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81.
The p21-activated kinases signal through a number of cellular pathways fundamental to growth, differentiation and apoptosis.
A wealth of information has accumulated at an impressive pace in the recent past, both with regard to previously identified
targets for p21-activated kinases that regulate the actin cytoskeleton and cellular stress pathways and with regard to newly
identified targets and their role in cancer. Emerging data also provide new clues towards a previously unappreciated link
between these various cellular processes. The present review attempts to provide a quick tutorial to the reader about the
evolving significance of p21-activated kinases and small GTPases in breast cancer, using information from mouse models, tissue
culture studies, and human materials. 相似文献
82.
BACKGROUND: Intradiploic hematoma of the skull was first reported in 1934. The pathogenesis of this lesion is unclear. It is a very rare benign reactive process occurring after minor head trauma, with only seven cases reported in the literature to date. CASE DESCRIPTION: A 3-year-old right hand dominant male presented with a non-tender parietal scalp swelling of a 1-year duration. History included a skull fracture located in the same region 24 months before presentation. Neurological examination was unremarkable. Pathological examination after curettage of the lesion revealed features consistent with organizing hematoma. CONCLUSIONS: The pathology of chronic diploic hematoma mimics aneurysmal bone cyst, giant cell tumor, giant cell reparative granuloma, fibrous dysplasia, eosinophilic granuloma, intradiploic epidermoid and dermoid cyst, cavernous hemangioma, circumscribed osteomyelitis, and tuberculous granuloma. Chronic diploic hematoma is a lesion that must be differentiated from various skull lesions both radiologically and histologically as it is amenable to treatment with a complete cure once excised. 相似文献
83.
Martin A. Graham Suresh Senan Hernani Robin Jr. Nils Eckhardt Dennis Lendrem Jeffery Hincks Dennis Greenslade Roy Rampling Stanley B. Kaye Reinhard von Roemeling Paul Workman 《Cancer chemotherapy and pharmacology》1997,40(1):1-10
Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; SR 259075) is a selective hypoxic cell cytotoxic agent that is bioreductively activated in tumours to a reactive-drug
free radical. Preclinically the agent has been shown to possess additive and synergistic anti-tumour activity in combination
with radiotherapy and chemotherapy regimens. In the present study the pharmacokinetics and metabolism of tirapazamine were
investigated in mice and patients as part of pre-clinical and phase I investigations. The objectives of this work were twofold;
firstly, to evaluate retrospectively the utility of a pharmacokinetically guided dose-escalation (PGDE) strategy for tirapazamine,
and secondly, to investigate if pharmacologically relevant plasma concentrations could be achieved at tolerable doses. Pharmacokinetic
studies for PGDE were conducted in mice at four dose levels ranging from one-tenth of the LD10 to the LD50. The AUC at the LD10 (2932 μg ml-1min) was used to determine a target AUC value of 1173 μg ml-1min (equivalent to 40% of the mouse LD10 AUC) for clinical studies. A phase I study to investigate the tolerance of a single i.v. infusion of tirapazamine (once every
3 weeks) was initiated with close pharmacokinetic monitoring. The starting dose (36 mg/m2) was based on toxicity data obtained in the mouse, rat and dog. Doses were escalated by increases in the volume and duration
of infusion. A retrospective analysis of the pharmacokinetic and toxicity data was then made to determine the utility of a
PGDE approach. The drug exhibited a steep dose-lethality relationship in mice (LD10 294 mg/m2, LD50 303 mg/m2). The major gross toxicities were body-weight loss (15–20%), pilo-erection and hypoactivity at all dose levels. Sporadic
ptosis and conjunctivitis were observed at doses of >300 mg/m2. The plasma elimination of tirapazamine fitted a monoexponential open model, with rapid elimination from the plasma (t
1/2=36±0.65 min) occuring at the LD10 dose of 294 mg/m2. A 10.3-fold increase in dose resulted in a 25.0-fold increase in AUC. Clinically, doses were escalated over the range of
36–450 mg/m2. Ototoxicity (tinnitus and reversible hearing loss) was dose-limiting at 450 mg/m2 and the MTD was 390 mg/m2 for this schedule. Pharmacokinetic analyses in patients revealed that the elimination of tirapazamine in patients was generally
bi-phasic, with low inter-patient variability being found in clearance. A 12.5-fold increase in dose resulted in a 19.0-fold
increase in AUC. There was good quantitative agreement in metabolite formation between mice and humans with respect to the
two- and four-electron bioreductive metabolites. AUC values recorded for tirapazamine at the MTD of 390 mg/m2 (range 1035–1611 μg ml-1min) were similar to the target AUC in mice. Importantly, these levels are consistent with the levels required for radiation-dose
enhancement and effective combination with cisplatin in mice. Given (a) the similarities in plasma pharmacokinetics and metabolism
observed at the target AUC/MTD in mice, rats, dogs and humans, (b) the similar degree of plasma protein binding seen between
species and (c) the relatively low inter-patient variability noted in drug clearance, a successful PGDE approach should have
been feasible. The results also indicate that potentially therapeutic levels of tirapazamine are achievable in patients at
tolerable doses.
Received: 27 May 1996 / Accepted: 30 September 1996 相似文献
84.
