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961.
Ono M Tsuda H Shimizu C Yamamoto S Shibata T Yamamoto H Hirata T Yonemori K Ando M Tamura K Katsumata N Kinoshita T Takiguchi Y Tanzawa H Fujiwara Y 《Breast cancer research and treatment》2012,132(3):793-805
The purpose of the present study was to identify histological surrogate predictive markers of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC). Among 474 patients who received NAC and subsequent surgical therapy for stage II?CIII invasive breast carcinoma between 1999 and 2007, 102 (22%) had TNBC, and 92 core needle biopsy (CNB) specimens obtained before NAC were available. As controls, CNB specimens from 42 tumors of the hormone receptor-negative and HER2-positive (HR?/HER2+) subtype and 46 tumors of the hormone receptor-positive and HER2-negative (HR+/HER2?) subtype were also included. Histopathological examination including tumor-infiltrating lymphocytes (TIL) and tumor cell apoptosis, and immunohistochemical studies for basal markers were performed, and the correlation of these data with pathological therapeutic effect was analyzed. The rates of pCR at the primary site were higher for TNBC (32%) and the HR?/HER2+ subtype (21%) than for the HR+/HER2? subtype (7%) (P?=?0.006). Expression of basal markers and p53, histological grade 3, high TIL scores, and apoptosis were more frequent in TNBC and the HR?/HER2+ subtype than in the HR+/HER2? subtype (P?=?0.002 for TIL and P?<?0.001 for others). In TNBC, the pCR rates of tumors showing a high TIL score and of those showing a high apoptosis score were 37 and 47%, respectively, and significantly higher or tended to be higher than those of the tumors showing a low TIL score and of the tumors showing a low apoptosis score (16 and 27%, respectively, P?=?0.05 and 0.10). In a total of 180 breast cancers, the pCR rates of the tumors showing a high TIL score (34%) and of those showing a high apoptosis score (35%) were significantly higher than those of the tumors showing a low TIL score (10%) and those of the tumors showing a low apoptosis score (19%) (P?=?0.0001 and 0.04, respectively). Histological grade and basal marker expression were not correlated with pCR. Although the whole analysis was exploratory, the degree of TIL correlated with immune response appear to play a substantial role in the response to NAC in TNBC. 相似文献
962.
963.
Richard Tomasini Katsuya Tsuchihara Chiharu Tsuda Suzanne K. Lau Margareta Wilhelm Alessandro Ruffini Ming-sound Tsao Juan L. Iovanna Andrea Jurisicova Gerry Melino Tak W. Mak 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(3):797-802
The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73−/−) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73−/− mice show a high incidence of spontaneous tumors. Moreover, TAp73−/− mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells. 相似文献
964.
965.
Tsuda K 《Stroke; a journal of cerebral circulation》2006,37(4):944-5; author reply 945
966.
INTRODUCTION: Misfolded and unassembled glycoproteins are eliminated from the endoplasmic reticulum (ER) lumen by the ER-associated degradation (ERAD).We previously identified a Tyr595Cys (Y595C) mutation of protein S (PS) in a family of a quantitative PS deficiency. The mutation causes intracellular degradation and decreased secretion of the Y595C mutant PS. The aim of the present study was to further characterize the molecular basis of the intracellular degradation of the mutant. MATERIALS AND METHODS: We stably expressed the mutant in mammalian cells, and analyzed the intracellular localization of the protein. The intracellular degradation pathway was determined by pulse-chase analyses in the presence of various inhibitors of ERAD. RESULTS AND CONCLUSIONS: Endoglycosidase H digestion and immunofluorescence staining revealed the mutant being retained in the ER. Epoxomicin, a potent and specific proteasome inhibitor, and Ala-Ala-Phe-CH(2)Cl (AAF), an inhibitor of tripeptidyl peptidase II (TPPII), suppressed the intracellular degradation of the mutant by about 65% and 50%, respectively. When epoxomicin was combined with AAF, the inhibitory effect was substantially enhanced. Although castanospermine, an inhibitor of glucosidases I and II, did not affect the degradation, kifunensine, an inhibitor of ER mannosidase I, suppressed it. Thus, it appears that the Y595C mutant is degraded through more than one pathway of ERAD, including the proteasome-dependent pathway and an alternate proteasome-independent pathway where proteases such as TPPII may be involved. Production of the critical B isoform of Man(8)GlcNAc(2) targets the mutant for ERAD, however, the interaction with calnexin/calreticulin through monoglucosylated oligosaccharides may not be required for the degradation of the mutant. 相似文献
967.
