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101.
102.
Wayne L. Furman John H. Rodman Margaret E. Tonda Xiaolong Luo Bettye Arnold Neyssa Marina Leslie Garrison Roberta Hanna Charles B. Pratt William H. Meyer 《Cancer chemotherapy and pharmacology》1997,41(3):229-236
A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have
great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor
and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited,
and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels.
Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with
myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered
once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic
studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule
only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose
studied (1000 μg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing
doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77–1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase
63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were
<1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent
activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no
demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained
by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase
in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either
extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling
circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the
systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.
Received: 29 January 1997 / Accepted: 9 May 1997 相似文献
103.
Ewa Surmacz Marina A. Guvakova Mary K. Nolan Roberto F. Nicosia Laura Sciacca 《Breast cancer research and treatment》1998,47(3):255-267
Experimental evidence suggests an important role of the type I IGF receptor (IGF-IR) in breast cancer development. Breast tumors and breast cancer cell lines express the IGF-IR. IGF-IR levels are higher in cancer cells than in normal breast tissue or in benign mammary tumors. The ligands of the IGF-IR are potent mitogens promoting monolayer and anchorage-independent growth of breast cancer cells. Interference with IGF-IR activation, expression, or signaling inhibits growth and induces apoptosis in breast cancer cells. In addition, recent studies established the involvement of the IGF-IR in the regulation of breast cancer cell motility and adhesion. We have demonstrated that in MCF-7 cells, overexpression of the IGF-IR promotes E-cadherin-dependent cell aggregation, which is associated with enhanced cell proliferation and prolonged survival in three-dimensional culture.The expression or function of the IGF-IR in breast cancer cells is modulated by different humoral factors, such as estrogen, progesterone, IGF-II, and interleukin-1. The IGF-IR and the estrogen receptor (ER) are usually co-expressed and the two signaling systems are engaged in a complex functional cross-talk controlling cell proliferation.Despite the convincing experimental evidence, the role of the IGF-IR in breast cancer etiology, especially in metastatic progression, is still not clear. The view emerging from cellular and animal studies is that abnormally high levels of IGF-IRs may contribute to the increase of tumor mass and/or aid tumor recurrence, by promoting proliferation, cell survival, and cell-cell interactions. However, in breast cancer, except for the well established correlation with ER status, the associations of the IGF-IR with other prognostic parameters are still insufficiently documented. 相似文献
104.
105.
Should we treat elevated thyroid stimulating hormone levels in obese children and adolescents? 总被引:1,自引:0,他引:1
Alon Eliakim Marina Barzilai Baruch Wolach Dan Nemet 《International journal of pediatric obesity》2006,1(4):217-221
OBJECTIVE: To examine the prevalence of abnormal thyroid function tests among obese children and adolescents, and to study the effect of thyroid hormone supplementation on body weight, linear growth and lipid profiles in these children. DESIGN: Thyroid function tests and lipid profiles were measured in 196 obese children and adolescents. Thyroid auto-antibodies were measured in children with hyperthyrotropinemia (elevated thyroid stimulating hormone (TSH) and normal free thyroxine-FT4). All children with hyperthyrotropinemia participated in a combined dietary-behavioral-physical activity weight management intervention. Fifteen of the obese children with hyperthyrotropinemia were also treated with thyroid hormone substitution for 6 months and were compared to non-treated subjects (n = 26). RESULTS: Forty-one obese children had hyperthyrotropinemia (20.9%). Positive thyroid auto-antibodies were only found in 19.5% of these children. Treatment had no significant effect on body weight, linear growth and lipid profile, except for causing a greater decrease in triglyceride levels. TSH levels returned to normal ranges in the majority of children with hyperthyrotropinemia who participated in the combined intervention, irrespective of thyroxine treatment. CONCLUSIONS: Hyperthyrotropinemia is relatively common in obese children, but autoimmune thyroid disease accounts for a minority of the cases. TSH levels returned to normal in the majority of patients even without thyroid hormone administration. No beneficial effects on body weight, body mass index, linear growth and body lipids were found in treated subjects, suggesting that thyroid substitution is not necessary in most cases. 相似文献
106.
Marina Cuttini Veronica Casotto Marcello Orzalesi & THE EURONIC STUDY GROUP 《Acta paediatrica (Oslo, Norway : 1992)》2006,95(S452):42-46
An international project (EURONIC) was carried out to explore the end-of-life decision-making process in a large, representative sample of neonatal intensive care units (NICUs) in eight western European countries: France, Germany, Great Britain, Italy, Luxembourg, the Netherlands, Spain and Sweden. Structured questionnaires were used to record data on NICU organization and policies, and to survey staff views and practices regarding ethical decision-making. One hundred and twenty-two NICUs were recruited by census or random sampling (response rate 86%); 1235 physicians and 3115 nurses completed the staff questionnaire (response rates 89 and 85%, respectively). This paper focuses on the physicians' answers. In all countries but Italy, most physicians reported having been involved at least once in setting limits to intensive care because of a baby's incurable condition and/or poor neurological prognosis. Adopted strategies varied between countries. Practices such as the continuation of current treatment without intensifying it and the withholding of emergency manoeuvres appeared widespread. In contrast, the frequency of doctors reporting withdrawal of mechanical ventilation was highest in the Netherlands (93%), Sweden (91%) and the Great Britain (88%), intermediate in France and Germany, and lowest in Spain and Italy (34 and 21%, respectively).