M. S. Vidyasagar Suresh Rao Donald J. Fernandes Ramanujam A. S. 《Indian journal of otolaryngology and head and neck surgery》1998,50(1):69-72
Primary Ewing’s sarcoma of the nasal bone has not been previously described. This case presented as a mass in the left ala
of the nose in a five year old female child. The clinical, radiological, microscopic features are described and a review of
literature is presented. The case was treated with neoadjuvant chemotherapy and local electron beam radiation therapy. The
child was free of disease when she reported for follow up in July 1997. Although wide excision is part of the treatment approach
in Ewing’s sarcoma, in sites where surgery is not suitable local radiotherapy and chemotherapy adequately controls primary
disease. 相似文献
85.
M. S. Vidyasagar Suresh Rao Donald J. Fernandes A. S. Ramanujam 《Indian journal of otolaryngology and head and neck surgery》1998,50(1):69-72
Primary Ewing’s sarcoma of the nasal bone has not been previously described. This case presented as a mass in the left ala of the nose in a five year old female child. The clinical, radiological, microscopic features are described and a review of literature is presented. The case was treated with neoadjuvant chemotherapy and local electron beam radiation therapy. The child was free of disease when she reported for follow up in July 1997. Although wide excision is part of the treatment approach in Ewing’s sarcoma, in sites where surgery is not suitable local radiotherapy and chemotherapy adequately controls primary disease. 相似文献
86.
Chittukadu K. Gajalakshmi Viswanathan Shanta Ranganathan Rama 《Cancer causes & control : CCC》1998,9(2):131-136
Objectives: This study was carried out to evolve a method to improve the registration of cancer mortality data in Chennai (Madras, India). Methods: Data on cancer deaths have been collected from the Vital Statistics Department (VSD) by a population-based cancer registry (PBCR) in Chennai only since 1982. The low mortality-to-incidence ratio during 1982-84 suggested under-registration of mortality data. Since 1985, the PBCR has taken special effort to ascertain the vital status of cancer cases by sending reply-paid postcards and/or making house visits. The data on all deaths occurring in Chennai, irrespective of stated cause of death in the death certificate, have been collected from the VSD since 1992. Results: Deaths that occurred in Chennai and obtained by sending reply-paid postcards and/or making house visits were registered in VSD as non-cancer causes of death; hence, these data were not collected from VSD. The sensitivity and positive predictive values of death certificates on cancer diagnosis based on 1992 and 1993 mortality data were 57 percent and 99.5 percent, respectively. Conclusion: Since the accuracy of death certificate information on cancer diagnosis is relatively low in a developing country such as in India, collecting data on all deaths will improve the mortality data registration in PBCRs. 相似文献
87.
88.
Jaimanti Naresh K. Panda Suresh Sharma Ashok K. Gupta S. B. S. Mann 《Indian journal of otolaryngology and head and neck surgery》2004,56(2):99-104
Conclusion Patients with stage I and II tumors had the best results with radical radiotherapy alone 5 years survival for patients with
stage I and stage II tumors was 90-95% and 75-85% respectively Patients with advanced stage III & IV disease were treated
Unoperable stage IV cancer patients had poor outcome and received only palliative treatment 相似文献
89.
The clinical relevance of steroid hormone receptor corepressors. 总被引:2,自引:0,他引:2
Rakesh Kumar Anupama E Gururaj Ratna K Vadlamudi Suresh K Rayala 《Clinical cancer research》2005,11(8):2822-2831
90.
John M Pagel Christian Laugen Lynn Bonham Robert C Hackman David M Hockenbery Rama Bhatt David Hollenback Heather Carew Jack W Singer Oliver W Press 《Clinical cancer research》2005,11(13):4857-4866
PURPOSE: Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) is a transmembrane enzyme critical for the biosynthesis of phosphoglycerides whose product, phosphatidic acid, plays a key role in raf and AKT/mTor-mediated signal transduction. EXPERIMENTAL DESIGN: LPAAT-beta may be a novel target for anticancer therapy, and, thus, we examined the effects of a series of inhibitors of LPAAT-beta on multiple human non-Hodgkin's lymphoma cell lines in vitro and in vivo. RESULTS: We showed that five LPAAT-beta inhibitors at doses of 500 nmol/L routinely inhibited growth in a panel of human lymphoma cell lines in vitro by >90%, as measured by [3H]thymidine incorporation. Apoptotic effects of the LPAAT-beta inhibitors were evaluated either alone or in combination with the anti-CD20 antibody, Rituximab. The LPAAT-beta inhibitors induced caspase-mediated apoptosis at 50 to 100 nmol/L in up to 90% of non-Hodgkin's lymphoma cells. The combination of Rituximab and an LPAAT-beta inhibitor resulted in a 2-fold increase in apoptosis compared with either agent alone. To assess the combination of Rituximab and a LPAAT-beta inhibitor in vivo, groups of athymic mice bearing s.c. human Ramos lymphoma xenografts were treated with the LPAAT-beta inhibitor CT-32228 i.p. (75 mg/kg) daily for 5 d/wk x 4 weeks (total 20 doses), Rituximab i.p. (10 mg/kg) weekly x 4 weeks (4 doses total), or CT-32228 plus Rituximab combined. Treatment with either CT-32228 or Rituximab alone showed an approximate 50% xenograft growth delay; however, complete responses were only observed when the two agents were delivered together. CONCLUSIONS: These data suggest that Rituximab, combined with a LPAAT-beta inhibitor, may provide enhanced therapeutic effects through apoptotic mechanisms. 相似文献