全文获取类型
收费全文 | 319篇 |
免费 | 28篇 |
国内免费 | 1篇 |
专业分类
儿科学 | 4篇 |
妇产科学 | 58篇 |
基础医学 | 60篇 |
临床医学 | 14篇 |
内科学 | 48篇 |
皮肤病学 | 1篇 |
神经病学 | 44篇 |
特种医学 | 11篇 |
外科学 | 19篇 |
预防医学 | 9篇 |
药学 | 10篇 |
肿瘤学 | 70篇 |
出版年
2023年 | 1篇 |
2022年 | 3篇 |
2021年 | 1篇 |
2020年 | 1篇 |
2019年 | 3篇 |
2018年 | 5篇 |
2017年 | 8篇 |
2016年 | 11篇 |
2015年 | 5篇 |
2014年 | 7篇 |
2013年 | 7篇 |
2012年 | 21篇 |
2011年 | 20篇 |
2010年 | 15篇 |
2009年 | 10篇 |
2008年 | 9篇 |
2007年 | 17篇 |
2006年 | 14篇 |
2005年 | 12篇 |
2004年 | 16篇 |
2003年 | 25篇 |
2002年 | 21篇 |
2001年 | 21篇 |
2000年 | 25篇 |
1999年 | 10篇 |
1998年 | 5篇 |
1997年 | 4篇 |
1996年 | 2篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 5篇 |
1991年 | 9篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1985年 | 7篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1979年 | 2篇 |
排序方式: 共有348条查询结果,搜索用时 296 毫秒
1.
Gavin C. Jones Mireille N. Vankemmelbeke Jan H. Verheijen Claudia DeDood Anthony J. Day David J. Buttle 《International journal of experimental pathology》2004,85(4):A66-A67
Introduction In combination with the catalytic domain, the ancillary domains of the ADAMTS' are proposed to regulate activity via interactions with sulfated GAGs, the extracellular matrix (ECM) and cell surface. Interactions with both GAGs and the ECM have been attributed to the thrombospondin (TSP) type 1 motifs and spacer region ( Kuno and Matsushima 1998 ; Flannery et al. 2002 ). ADAMTS‐1, ‐4 and ‐5, all undergo cleavage within their respective spacer regions ( Flannery et al. 2002 ; Rodriguez‐Manzaneque et al. 2000 ; Georgiadis et al. 2002 ), an event which has been reported to increase activity towards the interglobular domain of aggrecan and decrease the heparin affinity of ADAMTS‐4 ( Flannery et al. 2002 ; Gao et al. 2002 ). Materials and methods V5‐ and His‐tagged recombinant human ADAMTS‐4 constructs terminating after the catalytic (?DTS), disintegrin‐like (?TS), TSP (?S) or spacer region (Full) were expressed in High‐Five cells. Proteoglycanase activities of the resultant proteins were assayed with solution digests of aggrecan and a polyacrylamide‐entrapped aggrecan particle assay. Proteolytic activity was measured using a novel, nonglycosylated, reporter substrate assay. Results All forms of ADAMTS‐4 were active to varying degrees in the reporter substrate assay. Digestion of aggrecan in solution digests was apparent in all proteins with the exception of the catalytic domain in isolation (?DTS). Activity towards aggrecan decreased with increasing truncation of the protein. Discussion Removal of the cysteine‐rich‐spacer domain and further C‐terminal truncations decrease the activity of ADAMTS‐4 towards aggrecan, whilst the proteolytic activity remains intact. Cleavages releasing the ancillary domains of ADAMTS' may therefore alter the catalytic activity of these enzymes against proteoglycans and also nonglycosylated polypeptides. More information is required about potential substrates for the processed forms of ADAMTS‐4. 相似文献
2.
Brooks TD Slomp J Quax PH De Bart AC Spencer MT Verheijen JH Charlton PA 《Clinical & experimental metastasis》2000,18(6):445-453
Recent reports suggest that elevated levels of plasminogen activator inhibitor-1 (PAI-1) may contribute to tumour progression.
