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1.
Aflatoxin B1 has been suggested as a causative agent for a G to T mutation at codon 249 in the p53 gene in human hepatocellular carcinomas from southern Africa and Qidong in China. To test this hypothesis, nine tumors induced by aflatoxin B1 in nonhuman primates were analyzed for mutations in the p53 gene. These included four hepatocellular carcinomas, two cholangiocarcinomas, a spindle cell carcinoma of the bile duct, a hemangioendothelial sarcoma of the liver, and an osteogenic sarcoma of the tibia. None of the tumors showed changes at the third position of codon 249 by cleavage analysis of the HaeIII enzyme site at codon 249. A point mutation was identified in one hepatocellular carcinoma at the second position of codon 175 (G to T transversion) by sequencing analysis of the four conserved domains (II to V) in the p53 gene. These data suggest that mutations in the p53 gene are not necessary in aflatoxin B1 induced hepatocarcinogenesis in nonhuman primates. The occurrence of mutation in codon 249 of the p53 gene in selective samples of human hepatocellular cancers may indicate involvement of environmental carcinogens other than aflatoxin B1 or that hepatitis B virus-related hepatitis is a prerequisite for aflatoxin B1 induction of G to T transversion in codon 249. 相似文献
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Cardiac damage induced by 2-amino-3-methyl-imidazo[4,5-f]quinoline in nonhuman primates. 总被引:1,自引:1,他引:0
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U P Thorgeirsson A Farb R Virmani R H Adamson 《Environmental health perspectives》1994,102(2):194-199
The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus and rhesus monkeys. The finding of high cardiac IQ-DNA adduct levels prompted a histopathological study of perfusion-fixed hearts from 10 tumor-bearing monkeys chronically dosed with IQ at 10 mg/kg or 20 mg/kg 5 days per week for 48-80 months. Two monkeys dosed only with the vehicle for IQ, hydroxypropylcellulose, served as controls. All the monkeys had normal heart weights, and no abnormalities were observed upon gross inspection of the hearts. Microscopically, focal myocardial lesions were observed in 8 of 10 monkeys dosed with IQ. Light microscopic abnormalities included myocyte necrosis with or without chronic inflammatory infiltrates, interstitial fibrosis with myocyte hypertrophy or atrophy, and vasculitis. Electron microscopic findings included disruption of the mitochondrial architecture (i.e., mitochondrial swelling and clearing of matrix densities), myofibrillar loss, disorganization of the normal alignment of sarcomeres, and occasional myocytes showing nuclear hypertrophy or peripheral clumping of the nuclear chromatin. There was some correlation between the cumulative dose of IQ and the extent of the myocardial abnormalities. These findings suggest that chronic exposure to IQ can lead to myocardial damage in monkeys. Although focal and not associated with clinical evidence of heart failure, these abnormalities may represent the initial stages of IQ-induced toxic cardiomyopathy. 相似文献
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Füst G Arason GJ Kramer J Szalai C Duba J Yang Y Chung EK Zhou B Blanchong CA Lokki ML Bödvarsson S Prohászka Z Karádi I Vatay A Kovács M Romics L Thorgeirsson G Yu CY 《International immunology》2004,16(10):1507-1514
The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking. 相似文献
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Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion 总被引:8,自引:0,他引:8
Santoni-Rugiu E Jelnes P Thorgeirsson SS Bisgaard HC 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2005,113(11-12):876-902
Although normally quiescent, the adult mammalian liver possesses a great capacity to regenerate after different types of injuries in order to restore the lost liver mass and ensure maintenance of the multiple liver functions. Major players in the regeneration process are mature residual cells, including hepatocytes, cholangiocytes and stromal cells. However, if the regenerative capacity of mature cells is impaired by liver-damaging agents, hepatic progenitor cells are activated and expand into the liver parenchyma. Upon transit amplification, the progenitor cells may generate new hepatocytes and biliary cells to restore liver homeostasis. In recent years, hepatic progenitor cells have been the subject of increasing interest