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551.
552.
Thirty-one patients with malignant carcinoid tumors were treated with streptozocin—alone (n=7) or in combination with FU (n=24). The responses to treatment were followed by the determination of tumor markers, urinary 5-HIAA, serum PP, HCG-a and -β subunits, as well as determination of the size of liver metastases on computerized tomography or ultrasonography. Three patients (9.7%) showed objective responses with a mean remission time of 2.7 months. Eighteen patients (58%) showed stable disease, whereas ten patients (32.3%) showed progressive disease directly from the start of therapy. A good correlation was found between the changes in tumor markers and tumor size, although the changes occurred earlier in the markers than in the size. Estimated median survival from the time of histologically verified carcinoid tumor was 41 months and from start of therapy 22 months. Our data indicate that combination treatment with streptozocin and 5-fluorouracil is of little value for patients with malignant carcinoid tumors. 相似文献
553.
M Bergstr?m C Muhr P O Lundberg K Bergstr?m H Lundqvist G Antoni K J Fasth B L?ngstr?m 《Journal of computer assisted tomography》1987,11(3):384-389
Four patients with hormonally inactive pituitary adenomas were examined with positron emission tomography (PET) after injection, during different examinations, of L-[methyl-11C]methionine and D-[methyl-11C]methionine, respectively. After the rapid distribution phase, the enantiomer L-[11C]methionine, which is metabolically active, showed a considerable continuous irreversible trapping attributed to amino acid metabolism. The stereoisomer D-[11C]methionine, which does not participate in protein synthesis, showed a rapid distribution within the whole adenoma tissue, with a distribution space on the order of 100%. A minimal irreversible trapping was observed which could be explained by technical factors. It is concluded that PET using the two enantiomers allows a separation of passive distribution and metabolism, and that L-[11C]methionine can be used for in vivo quantitative studies of amino acid metabolism of pituitary adenomas. 相似文献
554.
Lundqvist A Abrams SI Schrump DS Alvarez G Suffredini D Berg M Childs R 《Cancer research》2006,66(14):7317-7325
The proteasome inhibitor, bortezomib, and the histone deacetylase inhibitor, depsipeptide (FK228), up-regulate tumor death receptors. Therefore, we investigated whether pretreatment of malignant cells with these agents would potentiate natural killer (NK)-mediated tumor killing. NK cells isolated from healthy donors and patients with cancer were expanded in vitro and then tested for cytotoxicity against tumor cell lines before and after exposure to bortezomib or depsipeptide. In 11 of 13 (85%) renal cell carcinoma cell lines and in 16 of 37 (43%) other cancer cell lines, exposure to these drugs significantly increased NK cell-mediated tumor lysis compared with untreated tumor controls (P < 0.001). Furthermore, NK cells expanded from patients with metastatic renal cell carcinoma were significantly more cytotoxic against autologous tumor cells when pretreated with either bortezomib or depsipeptide compared with untreated tumors. Tumors sensitized to NK cell cytotoxicity showed a significant increase in surface expression of DR5 [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R2; P < 0.05]; in contrast, surface expression of MHC class I, MIC-A/B, DR4 (TRAIL-R1), and Fas (CD95) did not change. The enhanced susceptibility to NK cell killing was completely abolished by blocking TRAIL on NK cells, and partially abolished by blocking DR5 on tumor cells. These findings show that drug-induced sensitization to TRAIL could be used as a novel strategy to potentiate the anticancer effects of adoptively infused NK cells in patients with cancer. 相似文献
555.
Astatinated trastuzumab, a putative agent for radionuclide immunotherapy of ErbB2-expressing tumours 总被引:1,自引:0,他引:1
Persson MI Gedda L Jensen HJ Lundqvist H Malmström PU Tolmachev V 《Oncology reports》2006,15(3):673-680
The anti-ErbB2 antibody trastuzumab is used for the treatment of patients with advanced breast cancer, resulting in a response rate of 40-60%. Coupling with a cytotoxic nuclide, e.g. alpha-emitting 211At, may further increase tumour response. The tumour-targeting properties of trastuzumab, astatinated using N-succinimidyl-para-(tri-n-methylstannyl)-benzoate, were evaluated and compared with those of radioiodinated trastuzumab in this study. We found that astatinated trastuzumab retains high specificity towards ErbB2. While the immunoreactive fraction of radioiodinated trastuzumab was higher than that of astatinated trastuzumab (76+/-9% versus 54+/-28%), both radioconjugates showed high affinity (KD 0.75+/-0.16 nM versus 1.8+/-0.3 nM). A growth inhibition study indicated a dose-dependent cell deactivation, in which approximately 74 cell-associated astatine decays per cell gave a survival fraction of 4.5+/-0.8x10(-4). Results of a comparative animal study on normal mice gave no indication that astatination would have any adverse effects on the biodistribution of the antibody. In conclusion, the results of the study suggest that astatinated trastuzumab is a promising candidate for treating ErbB2-expressing tumours. 相似文献
556.
