全文获取类型
收费全文 | 18893篇 |
免费 | 1148篇 |
国内免费 | 85篇 |
专业分类
耳鼻咽喉 | 182篇 |
儿科学 | 600篇 |
妇产科学 | 416篇 |
基础医学 | 2485篇 |
口腔科学 | 371篇 |
临床医学 | 2190篇 |
内科学 | 4458篇 |
皮肤病学 | 527篇 |
神经病学 | 1892篇 |
特种医学 | 413篇 |
外科学 | 1450篇 |
综合类 | 103篇 |
一般理论 | 8篇 |
预防医学 | 1946篇 |
眼科学 | 305篇 |
药学 | 1283篇 |
中国医学 | 69篇 |
肿瘤学 | 1428篇 |
出版年
2024年 | 12篇 |
2023年 | 167篇 |
2022年 | 328篇 |
2021年 | 544篇 |
2020年 | 329篇 |
2019年 | 525篇 |
2018年 | 643篇 |
2017年 | 403篇 |
2016年 | 484篇 |
2015年 | 549篇 |
2014年 | 768篇 |
2013年 | 994篇 |
2012年 | 1564篇 |
2011年 | 1586篇 |
2010年 | 820篇 |
2009年 | 784篇 |
2008年 | 1292篇 |
2007年 | 1273篇 |
2006年 | 1238篇 |
2005年 | 1230篇 |
2004年 | 1057篇 |
2003年 | 1020篇 |
2002年 | 930篇 |
2001年 | 89篇 |
2000年 | 78篇 |
1999年 | 131篇 |
1998年 | 160篇 |
1997年 | 146篇 |
1996年 | 138篇 |
1995年 | 107篇 |
1994年 | 79篇 |
1993年 | 91篇 |
1992年 | 61篇 |
1991年 | 38篇 |
1990年 | 39篇 |
1989年 | 42篇 |
1988年 | 26篇 |
1987年 | 24篇 |
1986年 | 34篇 |
1985年 | 35篇 |
1984年 | 32篇 |
1983年 | 29篇 |
1982年 | 30篇 |
1981年 | 33篇 |
1980年 | 34篇 |
1979年 | 17篇 |
1978年 | 15篇 |
1976年 | 12篇 |
1974年 | 11篇 |
1973年 | 11篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
91.
Tania Crombet Marta Osorio Teresa Cruz Carlos Roca Ramón del Castillo Rosa Mon Normando Iznaga-Escobar René Figueredo James Koropatnick Enrique Renginfo Eduardo Fernández Daniel Alvárez Olga Torres Mayra Ramos Idrissa Leonard Rolando Pérez Agustín Lage 《Journal of clinical oncology》2004,22(9):1646-1654
PURPOSE: To evaluate safety and preliminary efficacy of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy (RT) in unresectable head and neck cancer patients. Secondary end points were the measurement of h-R3 serum levels and the assessment of the potential mechanisms of antitumor effect on patient biopsies. Anti-idiotypic response to h-R3 was assessed. To predict pharmacologic effect, a mathematical model for antibodies recognizing antigens expressed in tumors and normal tissues was built. PATIENTS AND METHODS: Twenty-four patients with advanced carcinomas of the head and neck received six once-weekly infusions of h-R3 at four dose levels in combination with RT. Pretreatment tumor biopsies were obtained to evaluate epidermal growth factor receptor expression as an enrollment criterion. Second biopsies were taken to evaluate the proliferative activity and angiogenesis in comparison with the pretreatment samples. Patient serum samples were collected to measure h-R3 levels and anti-idiotypic response. RESULTS: The combination of h-R3 and RT was well tolerated. Antibody-related adverse events consisted in infusion reactions. No skin or allergic toxicity appeared. Overall survival significantly increased after the use of the higher antibody doses. Immunohistochemistry studies of tumor specimens before and after treatment revealed that antitumor response correlated with antiproliferative and antiangiogenic effect. One patient developed antibodies to h-R3. The mathematical model predicted that the maximum difference between the area under the curve in tumors and normal tissues is reached when the antibody has intermediate affinity. CONCLUSION: h-R3 is a well-tolerated drug that may enhance radiocurability of unresectable head and neck neoplasms. 相似文献
92.
