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41.
The hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in 6-
thioguanine (TG) resistant T-lymphocytes is a useful target for the study
of somatic in vivo mutagenesis, since it provides information about a broad
spectrum of mutation. Mutations in the hprt coding region were studied in
124 TG-resistant T-cell clones from 38 healthy, non- smoking male donors
from a previously studied population of bus maintenance workers,
fine-mechanics and laboratory personnel. Their mean age was 43 years (range
23-64) and their hprt mutant frequency was 9.3 +/- 5.2 x 10(-6) (mean +/-
SD, range 1.4-22.6 x 10(-6)). Sequence analysis of hprt cDNA identified 115
unique mutations; 76% were simple base substitutions, 10% were +/-1 bp
frameshifts, and 10% were small deletions within exons (3-52 bp). In
addition, two tandem base substitutions and one complex mutation were
observed. Simple base substitutions were observed at 55 (20%) of 281 sites
known to be mutable in the hprt coding sequence. The distribution of these
mutations was significantly different than would be expected based upon a
Poisson distribution (P < 0.0001), suggesting the existence of
'hotspots'. All of the 87 simple base substitutions occurred at known
mutable sites, but eight were substitutions of a kind that have not
previously been reported at these sites. The most frequently mutated sites
were cDNA positions 197 and 146, with six and five independent mutations
respectively. Four mutations were observed at position 131, and three each
at positions 143, 208, 508 and 617. Transitions (52%) were slightly more
frequent than tranversions (48%), and mutations at GC base pairs (56%) more
common than mutations at AT base pairs (44%). GC > AT was the most
common type of base pair substitution (37%). The majority of the mutations
at GC base pairs (78%) occurred at sites with G in the non-transcribed
strand. All but one of eight mutations at CpG- sites were of the kind
expected from deamination of methylated cytosine. Deletion of a single base
pair (-1 frameshift) was three times more frequent than insertion of a
single bp (+1 frameshift). Almost half (6/13) of the small (3-52 bp)
deletions within the coding sequence clustered in the 5' end of exon 2.
Short repeats and other sequence motifs that have been associated with
replication error were found in the flanking regions of most of the
frameshifts and small deletions. However, several differences in the local
sequence context between +/-1 frameshift and deletion mutations were also
noticed. The present results identify positions 197, 146 and possibly 131
as hotspots for base substitution mutations, and confirm previously
reported hotspots at positions 197, 508 and 617. In addition, the earlier
notion of a deletion hotspot in the 5'end of exon 2 was confirmed. The
observations of these mutational cluster regions in different human
populations suggest that they are due to endogeneous mechanisms of
mutagenesis, or to ubiquitous environmental influences. The emerging
background spectrum of somatic in vivo mutation in the human hprt gene
provides a useful basis for comparisons with radiation or chemically
induced mutational spectra, as well as with gene mutations in human tumors.
相似文献
42.
Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene 总被引:3,自引:0,他引:3
Yeowell-O'Connell K; Rothman N; Smith MT; Hayes RB; Li G; Waidyanatha S; Dosemeci M; Zhang L; Yin S; Titenko-Holland N; Rappaport SM 《Carcinogenesis》1998,19(9):1565-1571
Benzene oxide (BO) reacts with cysteinyl residues in hemoglobin (Hb) and
albumin (Alb) to form protein adducts (BO-Hb and BO-Alb), which are
presumed to be specific biomarkers of exposure to benzene. We analyzed
BO-Hb in 43 exposed workers and 42 unexposed controls, and BO-Alb in a
subsample consisting of 19 workers and 19 controls from Shanghai, China, as
part of a larger cross-sectional study of benzene biomarkers. The adducts
were analyzed by gas chromatography-mass spectrometry following reaction of
the protein with trifluoroacetic anhydride and methanesulfonic acid. When
subjects were divided into controls (n = 42) and workers exposed to < or
=31 (n = 21) and >31 p.p.m. (n = 22) benzene, median BO-Hb levels were
32.0, 46.7 and 129 pmol/g globin, respectively (correlation with exposure:
Spearman r = 0.67, P < 0.0001). To our knowledge, these results
represent the first observation in humans that BO-Hb levels are
significantly correlated with benzene exposure. Median BO-Alb levels in
these 3 groups were 103 (n = 19), 351 (n = 7) and 2010 (n = 12) pmol/g Alb,
respectively, also reflecting a significant correlation with exposure
(Spearman r = 0.90, P < 0.0001). The blood dose of BO predicted from
both Hb and Alb adducts was very similar. These results clearly affirm the
use of both Hb and Alb adducts of BO as biomarkers of exposure to high
levels of benzene. As part of our investigation of the background levels of
BO-Hb and BO-Alb found in unexposed persons, we analyzed recombinant human
Hb and Alb for BO adducts. Significant levels of both BO-Hb (19.7 pmol/g)
and BO-Alb (41.9 pmol/g) were detected, suggesting that portions of the
observed background adducts reflect an artifact of the assay, while other
portions are indicative of either unknown exposures or endogenous
production of adducts.
相似文献
43.
Liu JM; Chen YM; Chao Y; Liu SM; Tiu CM; Wu HW; Chiou TC; Hsieh RK; Chen LT; Whang-Peng J 《Japanese journal of clinical oncology》1998,28(7):431-435
BACKGROUND: To evaluate the efficacy and toxicity of cisplatin/etoposide
continuous infusion chemotherapy for cancer of unknown primary site in
Taiwan, a region with a high prevalence of endemic viral infections.
