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621.
622.
AZD0865 is a member of a drug class that inhibits gastric H+,K+-ATPase by K+-competitive binding. The objective of these experiments was to characterize the mechanism of action, selectivity and inhibitory potency of AZD0865 in vitro. In porcine ion-leaky vesicles at pH 7.4, AZD0865 concentration-dependently inhibited K+-stimulated H+,K+-ATPase activity (IC50 1.0 ± 0.2 μM) but was more potent at pH 6.4 (IC50 0.13 ± 0.01 μM). The IC50 values for a permanent cation analogue, AR-H070091, were 11 ± 1.2 μM at pH 7.4 and 16 ± 1.8 μM at pH 6.4. These results suggest that the protonated form of AZD0865 inhibits H+,K+-ATPase. In ion-tight vesicles, AZD0865 inhibited H+,K+-ATPase more potently (IC50 6.9 ± 0.4 nM) than in ion-leaky vesicles, suggesting a luminal site of action. AZD0865 inhibited acid formation in histamine- or dibutyryl-cAMP-stimulated rabbit gastric glands (IC50 0.28 ± 0.01 and 0.26 ± 0.003 μM, respectively). In ion-leaky vesicles at pH 7.4, AZD0865 (3 μM) immediately inhibited H+,K+-ATPase activity by 88 ± 1%. Immediately after a 10-fold dilution H+,K+-ATPase inhibition was 41%, indicating reversible binding of AZD0865 to gastric H+,K+-ATPase. In contrast to omeprazole, AZD0865 inhibited H+,K+-ATPase activity in a K+-competitive manner (Ki 46 ± 3 nM). AZD0865 inhibited the process of cation occlusion concentration-dependently (IC50 1.7 ± 0.06 μM). At 100 μM, AZD0865 reduced porcine renal Na+,K+-ATPase activity by 9 ± 2%, demonstrating a high selectivity for H+,K+-ATPase. Thus, AZD0865 potently, K+-competitively, and selectively inhibits gastric H+,K+-ATPase activity and acid formation in vitro, with a fast onset of effect. 相似文献
623.
Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy 总被引:2,自引:1,他引:1
Thymidine phosphorylase (TP) is a key enzyme in the pyrimidine nucleoside salvage pathway, but it also recognizes and inactivates various anti-cancer chemotherapeutic agents. Moreover, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF), an angiogenic factor with anti-apoptotic properties. Increased expression of PD-ECGF/TP is found in many tumor and stromal cells, and elevated TP levels are associated with aggressive disease and/or poor prognosis. Thus, progression and metastasis of TP-expressing tumors might be abrogated by TP inhibitors that are used as single agents or in combination with (TP-sensitive) nucleoside analogues. On the other hand, increased TP activity in tumors may be exploited for the tumor-specific activation of fluoropyrimidine prodrugs, such as capecitabine. This review will focus on the different biological activities of PD-ECGF/TP and their implications for cancer progression and treatment. 相似文献
624.
Role of thymidine phosphorylase in an in vitro model of human bladder cancer invasion 总被引:2,自引:0,他引:2
Jones A Fujiyama C Turner K Cranston D Williams K Stratford I Bicknell R Harris AL 《The Journal of urology》2002,167(3):1482-1486
PURPOSE: It has been previously demonstrated that the angiogenic factor thymidine phosphorylase is elevated significantly in invasive bladder cancer. We report that it is not merely an incidental finding. Thymidine phosphorylase has a functional role in bladder cancer invasion. MATERIALS AND METHODS: The superficial bladder cancer cell line RT112 was transfected by retroviral techniques to generate the RT112-TP clone that expressed significantly elevated levels of thymidine phosphorylase, comparable to those of invasive human bladder cancers. The empty vector control RT112-EV was generated for comparison. Growth of these transfectants was examined using a new in vitro model of bladder cancer invasion based on de-epithelialized rat bladder and by assessing growth as xenografts in nude mice. The effect of 5-deoxy-5-fluorouridine, a prodrug activated by TP to produce 5-fluorouracil, was also examined. RESULTS: RT112-TP high thymidine phosphorylase expressing cells invaded into the stroma of the in vitro model but wild-type RT112 and RT112-EV cells did not. This invasion was abolished by 5-deoxy-5-fluorouridine. Invasion correlated with thymidine phosphorylase expression on immunohistochemical testing. There was also a significantly greater xenograft growth rate for RT112-TP than for RT112-EV, confirming the malignant growth advantage conferred by thymidine phosphorylase. CONCLUSIONS: We demonstrated that thymidine phosphorylase may have a functional role in bladder cancer invasion and the apparent advantage of thymidine phosphorylase expression to tumor cells can be exploited by therapies that utilize prodrugs such as 5-deoxy-5-fluorouridine, which is activated by thymidine phosphorylase and inhibited invasion in our model. 相似文献
625.