due to their therapeutic potential in numerous liver diseases as alternative or supportive/complementary tools to liver transplantation. While the first investigations on hepatic progenitor cells have focused on their origin and phenotypic characterization, recent attention has focused on the influence of the hepatic microenvironment on their activation and proliferation. This microenvironment comprises the extracellular matrix, epithelial and non-epithelial resident liver cells, and recruited inflammatory cells as well as the variety of growth-modulating molecules produced and/or harboured by these elements. The cellular and molecular responses to different regenerative stimuli seem to depend on the injury inflicted and consequently on the molecular microenvironment created in the liver by a certain insult. This review will focus on molecular responses controlling activation and expansion of the hepatic progenitor cell niche, emphasizing similarities and differences in the microenvironments orchestrating regeneration by recruitment of progenitor cell populations or by replication of mature cells. 相似文献
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Preisegger KH Factor VM Fuchsbichler A Stumptner C Denk H Thorgeirsson SS 《Laboratory investigation; a journal of technical methods and pathology》1999,79(2):103-109
Many acute and chronic liver diseases are often associated with atypical ductular proliferation (ADP). These ADPs have gained increasing interest since a number of recent observations suggest that ADPs may represent progenies of the putative liver stem cell compartment. In this study, we show that feeding mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in persistent proliferation of primitive ductules with poorly defined lumens. Similar to oval cell proliferation in other rodent models as well as in various human liver diseases, DDC-induced ADP originated from the portal tract, spread into the hepatic lobule, and was associated closely with appearance of hepatocytes harboring an antigen (A6), which normally is expressed in biliary epithelium. Furthermore, DDC treatment severely inhibited the regenerative capacity of mice after partial hepatectomy. The development of ADP was selectively blocked in DDC-fed TGF-beta1 transgenic mice producing active TGF-beta1 in the liver and no accumulation of new hepatocytes expressing the A6 antigen was observed. Moreover, the transforming growth factor beta1 (TGF-beta1) transgenic mice did not survive beyond 3 weeks from starting the DDC-containing diet. The results suggest that persistent activation of the hepatic stem cell compartment is essential for liver regeneration in the DDC model and that active TGF-beta1 may negatively control activation of stem cells in the liver. These data further emphasize the relevance of the DDC model as an experimental tool for studying chronic liver diseases. 相似文献
7.
Chan CC Factor V Li Q Nagy P Peng B Thorgeirsson SS 《Ocular immunology and inflammation》1996,4(4):183-191
Transforming growth factor-beta (TGFsZ) is a potent regulator of cellular growth and immune function. The authors studied ocular histology and endotoxin-induced uveitis in a TGF-sZ(1) transgenic (Tg) murine model. TGF-sZ(1) Tg mice were generated by micro injecting a gene constructed by fusing the mouse albumin enhancer/promoter and porcine TGF-sZ(1) cDNA. The eyes of Tg mice from two to 14 weeks of age were studied histologically. Tg mice, two to five weeks of age exhibited mild fragmentation of the lens fibers and retinal edema. No pathology was found from six to ten weeks of age, however, a progressive increased frequency of cataract was observed from 11 to 14 weeks of age. Plasma TGF-sZ(1) levels were much higher in Tg mice than age-matched wild type control littermates (wt). Endotoxin-induced uveitis (EIU) in six-to eight-week-old Tg and wt mice was induced by footpad injection of lipopolysaccharide (LPS). Mice were euthanized 24 hr after LPS injection, the eyes were collected for histology and serum assayed for IL-6 and TGF-sZ(1). There was a decrease in the mean numbers of infiltrating cells in Tg mice compared to wt mice. Serum IL-6 and TGF-sZ(1) were much higher in Tg mice. The authors concluded that expression of the TGF-sZ(1) transgene in the eyes may have effect on lens growth. Overexpression of TGF-sZ(1) results in little or no effect on the development of EIU. 相似文献
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