METHOD: Between April 1994 and February 1996, 20 patients with a diagnosis
of CUPS were treated, including 15 males and five females, of average age
63.3 years (range 41-83 years). Continuous intravenous infusion of
etoposide 80 mg/m2 and cisplatin 25 mg/m2 was given for 3 days every 3
weeks. Pretreatment tumor marker and viral serology studies were performed
for baseline evaluation. Nearly two-thirds of the patients had poorly
differentiated carcinoma. The average number of metastatic sites was 2.65
(range 1-4), with liver and lymph node involvement predominating. RESULTS:
The overall response rate was 25% (95% CI 17.7-32.3%); 30.7% for poorly
differentiated cancers and 25% for well differentiated cancers. Median
survival was 4 months (range 1-12 months), 4.8 months for patients
attaining partial response. Toxicity was moderate, grade 3 and 4
neutropenia occurred in 55% and grade 3 and 4 thrombocytopenia in 40%;
other toxicities were mild. CA125 and CA199 were elevated in more than 50%
of patients. Viral serology studies were not significantly different from
those of the indigenous population. CONCLUSION: Etoposide and cisplatin
combination chemotherapy has modest activity in patients with extensive
CUPS and, at the schedule and dosage given, it is associated with moderate
toxicity.
相似文献
44.
Federle MP Chezmar JL Rubin DL Weinreb JC Freeny PC Semelka RC Brown JJ Borello JA Lee JK Mattrey R Dachman AH Saini S Harmon B Fenstermacher M Pelsang RE Harms SE Mitchell DG Halford HH Anderson MW Johnson CD Francis IR Bova JG Kenney PJ Klippenstein DL Foster GS Turner DA 《Journal of magnetic resonance imaging : JMRI》2000,12(1):186-197
The short-term safety of mangafodipir trisodium (MnDPDP) injection was studied in 546 adults with known or suspected focal liver lesions. An initial contrast-enhanced computed tomography examination was followed by unenhanced magnetic resonance imaging (MRI), injection of MnDPDP (5 micromol/kg), and enhanced MRI. Adverse events were reported for 23% of the patients; most were mild to moderate in intensity, did not require treatment, and were not drug related. The most commonly reported adverse events were nausea (7%) and headache (4%). The incidence of serious adverse events was low (nine events in six patients) and not drug related. Injection-associated discomfort was reported for 69% of the patients, and the most commonly reported discomforts included heat (49%) and flushing (33%). Changes in laboratory values and vital signs were generally transient, were not clinically significant, and did not require treatment. There were no clinically significant short-term risks from exposure to MnDPDP. 相似文献
45.
46.
p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue. 总被引:2,自引:0,他引:2
Rhonda A Kwong Larry H Kalish Tuan V Nguyen James G Kench Ronaldo J Bova Ian E Cole Elizabeth A Musgrove Robert L Sutherland 《Clinical cancer research》2005,11(11):4107-4116
PURPOSE: The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16(INK4A) and p14(ARF). This study addressed the role of p14(ARF) as a potential prognostic marker in this disease. EXPERIMENTAL DESIGN: p14(ARF) protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Cox's proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with p14(ARF) (p16(INK4A), p53, pRb, p21(WAF1/CIP1), E2F-1). RESULTS: On multivariate analysis, p14(ARF) positivity (nucleolar p14(ARF) staining and/or nuclear p14(ARF) staining in >/=30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14(ARF) positivity was cosegregated with positive (>/=1%) p16(INK4A) staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14(ARF) negative and p53 positive (>50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed. CONCLUSIONS: These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14(ARF) protein predicts for improved DFS and OS independent of established prognostic markers. 相似文献
47.
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50.
Fulvio Bruni Anna Laura Pasqui Marcello Pastorelli Giovanni Bova Michela Cercignani Alberto Palazzuoli Tatsuya Sawamura W R Gioffre Alberto Auteri Luca Puccetti 《Clinical and applied thrombosis/hemostasis》2005,11(4):417-428
Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular mortality by decreasing cholesterol as well as by non-lipid-related actions. Oxidized low-density lipoproteins (ox-LDL) are pro-atherogenic molecules and potent platelet agonists. CD36 and lectin-like ox-LDL receptor-1 (LOX-1) are specific ox-LDL receptors also expressed in platelets. This study was planned to address whether treatment with atorvastatin 10 mg/day, pravastatin 40 mg/day or simvastatin 20 mg/day could affect platelet CD36 and LOX-1 expression. Twenty-four patients for each treatment were evaluated after 3, 6, and 9 days and at 6 weeks for complete lipid profile (chromogenic), ox-LDL (ELISA), platelet P-selectin (P-sel), CD36, LOX-1 (FACS), and intracellular citrullin recovery (iCit) (HPLC). Data show hyperactivated platelets (P-sel absolute values, percent variation in activated cells, all p < 0.001), and CD36 and LOX-1 overexpression (all p < 0.001) in patients at baseline. P-sel, CD36, and LOX-1 were significantly decreased by atorvastatin and simvastatin (all p < 0.01) and related with iCit increase (r = 0.58, p < 0.001) and platelet-associated ox-LDL (r = 0.51, p < 0.01) at 9 days. Pravastatin reduced LOX-1 and P-sel (p < 0.05) at 6 weeks in relation with decreased LDL and ox-LDL (r = 0.39, p < 0.01 and r = 0.37, p < 0.01, respectively). These data suggest that atorvastatin and simvastatin reduce platelet activity by exposure of CD36 and LOX-1 before significant LDL reduction, whereas pravastatin action is detected later and in relation with LDL and ox-LDL lowering. Rapid and consistent reduction of CD36 and LOX-1 could be considered a direct anti-atherothrombotic mechanism related to the role of ox-LDL in platelet activation, platelet-endothelium interactions, and NO synthase activity. 相似文献