeleton and upregulation of the mesenchymal marker vimentin. Finally, SP cells could not respond to the TGF‐β1 stimulus on cell migration. Taken together, the data in the present study suggests that Spred2 is a regulator of TGF‐β1‐induced malignance in transformed keratinocytes. 相似文献
9.
Novel oral transforming growth factor‐β signaling inhibitor EW‐7197 eradicates CML‐initiating cells 下载免费PDF全文
Kazuhito Naka Kaori Ishihara Yoshie Jomen Cheng Hua Jin Dong‐Hyun Kim Yoon‐Kang Gu Eun‐Sook Jeong Shaoguang Li Daniela S. Krause Dong‐Wook Kim Eunjin Bae Yoshihiro Takihara Atsushi Hirao Hiroko Oshima Masanobu Oshima Akira Ooshima Yhun Yhong Sheen Seong‐Jin Kim Dae‐Kee Kim 《Cancer science》2016,107(2):140-148
Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia‐initiating cells (CML‐LICs). However, little is known about the therapeutic benefits such CML‐LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW‐7197, an orally bioavailable transforming growth factor‐β signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML‐LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW‐7197 to CML‐affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW‐7197 plus TKI was effective in eliminating CML‐LICs even if they expressed the TKI‐resistant T315I mutant BCR‐ABL1 oncogene. Collectively, these results indicate that EW‐7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML‐LICs. 相似文献
10.