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排序方式: 共有271条查询结果,搜索用时 36 毫秒
41.
Kalderén C Forsgren M Karlström U Stefansson K Svensson R Berglund MM Palm G Selander M Sundbom M Nilsson J Sjögren A Zachrisson K Gelius SS 《Biochemical pharmacology》2012,83(5):644-652
The truncated [1+9-76] CCL2 analogue, also known as 7ND, has been described in numerous reports as an anti-inflammatory and anti-fibrotic agent in a wide spectrum of animal models, e.g. models of cardiovascular disease, graft versus host disease and bleomycin-induced pulmonary fibrosis. 7ND has been reported to function as a competitive inhibitor of CCL2 signaling via CCR2 in human in vitro systems. In contrast, the mechanistic basis of 7ND action in animal models has not been previously reported. Here we have studied how 7ND interacts with CCL2 and CCR2 of murine origin. Surprisingly, 7ND was shown to be a weak inhibitor of murine CCL2/CCR2 signaling and displaced murine CCL2 (JE) from the receptor with a K(i)>1 μM. Using surface plasmon resonance, we found that 7ND binds murine CCL2 with a K(d) of 670 nM, which may indicate that 7ND inhibits murine CCL2/CCR2 signaling by a dominant negative mechanism rather than by competitive binding to the CCR2 receptor. In addition we observed that sub-nanomolar levels of 7ND mediate anti-fibrotic effects in CCR2 negative fibroblasts cultured from fibrotic lung of bleomycin-induced mice. Basal levels of extracellular matrix proteins were reduced (collagen type 1 and fibronectin) as well as expression levels of α-smooth muscle actin and CCL2. Our conclusion from these data is that the previously reported effects of 7ND in murine disease models most probably are mediated via mechanisms independent of CCR2. 相似文献
42.
Hiddo J. L. Heerspink PhD C. David Sjöström MD Silvio E. Inzucchi MD Melissa K. Hallow PhD Valerie A. Cain MS Peter Rossing MD Bergur V. Stefansson PhD Peter Sartipy PhD 《Diabetes, obesity & metabolism》2019,21(3):720-725
The sodium glucose co-transporter-2 inhibitor dapagliflozin has been shown to decrease urinary albumin-to-creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non-response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR-adjusted mean change from baseline was −71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined. 相似文献
43.
S Papiol D Malzahn A K?stner S Sperling M Begemann H Stefansson H Bickeb?ller K-A Nave H Ehrenreich 《Translational psychiatry》2011,1(10):e45
Genotype–phenotype correlations of common monogenic diseases revealed that the degree of deviation of mutant genes from wild-type structure and function often predicts disease onset and severity. In complex disorders such as schizophrenia, the overall genetic risk is still often >50% but genotype–phenotype relationships are unclear. Recent genome-wide association studies (GWAS) replicated a risk for several single-nucleotide polymorphisms (SNPs) regarding the endpoint diagnosis of schizophrenia. The biological relevance of these SNPs, however, for phenotypes or severity of schizophrenia has remained obscure. We hypothesized that the GWAS ‘top-10'' should as single markers, but even more so upon their accumulation, display associations with lead features of schizophrenia, namely positive and negative symptoms, cognitive deficits and neurological signs (including catatonia), and/or with age of onset of the disease prodrome as developmental readout and predictor of disease severity. For testing this hypothesis, we took an approach complementary to GWAS, and performed a phenotype-based genetic association study (PGAS). We utilized the to our knowledge worldwide largest phenotypical database of schizophrenic patients (n>1000), the GRAS (Göttingen Research Association for Schizophrenia) Data Collection. We found that the ‘top-10'' GWAS-identified risk SNPs neither as single markers nor when explored in the sense of a cumulative genetic risk, have any predictive value for disease onset or severity in the schizophrenic patients, as demonstrated across all core symptoms. We conclude that GWAS does not extract disease genes of general significance in schizophrenia, but may yield, on a hypothesis-free basis, candidate genes relevant for defining disease subgroups. 相似文献
44.
Frederik Persson Peter Rossing Priya Vart Glenn M. Chertow Fan Fan Hou Niels Jongs John J.V. McMurray Ricardo Correa-Rotter Harpreet S. Bajaj Bergur V. Stefansson Robert D. Toto Anna Maria Langkilde David C. Wheeler Hiddo J.L. Heerspink 《Diabetes care》2021,44(8):1894
OBJECTIVEThe Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status.RESEARCH DESIGN AND METHODSWe enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200–5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death.RESULTSOf 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes.CONCLUSIONSDapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status. 相似文献
45.
