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Ron Firestein Kaori Shima Katsuhiko Nosho Natsumi Irahara Yoshifumi Baba Emeric Bojarski Edward L. Giovannucci William C. Hahn Charles S. Fuchs Shuji Ogino 《International journal of cancer. Journal international du cancer》2010,126(12):2863-2873
Alterations in the Wnt/β‐catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin‐dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for β‐catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including β‐catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase‐2 (COX‐2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE‐1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with β‐catenin activation (p = 0.0002), female gender (p < 0.0001) and FASN overexpression (p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer‐specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03–2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18–3.56; p = 0.011) that was adjusted for potential confounders including β‐catenin, COX‐2, FASN, LINE‐1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and β‐catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis. 相似文献
43.
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
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Mao Akagawa Tatsuya Shirai Mitsuru Sada Norika Nagasawa Mayumi Kondo Makoto Takeda Koo Nagasawa Ryusuke Kimura Kaori Okayama Yuriko Hayashi Toshiyuki Sugai Takeshi Tsugawa Haruyuki Ishii Hisashi Kawashima Kazuhiko Katayama Akihide Ryo Hirokazu Kimura 《Viruses》2022,14(11)
Molecular interactions between respiratory syncytial virus (RSV) fusion protein (F protein) and the cellular receptor Toll-like receptor 4 (TLR4) and myeloid differentiation factor-2 (MD-2) protein complex are unknown. Thus, to reveal the detailed molecular interactions between them, in silico analyses were performed using various bioinformatics techniques. The present simulation data showed that the neutralizing antibody (NT-Ab) binding sites in both prefusion and postfusion proteins at sites II and IV were involved in the interactions between them and the TLR4 molecule. Moreover, the binding affinity between postfusion proteins and the TLR4/MD-2 complex was higher than that between prefusion proteins and the TLR4/MD-2 complex. This increased binding affinity due to conformational changes in the F protein may be able to form syncytium in RSV-infected cells. These results may contribute to better understand the infectivity and pathogenicity (syncytium formation) of RSV. 相似文献
46.
Certain mammalian species are resistant to cancer, and a better understanding of how this cancer resistance arises could provide valuable insights for basic cancer research. Recent technological innovations in molecular biology have allowed the study of cancer‐resistant mammals, despite the fact that they are not the classical model animals, which are easily studied using genetic approaches. Naked mole‐rats (NMRs; Heterocephalus glaber) are the longest‐lived rodent, with a maximum lifespan of more than 37 years, and almost never show spontaneous carcinogenesis. NMRs are currently attracting much attention from aging and cancer researchers, and published studies on NMR have continued to increase over the past decade. Cancer development occurs via multiple steps and involves many biological processes. Recent research on the NMR as a model for cancer resistance suggests that they possess various unique carcinogenesis‐resistance mechanisms, including efficient DNA repair pathways, cell‐autonomous resistance to transformation, and dampened inflammatory response. Here, we summarize the molecular mechanisms of carcinogenesis resistance in NMR, which have been uncovered over the past two decades, and discuss future perspectives. 相似文献
47.
Hiroyuki Hisada Yoshiki Sakaguchi Kaori Oshio Satoru Mizutani Hideki Nakagawa Junichi Sato Dai Kubota Miho Obata Rina Cho Sayaka Nagao Yuko Miura Hiroya Mizutani Daisuke Ohki Seiichi Yakabi Yu Takahashi Naomi Kakushima Yosuke Tsuji Nobutake Yamamichi Mitsuhiro Fujishiro 《Current oncology (Toronto, Ont.)》2022,29(7):4678
Although the mortality rates of gastric cancer (GC) are gradually declining, gastric cancer is still the fourth leading cause of cancer-related death worldwide. This may be due to the high rate of patients who are diagnosed with GC at advanced stages. However, in countries such as Japan with endoscopic screening systems, more than half of GCs are discovered at an early stage, enabling endoscopic resection (ER). Especially after the introduction of endoscopic submucosal dissection (ESD) in Japan around 2000, a high en bloc resection rate allowing pathological assessment of margin and depth has become possible. While ER is a diagnostic method of treatment and may not always be curative, it is widely accepted as standard treatment because it is less invasive than surgery and can provide an accurate diagnosis for deciding whether additional surgery is necessary. The curability of ER is currently assessed by the completeness of primary tumor removal and the possibility of lymph node metastasis. This review introduces methods, indications, and curability criteria for ER of EGC. Despite recent advances, several problems remain unsolved. This review will also outline the latest evidence concerning future issues. 相似文献
48.
Tatsuhiko Azegami Akinori Hashiguchi Takashin Nakayama Kaori Hayashi Takeshi Kanda Hiroshi Itoh 《Internal medicine (Tokyo, Japan)》2022,61(13):2027
A 46-year-old woman developed takotsubo cardiomyopathy and nephrotic syndrome. The first kidney biopsy suggested non-immune-complex-mediated membranoproliferative glomerulonephritis (MPGN), and she was diagnosed with glomerular endothelial injury associated with takotsubo cardiomyopathy. A second biopsy was performed two years later because of persistent proteinuria despite renin-angiotensin system inhibition. This biopsy indicated non-immune-complex-mediated MPGN, but a mesangial and subendothelial substance of a higher electron density than that in the first biopsy was detected, suggesting the possibility of glomerular disease with non-immune deposits rather than endothelial injury. Finally, she was diagnosed with fibronectin nephropathy. Although rare, fibronectin glomerulopathy should be considered in non-immune-complex-mediated MPGN. 相似文献
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Kubota Y Yano Y Seki S Takada K Sakuma M Morimoto T Akaike A Hiraide A 《American journal of pharmaceutical education》2011,75(3):43