The studies reported here were designed to help elucidate PAI-1's contribution to the invasive and migratory phenotype. Antibodies
to PAI-1 dose-dependently, and significantly, inhibited the invasive and migratory potential of human HT1080 fibrosarcoma
cells, as did an antibody to uPA and the plasmin inhibitor aprotinin. Invasion of the human melanoma cell line, BLM, was also
attenuated by the anti-PAI-1 monoclonal antibody MAI-12. The non-invasive human melanoma cell line, IF6, which does not express
uPA, provided further confirmation of PAI-1 and uPA's role as, upon transfection with uPA, this cell line attained an invasive
phenotype, which was again attenuated by MAI- 12. Although antibodies to PAI-1 did not affect the adhesion of HT1080 cells
to vitronectin, the antibody to uPA reduced their attachment. Addition of exogenous PAI-1, however, prevented HT1080 cell
adhesion (IC50 180nM) and promoted cell detachment from vitronectin. Furthermore melanoma cells transfected with a uPA variant, which had
an impaired interaction with PAI-1, were not invasive and had impaired binding to vitronectin. These data highlight the importance
of a balanced proteolysis and suggest an additional role for PAI-1 distinct from its role in proteolysis. These data also
suggest that uPA and PAI-1 may co-operate in the migratory process by respectively facilitating the attachment to, and subsequent
detachment from, vitronectin in the extracellular matrix. These results support the clinical findings and indicate that modulation
of PAI-1 activity may be of therapeutic benefit for the treatment of cancer.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
3.
Shamsah Kazani David J. Rowlands Ivan Bottoli Julie Milojevic Jose Alcantara Ieuan Jones Kenneth Kulmatycki Surendra Machineni Lidia Mostovy Ian Nicholls Jerry A. Nick Steven M. Rowe Nicholas J. Simmonds Raju Vegesna Jeroen Verheijen Henry Danahay Martin Gosling Phaninatha Sarma Ayalavajjala Robert Strieter 《Journal of cystic fibrosis》2021,20(2):250-256
BackgroundThis is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.MethodsSafety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level.ResultsClass IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.ConclusionsIcenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations.ClinicalTrials.gov: NCT02190604 相似文献
4.
de Groot FM de Bart AC Verheijen JH Scheeren HW 《Journal of medicinal chemistry》1999,42(25):5277-5283
New prodrugs of daunorubicin and doxorubicin designed for selective activation by the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are converted to the corresponding cytotoxic drugs upon proteolysis by the tumor-associated protease plasmin. Application of a self-eliminating spacer was essential for enzyme activation. A prodrug containing a chloro-substituted spacer was synthesized with the aim of enhancing the rate of conversion by plasmin. All prodrugs were highly stable in buffer solution and in serum and on the average 15-fold less cytotoxic than the parent drugs in seven human tumor cell lines. A marked in vitro selectivity was demonstrated by incubation of the doxorubicin prodrugs with a plasmin generating MCF-7 breast cancer cell line transfected with urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic effect as the free parent drug doxorubicin in the u-PA transfected cells, indicating complete conversion of the prodrug by plasmin. Addition of the plasmin inhibitor Trasylol drastically increased the ID(50) values in the u-PA transfected MCF-7 cells for both prodrugs 4 and 5. 相似文献
5.
Meijer CJ Rozendaal L Voorhorst FJ Verheijen R Helmerhorst TJ Walboomers JM 《Nederlands tijdschrift voor geneeskunde》2000,144(35):1675-1679
More than 99% of all cervical cancers contain high risk HPV. Only a persistent infection with high risk HPV of the cervical epithelium results in cervical cancer. Because the risk of cervical cancer is identical for all different HPV types, tests which detect all 14 high risk HPV types at one time are sufficient for clinical management. Testing for hr-HPV is mandatory for women with mild dyskaryosis and for the follow-up of women treated for CIN lesions. Based on efficiency to detect CIN3 and cervical cancer and preliminary cost benefit analysis, the combination of a high risk HPV test in conjunction with a cervical smear appears to be the best way of cervical cancer screening. A definite point of view on using high risk HPV testing for primary screening for cervical cancer will be obtained after the completion of a randomized trial of 44,000 women, in which the efficiency to detect CIN3 and cervical cancer by high risk HPV testing in conjunction with a cytomorphological smear is compared with screening by classical cytology. 相似文献
6.
7.
