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Núria Eritja Bo-Juen Chen Ruth Rodríguez-Barrueco Maria Santacana Sònia Gatius August Vidal 《Autophagy》2017,13(3):608-624
Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC. 相似文献
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《Bioorganic & medicinal chemistry》2019,27(15):3279-3284
Photodynamic therapy (PDT) is a treatment method using light and photosensitizers (PSs), which is categorized as a non-invasive surgery treatment for cancers. When the tumor is exposed to a specific light, the PSs become active and generate reactive oxygen species (ROS), mainly singlet oxygen which kills nearby cancer cells. PDT is becoming more widely recognized as a valuable treatment option for localized cancers and pre-cancers of skin as it has no long-term effects on the patient. But, due to the limited penetration rate of light into the skin and other organs, PDT can’t be used to treat large cancer cells or cancer cells that have grown deeply into the skin or other organs. Hence, in this study, our focus centers on synthesizing glucose-conjugated phthalocyanine (Pc) compatible with near-infrared (NIR) irradiation as second-generation photosensitizer, so that PDT can be used in a wider range to treat cancers without obstacles. 相似文献
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The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo 下载免费PDF全文
《Journal of cellular and molecular medicine》2017,21(7):1300-1314
Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20–40 years) and are classified as seminoma or non‐seminoma. TGCTs are commonly treated by orchiectomy and chemo‐ or radiotherapy. However, a subset of metastatic non‐seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small‐molecule inhibitor JQ1 in tumour therapy, which interferes with the function of ‘bromodomain and extraterminal (BET)’ proteins. JQ1‐treated TGCT cell lines display up‐regulation of genes indicative for DNA damage and cellular stress response and induce cell cycle arrest. Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, display down‐regulation of pluripotency factors and induction of mesodermal differentiation. In contrast, seminoma‐like TCam‐2 cells tolerated higher JQ1 concentrations and were resistant to differentiation. ECs xenografted in vivo showed a reduction in tumour size, proliferation rate and angiogenesis in response to JQ1. Finally, the combination of JQ1 and the histone deacetylase inhibitor romidepsin allowed for lower doses and less frequent application, compared with monotherapy. Thus, we propose that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs. 相似文献
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目的:分析阿托品联合综合疗法治疗青少年屈光不正弱视的近期疗效及安全性。方法:以2017年2月至2017年5月于我院接受诊治的60例青少年屈光不正弱视患者(患眼102只)为研究对象,按接受诊治时间先后顺序分为对照组和观察组各30例。患眼分别为52和50只。观察治疗前后所有屈光不正弱视患者的视觉敏感度、图像诱发电位(P-VEP)、立体视功能的改善、治疗有效率和不良反应的发生情况。结果:治疗后,两组患眼对比度、波幅均较治疗前显著升高(P0.05),潜伏期低于治疗前(P0.05),且观察组各空间频率下的对比度、波幅均显著高于对照组(P0.05),潜伏期低于对照组(P0.05);观察组患眼的矫正幅度范围和矫正分开范围显著高于对照组,矫正近立体视锐角显著低于对照组(P0.05);观察组的治疗总有效率为92.00%,高于对照组的71.15%(P0.05);两组患者均未见明显的不良反应发生。结论:阿托品联合综合疗法对青少年屈光不正弱视的近期疗效较好,且安全性高。 相似文献
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Sandra B. Barker Randolph T. Barker Nancy L. McCain Christine M. Schubert 《Anthrozo?s》2017,30(4):595-606
Using data from a previously published study on effects of a canine-assisted activity (CAA) on college student stress the week before final examinations, we examined whether participation in this activity had effects on perceptions of 1) family supports (i.e., emotional distance to family members and pets) and 2) current stressors. A total of 74 students completed the Family Life Space Diagram (FLSD), which uses an individual's structured drawings of distances between symbols of self and living entities, organizations, and stressors to reflect “emotional distances.” Participants were randomly assigned to order of CAA or FLSD, which was the intervention study control condition. Groups completed the FLSD after participating in CAA (Group A, n = 34) or prior to CAA (Group B, n = 40). Participants were primarily white (56.8%) females (75.7%) with a mean age of 19.38 years (SD = 1.75). Significant differences with large effect sizes were found for both groups in distances between 1) self-closest and self-average family member (Group A: t = 7.02, df = 33, p < 0.001, d = 1.205; Group B: t = 6.25, df = 39, p < 0.001, d = 0.987) and 2) self-closest personal stressor (t = 2.93, df = 18, p = 0.009, d = 1.311) and self-average personal stressor (t = 2.54, df = 18. p = 0.020, d = 1.138). In both cases, Group A (FLSD following CAA) placed personal stressors in closer proximity to self. Although CAA did not affect students’ current perceptions of family and pet relationships, the intervention may have increased their abilities to cope with personal stressors. Modified stress theory supports the proposition that positive emotions associated with CAA engage positive coping strategies, resulting in more positive perceptions of stressors. 相似文献
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BMP‐2 gene activated muscle tissue fragments for osteochondral defect regeneration in the rabbit knee 下载免费PDF全文
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At the Italian National Centre for Oncologic Hadrontherapy (CNAO) patients with upper-abdominal tumours are being treated with carbon ion therapy, adopting the respiratory gating technique in combination with layered rescanning and abdominal compression to mitigate organ motion. Since online imaging of the irradiated volume is not feasible, this study proposes a modelling approach for the estimation of residual motion of the target within the gating window. The model extracts a priori respiratory motion information from the planning 4DCT using deformable image registration (DIR), then combines such information with the external surrogate signal recorded during dose delivery. This provides estimation of a CT volume corresponding to any given respiratory phase measured during treatment. The method was applied for the retrospective estimation of tumour residual motion during irradiation, considering 16 patients treated at CNAO with the respiratory gating protocol. The estimated tumour displacement, calculated with respect to the reference end-exhale position, was always limited (average displacement is 0.32 ± 0.65 mm over all patients) and below the maximum motion defined in the treatment plan. This supports the hypothesis of target position reproducibility, which is the crucial assumption in the gating approach. We also demonstrated the use of the model as a simulation tool to establish a patient-specific relationship between residual motion and the width of the gating window. In conclusion, the implemented method yields an estimation of the repeatability of the internal anatomy configuration during gated treatments, which can be used for further studies concerning the dosimetric impact of the estimated residual organ motion. 相似文献