Maria Teresa Landi Andrea Baccarelli 《Cancer epidemiology, biomarkers & prevention》2003,12(10):1116-7; author reply 1118
93.
Silvana Chiara Maria Teresa Nobile Maura Vincenti Rita Lionetto Alberto Gozza Maria Cristina Barzacchi Ornella Sanguineti Lazzaro Repetto Riccardo Rosso 《Cancer chemotherapy and pharmacology》1998,42(4):336-340
To evaluate toxicity and efficacy of chemotherapy in elderly patients (≥65 years of age) with advanced colorectal cancer,
data from two consecutive trials conducted between 1984 and 1995 at the National Institute for Cancer Research were analysed
comparing the results of treatment in those 65 years of age or older and in those younger than 65 years. Of 215 patients recruited,
82 elderly patients (median age 70 years, median performance status 1) received one of the following regimens based on 5-fluorouracil
(5-FU): (1) weekly 5-FU 600 mg/m2 i.v. bolus (30 patients); (2) weekly 5-FU 600 mg/m2 bolus plus leucovorin (LV) 500 mg/m2 2-h i.v. infusion (28 patients); (3) Weekly 5-FU 2600 mg/m2 24-h continuous i.v. infusion plus LV 100 mg 4-h i.v. infusion and 50 mg orally every 4 h for five doses (24 patients). Overall,
1071 chemotherapy cycles were administered with a median number of 12 courses per patient. The main side effects were diarrhoea,
observed in 38% of patients, stomatitis in 24% of patients and hand-foot syndrome in 13% of patients, and haematological toxicity
affected only 15% of patients. No patient suffered grade IV toxicity. In three patients chemotherapy was discontinued because
of toxicity (two patients suffered grade III diarrhoea, one patient grade III hand-foot syndrome). No significant difference
in toxicity was evident between patients older than or younger than 65 years. Analysis of median dose intensity demonstrated
no difference between the two groups. Overall objective response was observed in 18% (95% confidence limits 11–29) of elderly
patients (15/82) in comparison with 23% (95% CL 17–32) of patients <65 years of age (31/133 pts). In conclusion, chemotherapy
in elderly patients with advanced colorectal cancer is a safe and effective treatment with acceptable toxicity and comparable
objective response rates.
Received: 6 January 1998 / Accepted: 27 February 1998 相似文献
94.
Dennis A Chakkalakal Jerzy R Novak Edward D Fritz Teresa J Mollner Daniel L McVicker Kevin L Garvin Michael H McGuire Terrence M Donohue 《Alcohol》2005,36(3):201-214
Alcohol abuse is associated with increases in both the incidence of fractures and complications in fracture healing. The purpose of this study was to determine the dose-dependent effects of ethanol on bone repair in a rat model. Three-month-old male Wistar rats were continuously fed liquid diets containing ethanol as either 36% or 26% of total calories or control diets for 6 weeks. Then, a bone repair model was created in all rats. Bone healing and liver metabolism were evaluated 7 weeks after bone injury. For each dose, there were three ethanol-feeding groups receiving (1) ethanol for 13 weeks, (2) control diet for 13 weeks (pair-fed), and (3) ethanol before bone injury and control diet (pair-fed) after injury. Another group was fed ethanol (36%) before injury and given control diet ad libitum after injury. There were also two nutritional controls consuming control diet and standard rat chow ad libitum for 13 weeks. Abnormal liver metabolism was evident at the higher ethanol dose - increases in cytochrome P4502E1 specific activity (5-fold; P < .01), triglyceride content (4-fold; P < .02), and liver weight (25%; P = .05) - compared with pair-fed controls. The higher dose of ethanol resulted in deficient bone repair when compared with rats receiving ethanol-free control diet by pair-feeding: 26% less (P = .02) rigidity of the repaired bone, 41% less (P = .02) intrinsic stiffness, 24% less intrinsic strength (P = .05), and 14% less (P = .001) ash density of the repair tissue. The reduced food consumption of ethanol-fed rats compared with that in the nutritional controls did not contribute to this deficiency. Furthermore, removal of ethanol (as 36% of calories) from the diet after bone injury completely restored normal bone healing and nearly normalized the liver metabolism. The lower ethanol dose (26% of calories) had a minimal effect on liver metabolism and bone repair. We conclude that ethanol (as 36% of calories) in the rat diet, especially during the postinjury period, was solely responsible for the observed inhibition of bone repair. 相似文献
95.
