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11.
Gulay Turan Ceyda Sancakli Usta Akin Usta Mehmet Kanter Lema Tavli Meric Karacan Cetin Celik Metin Eser 《Journal of molecular histology》2014,45(6):679-687
Ovarian cancer is the most common cause of death among all gynecologic malignancies and a result of complex interaction of multiple oncogenes and tumor suppressor genes. The aim of this study was to evaluate expression of HER-2/neu (c-erbB2), survivin and cycline D1 biomarkers in serous ovarian neoplasms and their correlations with clinicopathological variables in serous ovarian cancers. We analyzed pathological specimens of 62 patients with benign (n = 25), borderline (n = 14) and malignant (n = 23) serous ovarian neoplasms. Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded specimens. Significantly more immunoreactivity with HER-2/neu was detected in malignant tumors (100 %) compared to borderline (78.6 %) and benign tumors (48 %) (P < 0.01). Survivin expression was significantly higher in malignant tumors (91.3 %) than those found in borderline (71.4 %) and benign tumors (24 %) (P < 0.001). Similarly, higher cyclin D1 expression was observed in malignant tumors (95.6 %) compared to borderline (85.7 %) and benign tumors (48 %) (P < 0.001). Expression of all biomarkers analyzed significantly and gradually increased from benign to borderline and borderline to malignant serous tumors. In terms of clinicopathological variables, only tumor grade was associated with the expression of all biomarkers others exhibited different correlations in serous ovarian cancers. The expressions of HER-2/neu (c-erbB2), survivin and cycline D1 are positively correlated with the malignant potential of serous ovarian neoplasms. 相似文献
12.
Se Joon Choi Anne Panhelainen Yvonne Schmitz Kristin E. Larsen Ellen Kanter Min Wu David Sulzer Eugene V. Mosharov 《The Journal of biological chemistry》2015,290(11):6799-6809
1-Methyl-4-phenylpyridinium (MPP+), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, selectively kills dopaminergic neurons in vivo and in vitro via a variety of toxic mechanisms, including mitochondrial dysfunction, generation of peroxynitrite, induction of apoptosis, and oxidative stress due to disruption of vesicular dopamine (DA) storage. To investigate the effects of acute MPP+ exposure on neuronal DA homeostasis, we measured stimulation-dependent DA release and non-exocytotic DA efflux from mouse striatal slices and extracellular, intracellular, and cytosolic DA (DAcyt) levels in cultured mouse ventral midbrain neurons. In acute striatal slices, MPP+ exposure gradually decreased stimulation-dependent DA release, followed by massive DA efflux that was dependent on MPP+ concentration, temperature, and DA uptake transporter activity. Similarly, in mouse midbrain neuronal cultures, MPP+ depleted vesicular DA storage accompanied by an elevation of cytosolic and extracellular DA levels. In neuronal cell bodies, increased DAcyt was not due to transmitter leakage from synaptic vesicles but rather to competitive MPP+-dependent inhibition of monoamine oxidase activity. Accordingly, monoamine oxidase blockers pargyline and l-deprenyl had no effect on DAcyt levels in MPP+-treated cells and produced only a moderate effect on the survival of dopaminergic neurons treated with the toxin. In contrast, depletion of intracellular DA by blocking neurotransmitter synthesis resulted in ∼30% reduction of MPP+-mediated toxicity, whereas overexpression of VMAT2 completely rescued dopaminergic neurons. These results demonstrate the utility of comprehensive analysis of DA metabolism using various electrochemical methods and reveal the complexity of the effects of MPP+ on neuronal DA homeostasis and neurotoxicity. 相似文献
13.
The aim of this study was to evaluate the possible protective effects of caffeic acid phenethyl ester (CAPE) against cholestatic
oxidative stress and liver damage in the common bile duct ligated rats. A total of 18 male Sprague–Dawley rats were divided
into three groups: control, bile duct ligation (BDL) and BDL + received CAPE; each group contain 6 animals. The rats in CAPE
treated groups were given CAPE (10 μmol/kg) once a day intraperitoneally (i.p) for 2 weeks starting just after BDL operation.
