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91.
Chitra Subramanian Jason A Jarzembowski Anthony W Opipari Jr Valerie P Castle Roland PS Kwok 《Neoplasia (New York, N.Y.)》2011,13(8):726-734
Ku70 was first characterized as a nuclear factor that binds DNA double-strand breaks in nonhomolog end-joining DNA repair. However, recent studies have shown that Ku70 is also found in the cytoplasm and binds Bax, preventing Bax-induced cell death. We have shown that, in neuroblastoma cells, the binding between Ku70 and Bax depends on the acetylation status of Ku70, such that, when Ku70 is acetylated, Bax is released from Ku70, triggering cell death. Thus, to survive, in neuroblastoma cells, cytoplasmic Ku70 acetylation status is carefully regulated such that Ku70 is maintained in a deacetylated state, keeping Bax complexed with Ku70. We have shown that overexpression of CREB-binding protein (CBP), a known acetyltransferase that acetylates Ku70, releases Bax from Ku70, triggering apoptosis. Although we have shown that blocking deacetylase activity using non-type-specific inhibitors also triggers Ku70 acetylation and Bax-dependent cell death, the targets of these deacetylase inhibitors in neuroblastoma cells remain unknown. Here, we demonstrate that, in neuroblastoma cells, histone deacetylase 6 (HDAC6) binds Ku70 and Bax in the cytoplasm and that knocking down HDAC6 or using an HDAC6-specific inhibitor triggers Bax-dependent cell death. Our results show that HDAC6 regulates the interaction between Ku70 and Bax in neuroblastoma cells and may be a therapeutic target in this pediatric solid tumor. 相似文献
92.
Nahas CS Akhurst T Yeung H Leibold T Riedel E Markowitz AJ Minsky BD Paty PB Weiser MR Temple LK Wong WD Larson SM Guillem JG 《Annals of surgical oncology》2008,15(3):704-711
Background Patients with locally advanced rectal cancer may present with synchronous distant metastases. Choice of optimal treatment—neoadjuvant
chemoradiation versus systemic chemotherapy alone—depends on accurate assessment of distant disease. We prospectively evaluated
the ability of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) to detect distant disease in patients with locally advanced rectal cancer who were
otherwise eligible for combined modality therapy (CMT).
Methods Ninety-three patients with locally advanced rectal cancer underwent whole-body [18F]FDG PET scanning 2–3 weeks before starting CMT. Sites other than the rectum, mesorectum, or the area along the inferior
mesenteric artery were considered distant and were divided into nine groups: neck, lung, mediastinal lymph node (LN), abdomen,
liver, colon, pelvis, peripheral LN, and soft tissue. Two nuclear medicine physicians blinded to clinical information used
PET images and a five-point scale (0–4) to determine certainty of disease. A score greater than 3 was considered malignant.
Confirmation was based on tissue diagnosis, surgical exploration, and subsequent imaging.
Results At a median follow-up of 34 months, the overall accuracy, sensitivity, and specificity of PET in detecting distant disease
were 93.7%, 77.8%, and 98.7% respectively. Greatest accuracy was demonstrated in detection of liver (accuracy = 99.9%, sensitivity = 100%,
specificity = 98.8%) and lung (accuracy = 99.9%, sensitivity = 80%, specificity = 100%) disease; PET detected 11/12 confirmed
malignant sites in liver and lung. A total of 10 patients were confirmed to have M1 stage disease. All 10 were correctly staged
by pre-CMT PET; abdominopelvic computed tomography (CT) scans accurately detected nine of them.
Conclusion Baseline PET in patients with locally advanced rectal cancer reliably detects metastatic disease in liver and lung. PET may
play a significant role in defining extent of distant disease in selected cases, thus impacting the choice of neoadjuvant
therapy.
An erratum to this article can be found at 相似文献
93.
Yip Ronald ML Cheung Tommy T So Ho Chan Julia PS Ho Carmen TK Tsang Helen HL Yu Carrel KL Wong Priscilla CH 《Clinical rheumatology》2023,42(8):2013-2027
Clinical Rheumatology - Gout is one of the most common noncommunicable diseases in Hong Kong. Although effective treatment options are readily available, the management of gout in Hong Kong remains... 相似文献
94.