Conclusion: Ethically problematic clinical cases are approached differently in the various countries. The findings of this study may provide an opportunity for physicians to review their practices critically, in light of how other colleagues proceed, and foster an open discussion about these difficult issues. 相似文献
Conclusion: Ethically problematic clinical cases are approached differently in the various countries. The findings of this study may provide an opportunity for physicians to review their practices critically, in light of how other colleagues proceed, and foster an open discussion about these difficult issues. 相似文献
107.
108.
Lajos Pusztai Savitri Krishnamurti Jorge Perez Cardona Nour Sneige Francisco J. Esteva Marina Volchenok Patricia Breitenfelder Shu-Wan Kau Shin Takayama Stanislaw Krajewski John C. Reed Robert C. Bast Jr. Gabriel N. Hortobagyi 《Cancer investigation》2005,22(2):248-256
It has been suggested that expression of anti-apoptotic proteins such as Bcl-2 or BAG-1 may confer cellular resistance to chemotherapy. A corollary of this hypothesis is that expression of these proteins may predict clinical response to treatment and that Bcl-2- or BAG-1-positive cells may selectively be enriched in postchemotherapy tissue specimens. The goal of this exploratory pilot study was to assess these two predictions by using immunohistochemistry in 29 paired pre- and postchemotherapy breast tissue specimens obtained from patients who underwent preoperative doxorubicin-based chemotherapy. All breast cancers expressed BAG-1 protein, and, in individual tumors, 40-100% of neoplastic cells stained positive for this protein. Homogenous cytoplasmic staining was typically observed, though neoplastic cells also showed nuclear staining in many specimens. We found no correlation between prechemotherapy expression of BAG-1 and subsequent pathological response to cytotoxic therapy. Paired pre- and posttreatment specimens showed similar levels of BAG-1 expression when residual tumor could be assessed. Bcl-2 was expressed in 55% of cancers and was localized to the cytoplasm. Absence of Bcl-2 expression in prechemotherapy specimens was associated with more frequent complete pathological response (58% vs. 20%; p = 0.04). However, similar to BAG-1, no difference between pre- and posttherapy expression of Bcl-2 was observed in neoplastic cells in paired tissue specimens. These observations suggest that BAG-1 contributes an important cellular function to breast epithelial cells, which is reflected by its ubiquitous expression in these tissues. However, it does not appear to determine response to doxorubicin-based chemotherapy. In contrast, lack of Bcl-2 expression was associated with a higher probability of complete pathological response to doxorubicin-based chemotherapy. 相似文献
109.
Alba A. Brandes Enrico Franceschi Alicia Tosoni Stefania Bartolini Antonella Bacci Raffaele Agati Claudio Ghimenton Sergio Turazzi Andrea Talacchi Miran Skrap Gianluca Marucci Lorenzo Volpin Luca Morandi Stefano Pizzolitto Marina Gardiman Alvaro Andreoli Fabio Calbucci Mario Ermani 《Neuro-oncology》2010,12(3):283-288
O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation status is a prognostic factor in newly diagnosed glioblastoma patients. However, it is not yet clear whether, and if so how, MGMT methylation status may change. Moreover, it is unknown whether the prognostic role of this epigenetic feature is retained during the disease course. A retrospective analysis was made using a database of 614 glioblastoma patients treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age ≥18 years; performance status 0-2; histological diagnosis of glioblastoma at both first and second surgery for recurrence; postoperative treatment consisting of: (i) radiotherapy (RT) followed by adjuvant temozolomide (TMZ) until 2005 and (ii) TMZ concurrent with and adjuvant to RT after 2005; a time interval ≥3 months between first and second surgery. MGMT status was evaluated at first and second surgery in all 44 patients (M:F 32:12, median age: 49 years, range: 27–67 years). In 38 patients (86.4%), MGMT promoter status was assessable at both first and second surgery. MGMT methylation status, changed in 14 patients (37%) of second surgery samples and more frequently in methylated than in unmethylated patients (61.5% vs 24%, P = .03). The median survival was significantly influenced only by MGMT methylation status determined at first surgery (P = .04). Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. MGMT methylation status determined at first surgery appears to be of prognostic value; however, it is not predictive of outcome following second surgery. 相似文献