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61.
62.
Jayendra Kumar Krishnaswamy Arpita Singh Uthaman Gowthaman Renee Wu Pavane Gorrepati Manuela Sales Nascimento Antonia Gallman Dong Liu Anne Marie Rhebergen Samuele Calabro Lan Xu Patricia Ranney Anuj Srivastava Matthew Ranson James D. Gorham Zachary McCaw Steven R. Kleeberger Leonhard X. Heinz André C. Müller Keiryn L. Bennett Giulio Superti-Furga Jorge Henao-Mejia Fayyaz S. Sutterwala Adam Williams Richard A. Flavell Stephanie C. Eisenbarth 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(10):3056-3061
Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.Dendritic cells (DCs) are crucial for the initiation of an adaptive immune response. Upon acquiring antigens in the periphery, DCs undergo a maturation process that includes antigen processing, cytokine production, and up-regulation of costimulatory molecules. A mature DC must then migrate from peripheral tissues to draining lymph nodes (LNs) to fulfill its role as an antigen-presenting cell that primes naïve T cells (1). Although the signals that induce this maturation process are now well-established (1), relatively little is understood about DC migration aside from the primary chemotactic cue provided by CCR7 that guides DCs to the LN (2, 3).We recently described a genetically modified NLRP10 (NLR family, pyrin domain containing 10) knockout strain in which this migration step was disrupted while leaving the remainder of the DC maturation program, including CCR7 expression, intact (4). NLRP10 is the only NOD-like receptor (NLR) without a leucine-rich repeat domain, the putative pathogen-associated molecular pattern (PAMP)–binding domain. It has been proposed to both positively and negatively regulate other NLRs, such as NOD1 and NLRP3, respectively (5, 6). Although we found that NLRP3 inflammasome activation was unaltered in the absence of NLRP10, we discovered that Nlrp10−/− mice could not mount a productive T- or B-cell immune response due to a DC-intrinsic failure to emigrate out of inflamed tissues (4, 7).To understand the mechanism by which NLRP10 governs DC migration, we used an expression proteomic approach to identify molecules with altered expression in DCs generated from the Nlrp10−/− strain and discovered a profound reduction in DOCK8 (dedicator of cytokinesis 8). DOCK8 is a guanine nucleotide exchange factor (GEF) that has two functional domains, DOCK homology region (DHR) 1 and DHR2 (8). In murine DCs, the DHR2 domain has been implicated in regulating the Rho GTPase CDC42 (cell division control protein 42 homolog), which in turn maintains cell polarity of mature DCs during migration (9, 10). Furthermore, mice harboring inactivating mutations in Dock8 lack marginal zone B-cell development, long-term antibody production following immunization, and memory CD8+ T-cell responses to viral infections (11, 12). In humans, inactivating mutations in Dock8 were recently identified as the primary genetic cause underlying autosomal recessive hyper-IgE syndrome (13). This syndrome presents with eczema, recurrent infections of the skin and respiratory tract, increased serum IgE, eosinophilia, recurrent fungal and viral infections, extensive food and environmental allergies, and, in certain patients, squamous cell dysplasia and carcinomas (14).Given that DOCK8 regulates a wide array of immunologic processes in mouse and human, we sought to understand how NLRP10 regulates DOCK8. To our surprise, we discovered that loss of DOCK8 in the Nlrp10−/− strain was secondary to a point mutation within the Dock8 gene itself. In this study, we demonstrate that restoring DOCK8 function in the Nlrp10−/− strain leads to normal DC migration in vivo. We further show that deletion of Dock8, as well as spontaneous mutation of Dock8 in another inbred strain of mice, results in defective DC migration and, depending on the degree of impaired migration, also abrogates CD4+ T-cell activation. 相似文献
63.