The changes demonstrating the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated
bile ducts into lobules, inflammatory cell infiltration into the widened portal areas were observed in BDL group. Treatment
of BDL with CAPE attenuated alterations in liver histology. The proliferating cell nuclear antigen and the activity of TUNEL
in the BDL were observed to be reduced with the QE treatment. The application of BDL clearly increased the tissue hydroxyproline
(HP) content, malondialdehyde (MDA) levels and decreased the antioxidant enzyme (superoxide dismutase (SOD), glutathione peroxidase
(GPx)) activities. CAPE treatment significantly decreased the elevated tissue HP content, and MDA levels and raised the reduced
of SOD, and GPx enzymes in the tissues. The data indicate that CAPE attenuates BDL-induced cholestatic liver injury, bile
duct proliferation, and fibrosis. The hepatoprotective effect of CAPE is associated with antioxidative potential. 相似文献
14.
15.
The FDA has published guidelines by which to carry out and interpret in vitro induction studies using hepatocytes but do researchers in pharmaceutical companies actually follow these to the letter? In a survey of 30 participants in the pharmaceutical industry, 19 questions were posed regarding the species investigated, methodologies and interpretations of the data. Also addressed was the in-house decision making processes as a result of in vitro induction data. The survey showed that, although the basic methods were similar, no two researchers carried out and interpreted induction assays in exactly the same way. No single method was superior but all included enzyme activities as the major end point. Hepatocytes from animal species were used to confirm animal in vivo data but only human hepatocytes were used to predict human induction responses. If a compound was found to be positive in an in vitro induction assay, few would halt the development of the compound. The majority would consider other properties of the compound (bioavailability, clearance and therapeutic concentrations) and follow the FDA recommendation to conduct clinical drug-drug interaction studies. Overall, the results from this survey indicate that there is no standard pharmaceutical industry method or evaluation criterion by which in vitro assays are carried out. Rather than adhering to the FDA guidelines, some adapt methods and interpretation according to their own experience and need (whether screening or lead optimisation). There was general consensus that studies using human hepatocyte cultures currently provide the best indication of the in vivo induction potential of NCEs. In addition, the assessment of in vitro induction data from the literature suggest that the two-fold induction threshold and the percent of positive control criteria may not be the best methods to accurately assess the in vivo induction potential of a drug. Although the two-fold induction criterion is now obsolete, more predictive models for determining the clinical induction potential are needed. Alternative models are proposed and discussed herein. 相似文献
16.
Relationship between androgen-induced cell proliferation and sensitivity to exogenous growth factors
The relationship between growth factor responses and androgen-induced cell proliferation was studied in a mouse renal tumor (RAG) cell line, a hybrid (F614B16) rat prostate x RAG cell line, and an 8-azaguanine-resistant revertant of the F614B16 cell line. The hybrid F614B16 cells are very sensitive to androgens; treatment with 20 nM 5 alpha-dihydrotestosterone accelerated cell growth in the presence or absence of serum. In contrast, the RAG cells and 8-azaguanine-resistant F614B16 cells responded to 5 alpha-dihydrotestosterone only in the absence of serum. Variation in the proliferative response to androgens among these cell lines was associated with variation in growth factor sensitivity. Basic fibroblast growth factor (bFGF) stimulated basal and androgen-induced growth of F614B16 cells in serum-free and serum-supplemented media, whereas it inhibited RAG cell growth. Basic FGF stimulated basal, but not androgen-induced growth of revertant F614B16 cells. The cell lines also differed in sensitivity to epidermal growth factor, which had no effect on hybrid cell growth but inhibited RAG and revertant cell growth in a dose-dependent fashion in serum-free media. The results of these studies suggest that androgen-sensitivity is associated with a positive response to FGF and insensitivity to exogenous epidermal growth factor. 相似文献
17.
Marc D Tambini Marta Pera Ellen Kanter Hua Yang Cristina Guardia‐Laguarta David Holtzman David Sulzer Estela Area‐Gomez Eric A Schon 《EMBO reports》2016,17(1):27-36
In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer''s disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease. 相似文献
18.