Teresa Pekol J Scott Daniels Jason Labutti Ian Parsons Darrell Nix Elizabeth Baronas Frank Hsieh Liang-Shang Gan Gerald Miwa 《Drug metabolism and disposition》2005,33(6):771-777
Bortezomib [N-(2,3-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. Bortezomib binds the proteasome via the boronic acid moiety, and therefore, the presence of this moiety is necessary to achieve proteasome inhibition. Metabolites in plasma obtained from patients receiving a single intravenous dose of bortezomib were identified and characterized by liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Metabolite standards that were synthesized and characterized by LC/MS/MS and high field nuclear magnetic resonance spectroscopy (NMR) were used to confirm metabolite structures. The principal biotransformation pathway observed was oxidative deboronation, most notably to a pair of diastereomeric carbinolamide metabolites. Further metabolism of the leucine and phenylalanine moieties produced tertiary hydroxylated metabolites and a metabolite hydroxylated at the benzylic position, respectively. Conversion of the carbinolamides to the corresponding amide and carboxylic acid was also observed. Human liver microsomes adequately modeled the in vivo metabolism of bortezomib, as the principal circulating metabolites were observed in vitro. Using cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib, including CYP3A4, CYP2C19, CYP1A2, CYP2D6, and CYP2C9. The development of bortezomib has provided an opportunity to describe the metabolism of a novel boronic acid pharmacophore. 相似文献
96.
Catharina Wising Jozef Azem Madeleine Zetterberg Liselott A Svensson Karin Ahlman Teresa Lagerg?rd 《Toxicon》2005,45(6):767-776
We investigated the impact of highly purified Haemophilus ducreyi cytolethal distending toxin (HdCDT) on the apoptosis and necrosis of various human cells; including myeloid cells, epithelial cells, keratinocytes, and primary fibroblasts. The levels of apoptosis and necrosis induced in these cells were compared to those induced by HdCDT in human T cells and in the Jurkat T cell line. Levels of caspase-3 activity were measured, and membrane changes like phosphatidylserine (PS) translocation was evaluated after double-staining with the fluorescein isothiocyanate (FITC)-labeled annexin V and propidium iodide (PI) using flow cytometry. HdCDT induced various degrees of apoptosis and necrosis in dose- and time-dependent manners in cells of various lineages. Early and late apoptosis (annexin V-stained cells) were induced in more than 90% of T cells and monocytes after treatment with 100 ng/ml HdCDT for 24 and 48 h, respectively. The corresponding numbers for epithelial cells, keratinocytes, and fibroblasts were 26-32% after treatment with 100 ng/ml HdCDT for 48 h. HdCDT appears to eliminate effectively by inducing apoptosis those cells that are involved in immune responses. Epithelial cells, keratinocytes and fibroblasts, which are important for the healing of chancroid ulcers, are eliminated by apoptosis or necrosis after contact with HdCDT, albeit slower and to a lesser extent than T cells. 相似文献
97.
Filippo Festini Riccardo Ciuti Giovanni Taccetti Teresa Repetto Silvia Campana Maurizio De Martino 《The journal of maternal-fetal & neonatal medicine》2006,19(6):375-376
We report the case of a 30-year-old woman with cystic fibrosis (CF) chronically infected with Pseudomonas aeruginosa who delivered and breast-fed a healthy boy. While breast-feeding the woman had to undergo an i.v. antibiotic course with tobramycin, due to pulmonary exacerbation. Tobramycin was not detected in her milk and lactation could be continued. This is the first time that the presence of tobramycin in the milk of a CF woman during i.v. administration has been investigated. 相似文献
98.