968.
Taxol increases the amount and T cell activating ability of self-immune stimulatory multimolecular complexes found in ovarian cancer cells 总被引:4,自引:0,他引:4
Tsuda N Chang DZ Mine T Efferson C García-Sastre A Wang X Ferrone S Ioannides CG 《Cancer research》2007,67(17):8378-8387
It has been proposed that chemotherapy enhances tumor antigen (TA)-specific immunity. The molecular form of TA from ovarian tumor that activates cellular immunity is unknown. We report here identification of a novel molecular form of immunogenic TA for CD8(+) cells named self-immune stimulatory multimolecular complexes (ISMMC). ISMMC consist of a molecular complex of polyosome/ribosome-bound ubiquitinated nascent HER-2 polypeptides. This complex is chaperoned by heat shock protein Gp96, which mediates ISMMC uptake by antigen-presenting cells through the scavenger receptor CD91. RNAs in ISMMC stimulate immature dendritic cells to secrete interleukin 12 and induce IFN-gamma in peripheral blood mononuclear cells. ISMMC dissociate, retrotranslocate from the lysosome to cytoplasm, and are processed to peptides by the proteasome. At subpharmacologic doses, Taxol increased the amount of ISMMC by three to four times and modified their composition by inducing the attachment of cochaperones of HSP70, such as the mitotic-phase phosphoprotein 11J. On a total protein basis, Taxol induced ISMMC, expanded more CD8(+) cells, activated more CD56(+) NKG2D(+) cells to produce IFN-gamma, and were more potent inducers of high T-cell receptor density Perforin(+) cells than native ISMMC and peptide E75. Elucidation of the composition of ISMMC and identification of adducts formed by Taxol should be important for developing molecular cancer vaccines. 相似文献
969.
Shawn Tsuda Limaris Barrios Benjamin Schneider Daniel B. Jones 《Surgery for obesity and related diseases》2009,5(2):199-202
BackgroundTo determine the factors affecting rejection of bariatric candidates at an accredited, American College of Surgeons Level 1A, bariatric program. Bariatric surgery “Centers of Excellence” use a multidisciplinary team to screen patients for eligibility for surgery using insurance, medical history, psychological evaluation findings, and the surgeon assessment. Few studies have reported on the frequency or reasons for patients not being accepted for surgery among high-volume academic bariatric programs.MethodsFrom March to September 2007, 299 consecutive patients were accepted for evaluation into an accredited bariatric program and tracked for the incidence of rejection for weight loss surgery. The primary reasons for rejection included a lack of insurance coverage, being medically unfit, psychological or social inappropriateness, and a body mass index (BMI) that did not meet the cutoff (BMI <35 kg/m2 or <40 kg/m2 without co-morbid conditions).ResultsOf 299 screened patients, 90 (30.1%) were not accepted for surgery by the multidisciplinary team. The most frequent reason was the lack of insurance coverage (47.8%). Primary care physicians were the most common source of patient referral. All but 1 of the patients excluded because of an inadequate BMI (n = 13) had been referred by friends, co-workers, or themselves from information received from the Internet or television.ConclusionApproximately one third of screened patients were not accepted for surgery by an academic bariatric program. Self- or social referral appeared to correlate with rejection because the BMI did not meet the criteria for surgery. This suggests inadequate information among social referral networks and/or in the media. Long-term follow-up will determine the health outcomes of patients not cleared for weight loss surgery. 相似文献
970.
Effect of 14-membered-ring macrolides on production of interleukin-8 mediated by protease-activated receptor 2 in human keratinocytes 下载免费PDF全文
Tsuda T Ishikawa C Konishi H Hayashi Y Nakagawa N Matsuki M Mizutani H Yamanishi K 《Antimicrobial agents and chemotherapy》2008,52(4):1538-1541
The production of interleukin-8 induced by the activation of protease-activated receptor 2 and its synergism with interleukin-1beta were modulated by 14-membered-ring macrolides, namely, roxithromycin, erythromycin, and clarithromycin, in cultured normal human epidermal keratinocytes. Those macrolides may attenuate the protease-activated receptor 2-interleukin-8 axis and thereby modulate proinflammatory responses in the skin. 相似文献