Kanter M 《Journal of molecular histology》2010,41(6):395-402
The aim of this study was to evaluate the possible protective effects of quercetin (QE) against cholestatic oxidative stress
and liver damage in the common bile duct ligated rats. A total of 24 male Wistar albino rats were divided into three groups:
control, bile duct ligation (BDL) and BDL + received QE; each group contain 8 animals. The rats in QE treated groups were
given QE (15 mg/kg) once a day intraperitoneally for 4 weeks starting 3 days prior to BDL operation. The changes demonstrating
the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules,
mononuclear cells, and neutrophil infiltration into the widened portal areas were observed in BDL group. Treatment of BDL
with QE attenuated alterations in liver histology. The alpha smooth muscle actin (α-SMA), transforming growth factor beta
(TGF-β1) positive cells and the activity of TUNEL in the BDL were observed to be reduced with the QE treatment. The data indicate
that QE attenuates BDL-induced cholestatic liver injury, bile duct proliferation, and fibrosis. The hepatoprotective effect
of QE is associated with antioxidative potential. 相似文献
19.
Bao M Kanter EM Huang RY Maxeiner S Frank M Zhang Y Schuessler RB Smith TW Townsend RR Rohrs HW Berthoud VM Willecke K Laing JG Yamada KA 《Channels (Austin, Tex.)》2011,5(6):489-499
Gap junction channels in ventricular myocardium are required for electrical and metabolic coupling between cardiac myocytes and for normal cardiac pump function. Although much is known about expression patterns and remodeling of cardiac connexin(Cx)43, little is known about the less abundant Cx45, which is required for embryonic development and viability, is downregulated in adult hearts, and is pathophysiologically upregulated in human end-stage heart failure. We applied quantitative immunoblotting and immunoprecipitation to native myocardial extracts, immunogold electron microscopy to cardiac tissue and membrane sections, electrophysiological recordings to whole hearts, and high-resolution tandem mass spectrometry to Cx45 fusion protein, and developed two new tools, anti-Cx45 antisera and Cre(+);Cx45 floxed mice, to facilitate characterization of Cx45 in adult mammalian hearts. We found that Cx45 represents 0.3% of total Cx protein (predominantly 200 fmol Cx43 protein/μg ventricular protein) and colocalizes with Cx43 in native ventricular gap junctions, particularly in the apex and septum. Cre(+);Cx45 floxed mice express 85% less Cx45, but do not exhibit overt electrophysiologic abnormalities. Although the basal phosphorylation status of native Cx45 remains unknown, CaMKII phosphorylates 8 Ser/Thr residues in Cx45 in vitro. Thus, although downregulation of Cx45 does not produce notable deficits in electrical conduction in adult, disease-free hearts, Cx45 is a target of the multifunctional kinase CaMKII, and the phosphorylation status of Cx45 and the role of Cx43/Cx45 heteromeric gap junction channels in both normal and diseased hearts merits further investigation. 相似文献
20.
H O McDevitt D J Mathis C Benoist M R Kanter V E Williams 《Federation proceedings》1984,43(15):3021-3024
Class II major histocompatibility complex (MHC) molecules, the Ia antigens, are intimately involved in regulating the intensity and specificity of the cellular and humoral responses to T cell-dependent antigens. One approach to understanding the mechanism of this regulation is to analyze the structure and allelic polymorphism of Ia molecules. In addition there are regulatory polymorphisms in the expression of the I-E alpha and I-E beta class II MHC polypeptide chains. Analysis of the cDNA sequence indicates that I-A and I-E alpha chains are similar with short stretches of homology and other regions of nonhomology. Analysis of Northern blots of mRNA indicates that at least three separate types of regulatory polymorphisms result in failure of expression of I-E alpha. Comparison of allelic sequences of six alleles of the I-A alpha chain shows that almost all of the allelic polymorphism is in the first domain and that within the first domain it is clustered in three allelic hypervariable regions within the first domain of I-A alpha. The structural and functional implications of these findings are discussed. 相似文献