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Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma 总被引:1,自引:0,他引:1
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Chauhan D Singh A Brahmandam M Podar K Hideshima T Richardson P Munshi N Palladino MA Anderson KC 《Blood》2008,111(3):1654-1664
Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138(+) MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib-induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM. 相似文献
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Variations in the morphology of pancreas are not very common. We observed a rare variant of the uncinate process of the pancreas that extended in the mesentery of the small intestine. After its origin from the lower part of the head of the pancreas, the mesenteric process (MP) passed over the third part of the duodenum to enter the mesentery of the jejunum and ileum and extended up to the level of the pelvic brim. The branches of the superior mesenteric vessels were embedded in the extended MP of the pancreas. This aberrant extension of the pancreas was drained by a narrow duct, which joined the main pancreatic duct inside the head. We did not observe a separate uncinate process arising from the head. On histology normal acini and endocrine cells were observed in the extension. This variant is important as symptoms of pancreatic disease from such extensions may be confused with other commonly encountered acute or chronic abdominal conditions. 相似文献
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Teoh G Tai YT Urashima M Shirahama S Matsuzaki M Chauhan D Treon SP Raje N Hideshima T Shima Y Anderson KC 《Blood》2000,95(3):1039-1046
It has been reported that the activation of multiple myeloma (MM) cells by CD40 induces proliferation, growth arrest, and apoptosis. To determine whether the biologic sequelae of CD40 activation in MM cells depends on p53 function, we identified temperature-sensitive p53 mutations in the RPMI 8226 (tsp53E285K) and the HS Sultan (tsp53Y163H) MM cell lines. These cells were then used as a model system of inducible wtp53-like function because wild-type-like p53 is induced at permissive (30 degrees C) but not at restrictive (37 degrees C) temperatures. Using p21-luciferase reporter assays, we confirmed that CD40 induces p53 transactivation in RPMI 8226 and HS Sultan cells cultured under permissive, but not restrictive, conditions. Furthermore, CD40 activation of these MM cells under permissive, but not restrictive, temperatures increased the expression of p53 and p21 mRNA and protein. Importantly, CD40 activation induced the proliferation of RPMI 8226 and HS Sultan cells at restrictive temperatures and growth arrest and increased subG1 phase cells at permissive temperatures. These data confirmed that CD40 activation might have distinct biologic sequelae in MM cells, depending on their p53 status. 相似文献
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Ashish Correa Achint Patel Kinsuk Chauhan Harshil Shah Aparna Saha Mihir Dave Priti Poojary Abhishek Mishra Narender Annapureddy Shaman Dalal Ioannis Konstantinidis Renu Nimma Shiv Kumar Agarwal Lili Chan Girish Nadkarni Sean Pinney 《Journal of cardiac failure》2018,24(7):442-450
Background
Dialysis-requiring acute kidney injury (D-AKI) is a serious complication in hospitalized heart failure (HF) patients. However, data on national trends are lacking after 2002.Methods
We used the Nationwide Inpatient Sample (2002–2013) to identify HF hospitalizations with and without D-AKI. We analyzed trends in incidence, in-hospital mortality, length of stay (LoS), and cost. We calculated adjusted odds ratios (aORs) for predictors of D-AKI and for outcomes including in-hospital mortality and adverse discharge (discharge to skilled nursing facilities, nursing homes, etc).Results
We identified 11,205,743 HF hospitalizations. Across 2002–2013, the incidence of D-AKI doubled from 0.51% to 1.09%. We found male sex, younger age, African-American and Hispanic race, and various comorbidities and procedures, such as sepsis and mechanical ventilation, to be independent predictors of D-AKI in HF hospitalizations. D-AKI was associated with higher odds of in-hospital mortality (aOR 2.49, 95% confidence interval [CI] 2.36–2.63; P?<?.01) and adverse discharge (aOR 2.04, 95% CI 1.95–2.13; P?<?.01). In-hospital mortality and attributable risk of mortality due to D-AKI decreased across 2002–2013. LoS and cost also decreased across this period.Conclusions
The incidence of D-AKI in HF hospitalizations doubled across 2002–2013. Despite declining in-hospital mortality, LoS, and cost, D-AKI was associated with worse outcomes. 相似文献67.
Dinesh Singh Chauhan Yadavalli Guruprasad 《Journal of maxillofacial and oral surgery》2015,14(1):42-46
Goldenhar syndrome, a variant of hemifacial microsomia, is a well-known developmental anomaly of maxillofacial skeleton that is apparent at birth. The first and second branchial arch involvement during early embryonic development results in a wide spectrum of anomalies that may include macrostomia and lateral facial clefts. Though clefts of the orofacial region are among the most common congenital facial defects, the occurrence of lateral facial clefts (Tessier 7 cleft) in conditions such as the Goldenhar syndrome, is very rare (<5%). The lateral facial cleft, which results because of improper development of the perioral muscles of the face, gives an appearance of macrostomia giving rise to potential psychological, aesthetic and feeding problems. This clinical report describes the closure of a Tessier 7 cleft and the use of distraction osteogenesis to treat mandibular asymmetry in an 11-year-old female patient with Goldenhar’s syndrome. 相似文献
68.
Mitochondria organize themselves as dynamic populations within a cell, by undergoing continuous cycles of fission and fusion. The spatio-temporal distribution and abundance of mitochondria determines the cell’s energy budget and is thus intimately linked to the cell’s response to environmental stimuli during aging. The dynamic balance of mitochondrial fission and fusion can be studied in terms of antagonistic subpopulations that regulate the mitochondrial responses in space and time. The dynamic nature of these processes motivates mathematical modelling and the simulation of such complex process. In several neurodegenerative and metabolic diseases the dynamic balance of fission and fusion is disturbed. However, how this dynamics plays a role in the progression of diseases is largely unclear. Fission and fusion help mitochondria to regulate cellular energy (ATP) levels, and minimize accumulation of harmful oxidized material called reactive oxygen species which accelerate mutations in mitochondrial DNA (mtDNA) during aging. We discuss how systems biology approaches can be used to investigate the mechanisms controlling the fission–fusion dynamics under two categories: dissecting the design of its molecular regulatory motifs, and understanding complex mitochondrial responses through their population level interactions. This will help us to understand how different regulatory mechanisms regulate the ATP and mutation (mtDNA) landscape of mitochondria to a variety of environmental stimuli in order to maintain their function during aging. 相似文献
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