Elaine A Merrill Rebecca A Clewell Peter J Robinson Annie M Jarabek Jeffery M Gearhart Teresa R Sterner Jeffrey W Fisher 《Toxicological sciences》2005,83(1):25-43
Detection of perchlorate (ClO4-) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures. Perchlorate inhibits thyroid iodide (I-) uptake at the sodium (Na+)-iodide (I-) symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe the kinetics and distribution of both radioactive I- and cold ClO4- in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I- by ClO4-. The model successfully predicts the measured levels of serum and urinary ClO4- from drinking water exposures, ranging from 0.007 to 12 mg ClO4-/kg/day, as well as the subsequent inhibition of thyroid 131I- uptake. Thyroid iodine, as well as total, free, and protein-bound radioactive I- in serum from various tracer studies, are also successfully simulated. This model's parameters, in conjunction with corresponding model parameters established for the male, gestational, and lactating rat, can be used to estimate parameters in a pregnant or lactating human, that have not been or cannot be easily measured to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other human life stages. For example, by applying the adult male rat:adult human ratios of model parameters to those parameters established for the gestational and lactating rat, we can derive a reasonable estimate of corresponding parameters for a gestating or lactating human female. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model's successful prediction of free and bound radioactive I- and perchlorate's interaction with free radioactive I- provide a basis for extending the structure to address the complex hypothalamic-pituitary-thyroid feedback system. In this paper, bound radioactive I- refers to I- incorporated into thyroid hormones or iodinated proteins, which may or may not be bound to plasma proteins. 相似文献
99.
Cuiping Chen Rouchelle J Mireles Scott D Campbell Jian Lin Jessica B Mills Jinghai J Xu Teresa A Smolarek 《Drug metabolism and disposition》2005,33(4):537-546
The present study examined the interaction of four 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (atorvastatin, lovastatin, and simvastatin in acid and lactone forms, and pravastatin in acid form only) with multidrug resistance gene 1 (MDR1, ABCB1) P-glycoprotein, multidrug resistance-associated protein 2 (MRP2, ABCC2), and organic anion-transporting polypeptide 1B1 (OATP1B1, SLCO21A6). P-glycoprotein substrate assays were performed using Madin-Darby canine kidney (MDCK) cells expressing MDR1, and the efflux ratios [the ratio of the ratio of basolateral-to-apical apparent permeability and apical-to-basolateral permeability between MDR1 and MDCK] were 1.87, 2.32/4.46, 2.17/3.17, and 0.93/2.00 for pravastatin, atorvastatin (lactone/acid), lovastatin (lactone/acid), and simvastatin (lactone/acid), respectively, indicating that these compounds are weak or moderate substrates of P-glycoprotein. In the inhibition assays (MDR1, MRP2, Mrp2, and OATP1B1), the IC50 values for efflux transporters (MDR1, MRP2, and Mrp2) were >100 microM for all statins in acid form except lovastatin acid (>33 microM), and the IC50 values were up to 10-fold lower for the corresponding lactone forms. In contrast, the IC50 values for the uptake transporter OATP1B1 were 3- to 7-fold lower for statins in the acid form compared with the corresponding lactone form. These data demonstrate that lactone and acid forms of statins exhibit differential substrate and inhibitor activities toward efflux and uptake transporters. The interconversion between the lactone and acid forms of most statins exists in the body and will potentially influence drug-transporter interactions, and may ultimately contribute to the differences in pharmacokinetic profiles observed between statins. 相似文献
100.
Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer. 总被引:4,自引:0,他引:4
Sei Hoon Yang Leah E Mechanic Ping Yang Maria Teresa Landi Elise D Bowman Jason Wampfler Daoud Meerzaman Kyeong Man Hong Felicia Mann Tatiana Dracheva Junya Fukuoka William Travis Neil E Caporaso Curtis C Harris Jin Jen 《Clinical cancer research》2005,11(6):2106-2110
We evaluated somatic genetic alterations in the kinase domain of the EGFR gene in the tumors of 219 non-small cell lung cancer patients of primarily Caucasian and African American origins. We identified 26 patients (12%) whose tumors had a mutation in the EGFR gene, and 11 (5%) patients carried novel genomic variations consistent with germ-line polymorphisms. All but one mutation were identified in Caucasian patients affected with adenocarcinoma. EGFR mutations were more frequent in women and in nonsmokers, but a significant portion of the affected patients were men (12 of 26) and current or past smokers accounted for half of the patients affected (13 of 26). Screening subjects with EGFR mutations may identify patients whose tumors could respond to targeted therapy using tyrosine kinase inhibitors. 相似文献