Kammula US Kuntz EJ Francone TD Zeng Z Shia J Landmann RG Paty PB Weiser MR 《Cancer letters》2007,248(2):219-228
INTRODUCTION/HYPOTHESIS: Over-expression of the c-Met receptor tyrosine kinase has been described in a variety of cancers and implicated in tumor progression. Unlike some solid tumors, current evidence indicates that c-Met activation in colon cancer is unrelated to gene mutation, is ligand dependent, and occurs via a paracrine fashion. We hypothesize that over-expression of the c-Met receptor and its ligand, hepatocyte growth factor (HGF) in the tumor microenvironment is associated with tumor progression and metastases. METHODS: Primary tumor c-Met and HGF mRNA expression was analyzed in 60 colon adenocarcinomas. Receptor and ligand expression was analyzed for correlation and association with clinicopathologic features and outcome. RESULTS: Compared to adjacent normal mucosa, 69% and 48% of tumors showed a greater than 2- and greater than 10-fold elevation in c-Met mRNA, respectively. Elevated HGF mRNA was noted in 47% of tumors with 19% having a greater than 10-fold increase. Tumor c-Met expression was correlated with HGF expression, and a cohort of 33 patients could be defined with both low c-Met and HGF expression. Compared with the 27 tumors with either high c-Met or HGF, the cohort with low c-Met and HGF expression had fewer nodal and distant metastases as well as improved overall survival (HR=2.3, p<0.05). CONCLUSION: Evaluation of the c-Met receptor in context of ligand, HGF, allows identification of a metastatic phenotype that correlates with advanced stage and poor survival. c-Met and HGF co-expression in the tumor microenvironment could be useful in the molecular staging of colon cancer and viable therapeutic targets. 相似文献
95.
Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP) 总被引:8,自引:0,他引:8
Rowe PS; Oudet CL; Francis F; Sinding C; Pannetier S; Econs MJ; Strom TM; Meitinger T; Garabedian M; David A; Macher MA; Questiaux E; Popowska E; Pronicka E; Read AP; Mokrzycki A; Glorieux FH; Drezner MK; Hanauer A; Lehrach H; Goulding JN; O'Riordan JL 《Human molecular genetics》1997,6(4):539-549
Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with
homologies to endopeptidases, on the X-chromosome), are responsible for
X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family
of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has
raised important questions regarding PEX function at the molecular level.
The aim of this study was to analyse 99 HYP families for PEX gene
mutations, and to correlate predicted changes in the protein structure with
Zn2+ metallopeptidase gene function. Primers flanking 22 characterised
exons were used to amplify DNA by PCR, and SSCP was then used to screen for
mutations. Deletions, insertions, nonsense mutations, stop codons and
splice mutations occurred in 83% of families screened for in all 22 exons,
and 51% of a separate set of families screened in 17 PEX gene exons.
Missense mutations in four regions of the gene were informative regarding
function, with one mutation in the Zn2+-binding site predicted to alter
substrate enzyme interaction and catalysis. Computer analysis of the
remaining mutations predicted changes in secondary structure,
N-glycosylation, protein phosphorylation and catalytic site molecular
structure. The wide range of mutations that align with regions required for
protease activity in NEP suggests that PEX also functions as a protease,
and may act by processing factor(s) involved in bone mineral metabolism.
相似文献
96.
Jin K. Kim Michael R. Marco SeoHyun Choi Xuan Qu ChinTung Chen Moshe Elkabets Lauren Fairchild Oliver Chow Francisco M. Barriga Lukas E. Dow Kevin ORourke Bryan Szeglin Dmitry Yarilin Sho Fujisawa Katia ManovaTodorova Philip B. Paty Jinru Shia Christina Leslie J. Joshua Smith Scott Lowe Raphael Pelossof Francisco SanchezVega Julio GarciaAguilar 《Molecular oncology》2021,15(10):2766
Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS‐mt) and KRAS‐wild‐type (KRAS‐wt) patients. We found that KRAS‐mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment. 相似文献
97.
