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101.
Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. 总被引:16,自引:0,他引:16
Roy S Herbst Giuseppe Giaccone Joan H Schiller Ronald B Natale Vincent Miller Christian Manegold Giorgio Scagliotti Rafael Rosell Ira Oliff James A Reeves Michael K Wolf Annetta D Krebs Steven D Averbuch Judith S Ochs John Grous Abderrahim Fandi David H Johnson 《Journal of clinical oncology》2004,22(5):785-794
PURPOSE: Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect. CONCLUSION: Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials. 相似文献
102.
Carlos A. Fuster Diana Enrique Fuster Diana Nieves Martínez Alzamora Antonio García Vilanova Julia Giménez Climent Carlos Vázquez Albaladejo 《Clinical & translational oncology》2004,6(8):472-482
Introduction. Breast cancer remains the most frecuent tumor among women in developed countries. The prognosis is linked to a great variety clinic and pathological factors. The objectives from this study are to identify markers related to survival of patients with primary diagnosis of breast cancer. Material and methods. We have reviewed the medical dossier from 2.227 consecutive women diagnosed for infiltrating breast cancer between January 1966 and december 2000 in a single institution. For statistic analysis we used 10.0 SPSS software. Results. In the univariate analysis, factors with the strongest predictive value for overall survival were: PEV, estrogene and progesterone receptors, TNM stage, lymphatic vessel involvement, histologic grade, Scarff differentiation and mitosis rate, elastosis, presence of histiocitosis, and the percentage of involved stage I and III lymph nodes (Berg clasification). In the multivariate analysis, 5 factors; progesterone receptors, Scarff mitotic rate, lymphatic vessel involvement, percentage of involved stage I lymph nodes, and presence of metastasis; were independent prognostic markers of survival. Conclusions. Many independent factors interact in the survival of patients with primary breast cancer. Determination of hormonal receptors, mainly progesterone’s, appear as the most powerful indicators. The analysis has generated a prognostic simplified classification, based in the 5 independent variables, that provides specific rates for survival at 2, 5 and 10 years. 相似文献
103.
Hans Gelderblom Ramon Salazar Jaap Verweij George Pentheroudakis Maja J A de Jonge Martin Devlin Christel van Hooije Francis Seguy Rosendo Obach Joan Pru?onosa Paola Principe Chris Twelves 《Clinical cancer research》2003,9(11):4101-4107
PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured. RESULTS: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low. CONCLUSIONS: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability. 相似文献
104.
Ravi Salgia Thomas Lynch Arthur Skarin Joan Lucca Cathleen Lynch Ken Jung F Stephen Hodi Michael Jaklitsch Steve Mentzer Scott Swanson Jean Lukanich Raphael Bueno John Wain Douglas Mathisen Cameron Wright Panos Fidias Dean Donahue Shirley Clift Steve Hardy Donna Neuberg Richard Mulligan Iain Webb David Sugarbaker Martin Mihm Glenn Dranoff 《Journal of clinical oncology》2003,21(4):624-630
PURPOSE: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC. 相似文献
105.
Judit Anido Pablo Matar Joan Albanell Marta Guzmán Federico Rojo Joaquin Arribas Steve Averbuch Jose Baselga 《Clinical cancer research》2003,9(4):1274-1283
PURPOSE: ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that has shown clinical activity against EGFR-expressing tumors. Our aim was to explore the effects of ZD1839 in breast cancer cell lines expressing different levels of EGFR and the closely related HER2 receptor. EXPERIMENTAL DESIGN: We studied the growth-inhibitory effects of ZD1839 in a series of breast carcinoma cell lines. In HER2-overexpressing BT-474 breast cancer cells, we studied the effects of ZD1839 on cell growth and heterodimerization of receptors under basal and ligand-stimulated conditions. RESULTS: ZD1839 was an equally potent inhibitor of growth in breast cancer cells expressing high levels of EGFR and HER2. In BT-474 breast cancer cells, ZD1839 abolished EGF- and heregulin-induced activation of ErbB receptors and downstream signaling molecules. Because ZD1839 does not inhibit the HER2 tyrosine kinase in vitro, and because heregulin is a ligand that activates HER2 by binding to HER3 and HER4 but does not bind to the EGFR, our findings suggested that ZD1839 interfered with HER2 function in intact cells. Searching for mechanisms, we report that ZD1839 induces the formation of inactive unphosphorylated EGFR/HER2 and EGFR/HER3 heterodimers. Furthermore, ZD1839 completely abolishes basal and heregulin-induced formation of active phosphorylated HER2/HER3 heterodimers. CONCLUSIONS: ZD1839 inhibits the growth of HER2-overexpressing breast cancer cells, possibly by sequestration of HER2 and HER3 receptors in an inactive heterodimer configuration with the EGFR. Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors. 相似文献
106.