目的 探讨血小板衍化内皮细胞生长因子(PD-ECGF)在肾细胞癌中的表达及其预后意义.方法 采用免疫组化EnVision两步法检测2002年6月至2006年12月76例肾细胞癌患者肿瘤组织中PD-ECGF的表达水平,并分析其与肾细胞癌患者临床病理特征及预后的关系.结果 76例肾癌患者肿瘤组织中PD-ECGF高表达41例,低表达35例.PD-ECGF表达水平与肿瘤分期及组织学分级呈正相关.PD-ECGF高表达患者5年总生存率(60.98%)显著低于PD-ECFG低表达患者(94.29%,P=0.000).单因素分析显示肿瘤分期、淋巴结转移、远处转移、组织学分级及PD-ECGF表达水平均与肾癌患者5年生存率密切相关,Cox比例风险模型多因素分析显示肿瘤分期、组织学分级及PD-ECGF表达水平为影响肾癌患者预后的独立危险因素(OR=17.971、9.702、6.790,95%CI:3.010~107.290、1.835 ~ 51.305、1.156 ~ 39.894).结论 PD-ECGF在肾细胞癌的发生、发展中可能起重要作用,PD-ECGF高表达可能与肾细胞癌的预后有关. 相似文献
626.
目的观察左卡尼汀对新兵空腹5000 m越野跑前后血清葡萄糖(Glu)和游离脂肪酸(FFA)的影响,为探讨军训低血糖的预防方法提供依据。方法选入伍男性新兵54名,随机分为服药组(n=24)和对照组(n=30)。服药组于空腹越野跑5000 m前10 d开始口服左卡尼汀,1.0g,3次/d;对照组服安慰剂。检测跑前10 min与跑后即刻和4 h时Glu、糖原磷酸化酶同功酶BB(Glycogen phosphorylase isoenzyme BB,GPBB)、FFA和心型脂肪酸结合蛋白(heart-type fatty acid-bind-ing protein,H-FABP)的变化,并与对照组比较。结果服药组越野跑前10 min Glu为(4.65±0.32)mmol/L,越野跑后的即刻为(5.66±1.02)mmol/L,越野跑后4 h为(4.49±0.66)mmol/L,显著高于对照组〔(3.78±0.52)mmol/L(、4.36±0.48)mmol/L、(3.89±0.46)mmol/L〕(P<0.01)。服药组在越野跑后4 h,FFA为(126.27±56.77)μmol/L,显著高于对照组〔(99.78±18.76)μmol/L〕(P<0.01)。服药组越野跑后H-FABP无显著变化(P>0.05);2个组在越野跑后4 h,GPBB虽显著高于越野跑前10 min(P<0.01),但服药组在越野跑后即刻和4 h均显著低于对照组(P<0.01)。结论左卡尼汀可提高越野跑前后Glu水平,减少越野跑后FFA的下降,对预防新兵空腹越野跑所致的低血糖具有一定的保护作用。 相似文献
627.