Sundberg AL Orlova A Bruskin A Gedda L Carlsson J Blomquist E Lundqvist H Tolmachev V 《Cancer biotherapy & radiopharmaceuticals》2003,18(4):643-654
The overexpression of epidermal growth factor receptors, EGFR, in glioblastomas is well documented. Hence, the EGFR can be used as target structure for a specific targeting of glioblastomas. Both radiolabeled anti-EGFR antibodies and the natural ligand EGF are candidate agents for targeting. However, EGF, which has a rather low molecular weight (6 kDa), might have better tissue penetration properties through both normal tissue and tumors in comparison with anti-EGF antibodies and their fragments. The aim of this study was to prepare and evaluate in vitro an EGF-based antiglioma conjugate with residualizing label. Human recombinant EGF (hEGF) was coupled to isothiocyanate-benzyl-DTPA. The conjugate was purified from unreacted chelator using solid-phase extraction and labeled with (111)In. The labeling yield was 87% +/- 7%. The label was reasonably stable; the transchelation of (111)In to serum proteins was about 5% after incubation at 37 degrees C during 24 hours. The obtained [(111)In]benzyl-DTPA-hEGF conjugate was characterized in vitro using the EGFR expressing glioma cell line U343MGaCl2:6. The binding affinity, internalization, and retention of the conjugate were studied. The conjugate had receptor specific binding and the radioactivity was quickly internalized. The intracellular retention of radioactivity after interrupted incubation with conjugate was 71% +/- 1% and 59% +/- 1.5% at 24 and 45 hours, respectively. The dissociation constant was estimated to 2.0 nM. The results indicate that [(111)In]benzyl-DTPA-hEGF is a potential candidate for targeting glioblastoma cells, possibly using locoregional injection. 相似文献
557.
Pagani M Kovalev VA Lundqvist R Jacobsson H Larsson SA Thurfjell L 《European journal of nuclear medicine and molecular imaging》2003,30(11):1481-1488
Alzheimers disease (AD) and frontal lobe dementia (FLD) show characteristic patterns of regional cerebral blood flow (rCBF). However, these patterns may overlap with those observed in the aging brain in elderly normal individuals. The aim of this study was to develop a new method for better classification and recognition of AD and FLD cases as compared with normal controls. Forty-six patients with AD, 7 patients with FLD and 34 normal controls (CTR) were included in the study. rCBF was assessed by technetium-99m hexamethylpropylene amine oxime and a three-headed single-photon emission tomography (SPET) camera. A brain atlas was used to define volumes of interest (VOIs) corresponding to the brain lobes. In addition to conventional image processing methods, based on count density/voxel, the new approach also analysed other intrinsic properties of the data by means of gradient computation steps. Hereby, five factors were assessed and tested separately: the mean count density/voxel and its histogram, the mean gradient and its histogram, and the gradient angle co-occurrence matrix. A feature vector concatenating single features was also created and tested. Preliminary feature discrimination was performed using a two-sided t-test and a K-means clustering was then used to classify the image sets into categories. Finally, five-dimensional co-occurrence matrices combining the different intrinsic properties were computed for each VOI, and their ability to recognise the group to which each individual scan belonged was investigated. For correct classification of the AD-CTR groups, the gradient histogram in the parieto-temporal lobes was the most useful single feature (accuracy 91%). FLD and CTR were better classified by the count density/voxel histogram (frontal and occipital lobes) and by the mean gradient (frontal, temporal and parietal lobes, accuracy 98%). For AD and FLD the count density/voxel histogram in the frontal, parietal and occipital lobes classified the groups with the highest accuracy (85%). The concatenated joint feature correctly classified 96% of the AD-CTR, 98% of the FLD-CTR and 94% of the AD-FLD cases. 5D co-occurrence matrices correctly recognised 98% of the AD-CTR cases, 100% of the FLD-CTR cases and 98% of the AD-FLD cases. The proposed approach classified and diagnosed AD and FLD patients with higher accuracy than conventional analytical methods used for rCBF-SPET. This was achieved by extracting from the SPET data the intrinsic information content in each of the selected VOIs.An erratum to this article can be found at 相似文献
558.