A Competency-based Model of Child Depression: A Longitudinal Study of Peer, Parent, Teacher, and Self-evaluations 总被引:8,自引:0,他引:8
David A. Cole Joan M. Martin Bruce Powers 《Journal of child psychology and psychiatry, and allied disciplines》1997,38(5):505-514
In a two-wave longitudinal study of third and sixth graders ( N = 617), we obtained self-reports of depression and peer, teacher, parent, and self-reports of competence in five domains: academic, social, attractiveness, conduct, and athletic. Competency evaluations by others predicted change in self-perceived competence over time for girls, but not for boys. Depression predicted change in self-perceived competence over time for boys but not for girls. Among girls, the relative importance of parent, teacher, and peer appraisals shifted from third to sixth grade. For both boys and girls, self-perceptions of competence predicted change in depression scores over time. Furthermore, self-perceived competencies mediated the relation between competency appraisals by others and children's self-reported depression. Results are interpreted in light of a competency-based model of child depression. 相似文献
107.
Joan C. Engebretson RN DrPH Diane Wind Wardell RNC PhD 《Journal of obstetric, gynecologic, and neonatal nursing : JOGNN / NAACOG》1997,26(6):660-664
Nonnutritive sucking can provide low-birth-weight infants with an opportunity to organize their behavior, an important component of developmental care. A pacifier specifically designed for low-birth-weight infants facilitates their nonnutritive sucking to more fully meet their needs. The research and development of a pacifier for low-birth-weight infants incorporated a naturalistic approach and used the best model, the infant thumb, in the design. Clinical trials with infants randomized to control and experimental groups were conducted to compare the prototype pacifier to a commercially available pacifier. Observations using the Anderson Behavioral State Scale demonstrated that infants using the prototype pacifier more often were found to be in an alert state. This pacifier may contribute to infants' state organization for optimum feeding and could be a component in developmental care planning. 相似文献
108.
Angel Asensio Antonio Ramos Elena Mú?ez José L Vilanova Pedro Torrijos Fernando J García 《Infection control and hospital epidemiology》2005,26(12):903-909
OBJECTIVE: To investigate the effect of preoperative initiation of low molecular weight heparin as prophylaxis for deep venous thrombosis in patients at risk of developing surgical-site infections after knee arthroplasty. DESIGN: Case-control study nested in a cohort. The incidence of surgical-site infection in the cohort was calculated. With the use of data extracted from medical histories and after adjustment for other risk factors, the effect of preoperative heparinization on the risk of incisional and prosthetic infection among case-patients and control-patients (1:3 ratio) was assessed. SETTING: Orthopedic department in a tertiary-care referral hospital. PATIENTS: A cohort of 160 consecutive patients who had received prosthetic knee implants between October 1, 2001, and November 30, 2003. RESULTS: Eighteen patients with surgical-site infections were identified, yielding an incidence of incisional and prosthetic infection of 6.9 (95% confidence interval [CI95], 3.5 to 12.0) and 4.4 (CI95, 1.8 to 8.8) cases per 100 patients undergoing surgery, respectively. Surgical-site infection was associated with preoperative use of low molecular weight heparin (odds ratio [OR], 6.2 after adjustment for medical and surgical factors; CI95 1.5 to 23). Prosthetic infection was strongly associated with preoperative use of prophylaxis (OR, undetermined [100% exposure in case-patients vs 35% exposure in control-patients]; P = .002), but incisional surgical-site infection was not. CONCLUSION: The use of low molecular weight heparins immediately before knee arthroplasty as prophylaxis for deep venous thrombosis should be questioned because of probable increased risk of prosthetic infection. 相似文献
109.
Bernard F. Fuemmeler Larry L. Mullins Jill Van Pelt Melissa Y. Carpentier Joan Parkhurst 《Children's Health Care》2005,34(4):289-303
In this study, we compared levels of posttraumatic stress symptoms (PTSS) and general psychological distress between parents of childhood cancer survivors and parents of children with Type 1 diabetes mellitus (DM1). In this study, we also examined potential risk factors for PTSS. Participants included 47 parents of childhood cancer survivors and 31 parents of children with DM1. Participants completed self-report measures of posttraumatic stress, general psychological distress, coping strategies, social network size, and perceived illness uncertainty. Findings revealed that parents of children surviving cancer reported higher levels of PTSS and general distress than parents of children with DM1. In the total sample, lower levels of emotion-focused coping and greater perceived uncertainty were associated with increased frequency of both PTSS and general psychological distress after we accounted for demographic and illness variables. Having a child with cancer may increase the risk for experiencing PTSS. Interventions are warranted that focus specifically on the reduction of PTSS in parents of children surviving cancer. 相似文献
110.
Janie Canty-Mitchell Joan K. Austin Susan M. Perkins Rong Amy Qi Nancy Swigonski 《Children's Health Care》2005,34(1):1-18
Our objective was to examine health-related quality of life (HRQOL) in publicly insured children with special health care needs (CSHCN). Data were obtained from 183 caregivers of CSHCN (M = 10 years; 54% African American) in urban health clinics. CSHCN had poorer physical and psychosocial HRQOL than children in a normative sample. In regression analysis, children who had more health problems and more health visits in the previous 12 months had poorer physical HRQOL. Poorer psychosocial HRQOL was associated with more health problems and urban life stressors. Implications for practice and policy are discussed. 相似文献