Joao Paulo Oliveira-Costa Alex Fiorini de Carvalho Giorgia Gobbi da Silveira Peter Amaya Yongqi Wu Kyoung-Joo Jenny Park Mabel Pinilla Gigliola Maryam Lustberg Marcilei Eliza Cavicchioli Buim Elisa Napolitano Ferreira Luiz Paulo Kowalski Jeffrey J. Chalmers Fernando Augusto Soares Dirce Maria Carraro Alfredo Ribeiro-Silva 《Oncotarget》2015,6(25):20902-20920
Oral squamous cell carcinoma (OSCC) is the most common tumor of the oral cavity and has been associated with poor prognosis. Scarce prognostic markers are available for guiding treatment and/or sub-classifying patients. This study aims to identify biomarkers by searching for genes whose expression is increased or decreased during tumor progression (through T1 to T4 stages). Thirty-six samples from all tumor size stages (from T1 to T4) were analyzed using cDNA microarrays. Selected targets were analyzed by immunohistochemistry and in circulating tumor cells by immunofluorescence and Nanostring. Correlation was shown between PD-L1 and tumor size and lymph node metastasis, HOXB9 and tumor size, BLNK and perineural invasion, and between ZNF813 and perineural invasion. PD-L1 positivity was an independent prognostic factor in this cohort (p = 0.044, HH = 0.426). In CTCs from patients with locally advanced OSCC, we found a strong cytoplasmatic expression of PD-L1. PD-L1 is a ligand of PD-1 and is believed to limit T cell activity in inflammatory responses and limit autoimmune diseases. We demonstrated an important role for PD-L1 in primary tumors according to tumor size, and in disease specific survival. Therefore, we could further determine individuals with PD-L1+ CTCs, and possibly follow treatment using CTCs. 相似文献
64.
Giuseppe Nanni Pietro Familiari Alessandro Mor Amerigo Iaconelli Vincenzo Perri Francesco Rubino Giuseppe Boldrini Maria Paola Salerno Laura Leccesi Samuele Iesari Liliana Sollazzi Valter Perilli Marco Castagneto Gertrude Mingrone Guido Costamagna 《Obesity surgery》2012,22(12):1897-1902
Background
The effectiveness of restrictive procedures has been inferior to that of malabsorbitive ones. Recent variants of restrictive procedures, i.e., gastric banding and sleeve gastrectomy, confirm the strive for more efficacious solutions with less complications. We investigated the balance between effectiveness and complications for a new restrictive procedure, a Transoral Endoscopic Vertical Gastroplasty (TOGa?)Methods
Seventy-nine morbidly obese patients were submitted to one out of three surgical procedures: TOGa? (29 patients), laparoscopic gastric bypass (LRYGBP; 20 patients), and biliopancreatic diversion (BPD; 30 patients). Mean BMI were 41.7 (35.4?C46.6), 44.8 (36.4?C54), and 47.5 (41?C60.3), respectively. All the patients reached a 2-year follow-up.Results
In TOGa? group BMI, respectively at 12 and 24?months, was 34.5 and 35.5, with 44 and 48.3?% of patients with BMI lower than 35. In LRYGBP group, BMI was 30.7 and 29.2?kg/m2, with 80 and 85?% of patients with BMI?<?35. In BPD group, BMI was 30 and 29.6?kg/m2, with 100 and 93.3?% of patients with BMI?<?35. In TOGa? group, 59?% of patients with an initial BMI?<?45 reached a BMI?<?35, in comparison to 48?% recorded in the whole group and to 14.3?% in patients with initial BMI????45.Conclusions
In selected patients, TOGa?, was associated with good results after two years in terms of weight loss, even in comparison with LRYGBP and BPD. Minimal trauma, absence of complications, and short hospital stay justify this procedure for patients with low BMI. 相似文献65.
Paola Secchiero Laura Davico Bonino Paolo Lusso Maria Cristina Abele Gigliola Reato Simonetta Kerim Giorgio Palestro Giorgio Zauli & Guido Valente 《British journal of haematology》1998,101(3):492-499
Several lines of evidence have pointed to the involvement of a viral agent in the pathogenesis of Hodgkin's disease (HD). Therefore we investigated the presence of human herpesvirus type 7 (HHV-7) in 53 cases of HD by polymerase chain reaction (PCR), DNA in situ hybridization (ISH) and immunohistochemistry. HHV-7 DNA was frequently detected (68% of the cases) in HD biopsies by PCR independently of the histological type, whereas only 32% ( P < 0.05) of positive cases were found in 19 reactive lymph nodes. However, by applying the quantitative PCR technique, the majority of the samples showed a low level of viral load. Moreover, ISH for HHV-7 DNA was positive in a low number of small T lymphocytes and consistently negative in Hodgkin and Reed-Sternberg (HRS) cells, which appeared negative for HHV-7 also at immunohistochemistry. These results indicate that the high frequency of HHV-7 infection in HD: (i) is probably non-productive, (ii) mainly involves small lymphocytes belonging to the T-lineage, and (iii) is probably due to the recruitment of non-malignant reactive cells in HD tissue. 相似文献
66.