胃癌中胸苷磷酸化酶和二氢嘧啶脱氢酶含量及其比值的测定 总被引:1,自引:0,他引:1
目的 测定胃癌肿瘤组织及癌旁正常组织中胸苷磷酸化酶(TP)和二氢嘧啶脱氢酶(DPD)的含量,并计算两者的比值,为希罗达在胃癌的应用提供理论依据并探讨其临床意义。方法 收集2001年经手术切除的胃癌手术标本45例,分别取肿瘤组织及距肿瘤3cm正常组织各300mg,应用ELISA方法测定两者TP和DPD的含量,并计算TP/DPD比值。结果 肿瘤组织中TP含量(中位值1419.60ng/ml)明显高于癌旁正常组织(265.00ng/ml),两者含量差异有统计学意义(Z=5.819,P=0.000);肿瘤组织DPD含量(148,86ng/ml)与癌旁正常组织(142.06ng/m1)比较差异无统计学意义(Z=0.491,P=0.623);肿瘤组织与癌旁正常组织TP/DPD比值分别为5,89和2.09,差异有统计学意义(Z=3.403,P=0.001)。结论 胃癌组织较正常组织存在更高水平的TP和TP/DPD比值,联合检测TP和DPD可能较单一TP检测更具临床意义。 相似文献
628.
Ryutaro Mori Junko Ukai Yoshihisa Tokumaru Yoshimi Niwa Manabu Futamura 《Oncology Letters》2022,24(3)
Fluoro-deoxyuridine monophosphate (FdUMP) is an active metabolite of 5-fluorouracil (5-FU) synthesized through two hypothesized pathways: The orotate phosphoribosyl transferase-ribonucleotide reductase (OPRT-RR) pathway and the thymidine phosphorylase-thymidine kinase (TP-TK) pathway. In the present study, the mechanism underlying 5-FU resistance was investigated, focusing on changes in 5-FU metabolism using MCF-7, 5-FU-resistant MCF-7/5-FUR, MDA-MB-231 and 5-FU-resistant MDA-MB-231/5-FUR breast cancer cells. The amount of FdUMP present following treatment with 5-FU was determined by the density of the upper band of thymidylate synthase detected by western blotting, and its changes were investigated. MCF-7/5-FUR cells exhibited 5-FU resistance (36.6-fold), and showed decreased OPRT (−69.3%) and TK (−42.6%) levels. MDA-MB-231/5-FUR cells also exhibited 5-FU resistance (15.8-fold), and showed decreased TP (−79.0%) and increased TK (+184%) levels. MCF-7/5-FUR and MDA-MB-231/5-FUR cells both showed decreased synthesis of FdUMP by 91 and 86%, respectively. In MCF-7 and MCF-7/5-FUR cells, the synthesis of FdUMP was decreased when 5-FU was combined with an RR inhibitor, indicating that FdUMP was synthesized through the OPRT-RR pathway. The synthesis of FdUMP was decreased when 5-FU was combined with a TP inhibitor in MDA-MB-231 cells and combined with an RR inhibitor in MDA-MB-231/5-FUR cells, indicating that the synthesis pathway of FdUMP was changed from the TP-TK pathway to the OPRT-RR pathway on acquiring resistance to 5-FU. Notably, the synthesis of FdUMP was increased and the resistance to 5-FU was reversed in MCF-7/5-FUR cells (half maximal inhibitory concentration (IC50): 219.9 to 0.093 µM) and MDA-MB-231/5-FUR cells (IC50: 157.3 to 31.0 µM) when 5-FU was combined with a TP inhibitor. In conclusion, the metabolism of 5-FU and the mechanism underlying the resistance to 5-FU differed among cell lines, and inhibition of TP reversed resistance to 5-FU, thus suggesting that the combination of 5-FU and a TP inhibitor may be considered a promising cancer therapy. 相似文献
629.
目的 探讨子宫内膜癌组织中胸苷磷酸化酶(TP)的表达和微血管生成及其与临床病理特征的关系.方法 选取子宫内膜癌石蜡标本37例,不典型增生子宫内膜标本10例,正常子宫内膜标本18例作为对照组.采用SP免疫组织化学法检测组织中TP表达;用Ⅷ因子相关抗原(ⅧR:Ag)多克隆抗体计数组织内的微血管密度(MVD).结果 不典型增生和子宫内膜癌组TP以间质及间质和腺体同时表达为主,阳性率为80%(8/10)和94.6%(35/37).不典型增生组MVD较正常内膜组MVD高,但明显较内膜癌组低.子宫内膜癌TP表达及MVD均与临床病理特征相关.结论 TP在子宫内膜癌中高表达,其表达率与肌层浸润和组织学分级等临床病理因素相关. 相似文献
630.