C. Lybol C.M.G. Thomas E.A. Blanken F.C.G.J. Sweep R.H. Verheijen A.M. Westermann I.A. Boere A.K.L. Reyners L.F.A.G. Massuger R.Q.G.C.M. van Hoesel P.B. Ottevanger 《European journal of cancer (Oxford, England : 1990)》2013,49(4):860-867
BackgroundCisplatin-based chemotherapy (etoposide 100 mg/m2 days 1–5, methotrexate 300 mg/m2 day 1, cyclophosphamide 600 mg/m2 day 1, actinomycin D 0.6 mg/m2 day 2 and cisplatin 60 mg/m2 day 4, EMACP) was compared to EMA/CO (etoposide 100 mg/m2 days 1–2, methotrexate 300 mg/m2 day 1 and actinomycin D 0.5 mg i.v. bolus day 1 and 0.5 mg/m2 day 2, alternating with cyclophosphamide 600 mg/m2 day 8 and vincristine 1 mg/m2 day 8) for the treatment of high-risk gestational trophoblastic neoplasia (GTN).Patients and methodsIn the Netherlands, 83 patients were treated with EMACP and 103 patients with EMA/CO. Outcome measures were remission rate, median number of courses to achieve normal human chorionic gonadotrophin (hCG) concentrations, toxicity, recurrent disease rate and disease specific survival.ResultsRemission rates were similar (EMACP 91.6%, EMA/CO 85.4%). The median number of courses of EMA/CO to reach hCG normalisation for single-agent resistant disease and primary high-risk disease was three and five courses, respectively, compared to 1.5 (p = 0.001) and three (p < 0.001) courses of EMACP. Patients treated with EMACP more often developed fever, renal toxicity, nausea and diarrhoea compared to patients treated with EMA/CO. Patients treated with EMA/CO more often had anaemia, neuropathy and hepatotoxicity.ConclusionEMACP combination chemotherapy is an effective treatment for high-risk GTN, with a remission rate comparable to EMA/CO. However, the difference in duration of treatment is only slightly shorter with EMACP. Cisplatin-based chemotherapy in the form of EMACP in this study was not proven more effective than EMA/CO. 相似文献
8.
Guido J. Breedveld Gijs W.E. Santen Emmelien Aten Dirk J. Lefeber Jorrit I. Hoff Esther Brusse Frans W. Verheijen Rob M. Verdijk Marjolein Kriek Ben Oostra Martijn H. Breuning Monique Losekoot Johan T. den Dunnen Bart P. van de Warrenburg Anneke J.A. Maat‐Kievit 《Human mutation》2013,34(5):706-713
Spinocerebellar ataxias are phenotypically, neuropathologically, and genetically heterogeneous. The locus of autosomal recessive spinocerebellar ataxia type 7 (SCAR7) was previously linked to chromosome band 11p15. We have identified TPP1 as the causative gene for SCAR7 by exome sequencing. A missense and a splice site variant in TPP1, cosegregating with the disease, were found in a previously described SCAR7 family and also in another patient with a SCAR7 phenotype. TPP1, encoding the tripeptidyl‐peptidase 1 enzyme, is known as the causative gene for late infantile neuronal ceroid lipofuscinosis disease 2 (CLN2 disease). CLN2 disease is characterized by epilepsy, loss of vision, ataxia, and a rapidly progressive course, leading to early death. SCAR7 patients showed ataxia and low activity of tripeptidyl‐peptidase 1, but no ophthalmologic abnormalities or epilepsy. Also, the slowly progressive evolution of the disease until old age and absence of ultra structural curvilinear profiles is different from the known CLN2 phenotypes. Our findings now expand the phenotypes related to TPP1‐variants to SCAR7. In spite of the limited sample size and measurements, a putative genotype–phenotype correlation may be drawn: we hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7. 相似文献
9.
Jennifer Zenker Mark Stettner Salla Ruskamo Enric Domènech‐Estévez Hasna Baloui Jean‐Jacques Médard Mark H. G. Verheijen Jos F. Brouwers Petri Kursula Bernd C. Kieseier Roman Chrast 《Glia》2014,62(9):1502-1512
Peripheral myelin protein 2 (Pmp2, P2 or Fabp8), a member of the fatty acid binding protein family, was originally described together with myelin basic protein (Mbp or P1) and myelin protein zero (Mpz or P0) as one of the most abundant myelin proteins in the peripheral nervous system (PNS). Although Pmp2 is predominantly expressed in myelinated Schwann cells, its role in glia is currently unknown. To study its function in PNS biology, we have generated a complete Pmp2 knockout mouse (Pmp2‐/‐). Comprehensive characterization of Pmp2‐/‐ mice revealed a temporary reduction in their motor nerve conduction velocity (MNCV). While this change was not accompanied by any defects in general myelin structure, we detected transitory alterations in the myelin lipid profile of Pmp2‐/‐ mice. It was previously proposed that Pmp2 and Mbp have comparable functions in the PNS suggesting that the presence of Mbp can partially mask the Pmp2‐/‐ phenotype. Indeed, we found that Mbp lacking Shi‐/‐ mice, similar to Pmp2‐/‐ animals, have preserved myelin structure and reduced MNCV, but this phenotype was not aggravated in Pmp2‐/‐/Shi‐/‐ mutants indicating that Pmp2 and Mbp do not substitute each other's functions in the PNS. These data, together with our observation that Pmp2 binds and transports fatty acids to membranes, uncover a role for Pmp2 in lipid homeostasis of myelinating Schwann cells. GLIA 2014;62:1502–1512 相似文献