67.
Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost
Vaidya JS Baum M Tobias JS Massarut S Wenz F Murphy O Hilaris B Houghton J Saunders C Corica T Roncadin M Kraus-Tiefenbacher U Melchaert F Keshtgar M Sainsbury R Douek M Harrison E Thompson A Joseph D 《International journal of radiation oncology, biology, physics》2006,66(5):1335-1338
PURPOSE: Patients undergoing breast-conserving surgery were offered boost radiotherapy with targeted intraoperative radiotherapy (TARGIT) using the Intrabeam system to test the feasibility, safety, and efficacy of the new approach. METHODS AND MATERIALS: We treated 302 cancers in 301 unselected patients. This was not a low-risk group. One-third of patients (98/301) were younger than 51 years of age. More than half of the tumors (172, 57%) were between 1 cm and 2 cm, and one-fifth (62, 21%) were >2 cm; 29% (86) had a Grade 3 tumor and, in 29% (87), axillary lymph nodes contained metastasis. After primary surgery, 20 Gy was delivered intraoperatively to the surface of the tumor bed, followed by external-beam radiotherapy (EBRT), but excluding the usual boost. RESULTS: The treatment was well tolerated. The follow-up ranged from 3 to 80 months (164 and 90 patients completed 2 and 3 years follow-up, respectively). Four patients (1.3%) had local recurrence. The Kaplan-Meier estimate of local recurrence is 2.6% (SE = 1.7) at 5 years. This compares favorably with the 4.3% recurrence rate in boosted patients from the EORTC boost study, in which only 8.1% patients were node-positive, as opposed to 29% in our series. CONCLUSION: Targeted intraoperative radiotherapy combined with EBRT results in a low local recurrence rate. This could be attributed to both accurate targeting and timeliness of the treatment. These data support the need for a randomized trial to test whether the TARGIT boost is superior to conventional external boost, especially in high-risk women. 相似文献
68.
The mechanisms by which a GnRH analogue, leuprorelin acetate (LA), antagonizes the mitogenic effect of dihydrotestosterone (DHT) or epidermal growth factor (EGF) in prostate cancer cells is poorly understood. The mitogen-activated protein kinase system has a central role in growth regulation and, for this reason, we investigated the involvement of the extracellular signal-regulated kinase (ERK1/2) pathway in the response of both androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer cells to LA alone or combined with EGF or DHT. The evaluation of ERK activation was performed by using Western blot analysis and immunocytochemistry. EGF specifically induced ERK1/2 activity in both models and this effect was counteracted by an inhibitor of EGF-receptor phosphorylation. The addition of LA produced an appreciable reduction of ERK phosphorylation promoted by EGF in LNCaP cells, while it generally determined an increase in ERK activity in androgen-unresponsive PC-3 cells. The slight ERK activation induced by DHT in LNCaP cells was counteracted by LA and this effect was evident only by immunocytochemistry. Our findings suggest that the antiproliferative effect of LA in prostate cancer cells stimulated by hormones and growth factors may be, at least in part, mediated by the reduction of ERK1/2 activation in LNCaP cells and linked to the unexpected increase of this activity produced by the analogue in PC-3 cells. 相似文献
69.
70.
We have recently demonstrated that electromyogram (EMG) amplitude of the frowning muscles correlates with perception of effort
during leg-extension exercise. However, during aerobic exercise the relationship between facial EMG and perception of effort
has never been investigated. The aim of the present study was to investigate whether facial EMG reflects perception of effort
also during constant-workload cycling. We investigated the effects of exercise duration and exercise intensity on facial EMG
of the corrugator supercilii muscles, rating of perceived effort, heart rate, and blood lactate concentration. Twenty recreationally
active male and female volunteers performed a constant-workload time to exhaustion test on a cycle ergometer. Participants
were randomly allocated to the heavy-intensity [63 ± 3% peak power output (P
peak)], or the severe-intensity (80 ± 5% P
peak) group. The results show that facial EMG can differentiate between two exercise intensities during constant-workload cycling.
The effects of exercise duration are inconclusive. Facial EMG increased over time in the severe-intensity group, but not in
the heavy-intensity group. Future studies testing a wider range of exercise intensities are required to establish a correlation
between facial EMG and exercise intensity during aerobic exercise, and further investigations are needed to establish why
there is a discrepancy between facial EMG and perception of effort during lower-intensity aerobic exercise. 相似文献