BACKGROUND: Brainstem gliomas are highly heterogeneous tumors both in their clinical manifestation and in their pathology. Despite significant advances in the surgery for brainstem gliomas many aspects of this pathology are still unelear. OBJECTIVE: To evaluate the clinical, radiological and surgical outcome of 40 focal "intrinsic" brainstem gliomas and propose a surgical strategyoriented classification. MATERIALS AND METHODS: A total of 40 focal ‘intrinsie’ ("expanding variety") tumors have been operated over a period of 8.5-years (January 1998-June 2007). Our criteria included patients with (1) well-defined gadolinium enhancing tumor, (2) relatively long duration of symptoms (〉 six months) and (3) good neurological functional status and independent for all activities of davy living. The cutoff size of 2 cm was not rigidly adhered to. RESULTS: The "intrinsic" brainstem tumors were classified into three types: Expanding, diffuse infiltrative and pure ventral varieties. 相似文献
98.
99.
Immediate preoperative phlebotomy with autologous blood donation for aortic replacement 总被引:1,自引:0,他引:1
P S Paty D M Shah B B Chang J L Kaufman P J Feustel R P Leather 《Surgery, gynecology & obstetrics》1990,171(4):326-330
The preferential use of autologous blood provided by phlebotomy can reduce the need for homologous blood transfusion in patients undergoing extensive elective operations. This blood is usually provided either by intraoperative isovolemic hemodilution or phlebotomy one to two weeks preoperatively. To minimize the intraoperative time delay or preoperative period between phlebotomy and operation required in these patients, we performed preoperative isovolemic hemodilution in 69 patients one to two days prior to elective aortic replacement for infrarenal aneurysmal disease. Patients underwent phlebotomy a mean of 0.57 +/- 0.01 liter of whole blood; volume was replaced with lactated Ringer's solution. Hematocrit levels decreased from a mean value of 42.9 +/- 0.4 per cent to 33.7 +/- 0.3 per cent. Mean intraoperative blood loss was 1.2 +/- 0.05 liters. Hemodynamic parameters (blood pressure, cardiac output, pulmonary capillary wedge pressure, central venous pressure, oxygen delivery and systemic vascular resistance) remained stable throughout the perioperative and intraoperative time periods. In addition, we evaluated the technical modification of exclusion aneurysmorrhaphy (n = 50) versus open aneurysmorraphy (n = 19) on reduction of intraoperative homologous blood transfusion in these patients. Seventy-two per cent (36 of 50) of patients whose aneurysms were excluded received no homologous blood intraoperatively. Blood loss was decreased in the excluded versus open aneurysmorraphy group, 920 +/- 90 milliliters versus 2,030 +/- 250 milliliters, as were homologous blood transfusion requirements, 175 +/- 35 milliliters versus 570 +/- 119 milliliters. Two patients died (2.9 per cent mortality rate), and there was no increase in morbidity. Surgical treatment of large aortic aneurysms is frequently performed on an urgent basis; thus, provision of autologous blood for this operation in a short period of time may be beneficial. Isovolemic hemodilution performed during the immediate preoperative period can reduce homologous blood requirements and be safely performed without adverse effects on mortality, morbidity and myocardial performance. Exclusion aneurysmorrhaphy may further reduce dependence on homologous blood. 相似文献
100.
Increased oxidative stress is a mechanism that probably plays a major role in the development of diabetic complications, including peripheral neuropathy. This review summarises recent data from in vitro and in vivo studies that have been performed both to understand this aspect of the pathophysiology of diabetic neuropathy and to develop therapeutic modalities for its prevention or treatment. Extensive animal studies have demonstrated that oxidative stress may be a final common pathway in the development of diabetic neuropathy, and that antioxidants can prevent or reverse hyperglycaemia-induced nerve dysfunction. Most probably, the effects of antioxidants are mediated by correction of nutritive blood flow, although direct effects on endoneurial oxidative state are not excluded. In a limited number of clinical studies, antioxidant drugs including alpha-lipoic acid and vitamin E were found to reduce neuropathic symptoms or to correct nerve conduction velocity. These data are promising, and additional larger studies with alpha-lipoic acid are currently being performed. 相似文献