PURPOSE: To investigate the long-term outcomes of cataract surgery by analyzing data collected 5 years after surgery and comparing with preoperative and postoperative subjective and objective visual function results. SETTING: Norrlands University Hospital, Ume?, Sweden. METHODS: A prospective longitudinal population-based cohort study comprised 810 patients who had cataract surgery during a 1-year period within a geographically defined area. Evaluated were visual acuity data and Visual Function-14 questionnaire (VF-14) results before and after surgery. Five years later, the 590 patients still alive were offered eye examinations and asked to fill out the questionnaire. RESULTS: Of the 590 patients asked to participate at 5 years, 530 answered the questionnaire and 467 had eye examinations. The median VF-14 total score for all patients after surgery was 100; at 5 years, the score decreased to 96.7 (P = .001). Five years after surgery, 46% of patients had unchanged or better visual acuity in the operated eye, 37% had lost more than 0.1 logMAR unit, and 22% had a reduction in VF-14 score of 10 points or more. The two main reasons for the decline in visual acuity and VF-14 scores were age-related macular degeneration (ARMD) (47% and 60%, respectively) and glaucoma (12% and 11%, respectively). Age, co-morbidity, and VF-14 scores after surgery were independently associated with the VF-14 score 5 years after surgery. CONCLUSIONS: Subjective and objective visual function 5 years after cataract surgery remained stable in most patients. Co-morbidity, most commonly ARMD, was the most frequent cause of deterioration of visual acuity and decrease in VF-14 scores. Age and co-morbidity were independently associated with the VF-14 score 5 years after surgery. 相似文献
559.
Lundqvist T 《Current opinion in drug discovery & development》2005,8(4):513-519
This review comments on some recent trends and insights in the field of lead identification and optimization with a bias toward the increased use of biophysical methods, particularly in combination with three-dimensional structural information. While high-throughput screening, combinatorial chemistry and, most recently, in silico virtual screening techniques have made well-resourced but only partially successful attempts to meet the challenge of identifying new drug candidates by playing 'the large numbers game', another group of technologies are now approaching the same challenge from what might be considered the opposite extreme. The common strategy of these technologies is to focus on a smaller set of low-molecular-weight compounds whose interactions with a target are characterized with the aid of sensitive assays, most often high-quality biophysical techniques such as biosensors, calorimetry, nuclear magnetic resonance spectroscopy and X-ray crystallography. The advantages of such an approach include more optimal and chemically attractive starting points, immediate access to reliable measurements of binding properties, the mapping of ligand interactions on the atomic level and, most importantly, a greater control of experimental errors at the initial stages of drug discovery where compounds are either discovered or lost. When correctly supported, this more careful approach appears to deliver quality leads, even for the so-called 'difficult' targets. As these techniques are complementary to traditional methods, companies should be less hesitant to invest in them. The biophysical methods that are used to drive this approach have made something of a return to drug discovery after having been discarded for being too slow, too expensive or too old-fashioned by the over-optimistic supporters of high-throughput and statistical/computational in silico methods. 相似文献
560.
G M Portela-Gomes L Grimelius H Johansson R Bergstr?m G Lundqvist 《Acta chirurgica Scandinavica》1987,153(11-12):669-675
The effects of gastroenteroanastomosis, antral exclusion and antral resection on the enterochromaffin (argentaffin) cell system in the rat alimentary tract were studied 6 weeks after the operation. When measured as cell density per mm3 mucosa, the number of enterochromaffin cells was decreased in most gastrointestinal regions following the three surgical procedures. In the antral exclusion group this decrease was most apparent in the caecum and large intestine, and in the animals with antral resection it was most pronounced in the proximal and middle regions of the small intestine. When expressed per segment mucosa, the enterochromaffin cells were even more reduced in number in all three experimental groups, as a result of mucosal atrophy in the entire gastrointestinal tract. The atrophy was most pronounced in animals with gastroenteroanastomosis, and least pronounced in those with antral exclusion. The underlying mechanisms of the effects on the enterochromaffin cell system under these experimental conditions are discussed. 相似文献