Bergthorsson JT Agnarsson BA Gudbjartsson T Magnusson K Thoroddsen A Palsson B Bjornsson J Stefansson K Gulcher J Einarsson GV Amundadottir LT Barkardottir RB 《Cancer Genetics and Cytogenetics》2006,164(1):1-9
Testicular germ cell tumors (TGCT) arise by multistep carcinogenesis pathways involving selective losses and gains of chromosome material. To locate cancer genes underlying this selection, we performed a genome-wide study of allelic imbalance (AI) in 32 tumors, using 710 microsatellite markers. The highest prevalence of AI was found at 12p, in line with previous studies finding consistent gain of the region in TGCTs. High frequency of AI was also observed at chromosome arms 4p, 9q, 10p, 11q, 11p, 13q, 16q, 18p, and 22q. Within 39 candidate regions identified by mapping of smallest regions of overlap (SROs), the highest frequency of AI was at 12p11.21 approximately p11.22 (62%), 12p12.1 approximately p13.1 (53%), 12p13.1 approximately p13.2 (53%), 11q14.1 approximately q14.2 (53%), 11p13 approximately p14.3 (47%), 9q21.13 approximately q21.32 (47%), and 4p15.1 approximately p15.2 (44%). Two genes known to be involved in cancer reside in these regions, ETV6 at 12p13.2 (TEL oncogene) and WT1 at 11p13. We also found a significant association (P = 0.02) between AI at 10q21.1 approximately q22.2 and higher clinical stage. This study contributes to the ongoing search for genes involved in transformation of germ cells and provides a useful reference point to previous studies using cytogenetic techniques to map chromosome changes in TGCTs. 相似文献
46.
In a recent article, Wang and colleagues reported the discovery of a mechanism by which CARM1 regulates the genomic localization of BAF155 (a SWI/SNF subunit involved in chromatin remodeling) through post-translational methylation at R1064 arginine residues. This modification leads to the relocalization of BAF155-containing SWI/SNF complexes to regions containing genes involved in the Myc oncogenic pathway. The results presented are evidence that these interactions constitute a mechanism by which the BAF155 chromatin remodeling factor contributes to cancer. 相似文献
47.
48.
Heng Sheng Sow Hreinn Benonisson Cor Breukel Remco Visser Onno J.H.M. Verhagen Arthur E.H. Bentlage Conny Brouwers Jill W.C. Claassens Margot M. Linssen Marcel Camps Thorbald van Hall Ferry Ossendorp Marieke F. Fransen Gestur Vidarsson J. Sjef Verbeek 《International journal of cancer. Journal international du cancer》2019,144(2):345-354
Immunomodulatory antibodies blocking interactions of coinhibitory receptors to their ligands such as CTLA-4, PD1 and PD-L1 on immune cells have shown impressive therapeutic efficacy in clinical studies. The therapeutic effect of these antibodies is mainly mediated by reactivating antitumor T cell immune responses. Detailed analysis of anti-CTLA4 antibody therapy revealed that an optimal therapeutic efficacy also requires binding to Fc receptors for IgG, FcγR, mediating depletion of intratumoral regulatory T cells. Here, we investigated the role of Fc binding in anti-PD-L1 antibody therapy in the MC38 C57BL/6 and CT26 BALB/c colon adenocarcinoma tumor models. In the MC38 tumor model, all IgG subclasses anti-PD-L1 showed similar therapeutic efficacy when compared to each other in either wild-type mice or in mice deficient for all FcγR. In contrast, in the CT26 tumor model, anti-PD-L1 mIgG2a, the IgG subclass with the highest affinity for activating FcγR, showed stronger therapeutic efficacy than other IgG subclasses. This was associated with a reduction of a myeloid cell subset with high expression of PD-L1 in the tumor microenvironment. This subclass preference for mIgG2a was lost in C57BL/6 × BALB/c F1 mice, indicating that the genetic background of the host may determine the additional clinical benefit of the high affinity antibody subclasses. Based on these data, we conclude that FcγR are not crucial for anti-PD-L1 antibody therapy but might play a role in some tumor models. 相似文献
49.
Topor Alain Stefansson Claes-Göran Denhov Anne Bülow Per Andersson Gunnel 《Social psychiatry and psychiatric epidemiology》2019,54(8):919-926
Social Psychiatry and Psychiatric Epidemiology - Persons with severe mental health problems (SMHP) point out financial strain as one of their main problems. De-institutionalisation in welfare... 相似文献
50.
Mauland KK Trovik J Wik E Raeder MB Njølstad TS Stefansson IM Oyan AM Kalland KH Bjørge T Akslen LA Salvesen HB 《British journal of cancer》2011,104(6):921-926