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31.
Shojaei F 《Cancer letters》2012,320(2):130-137
It has been nearly 9years since the FDA (Food and Drug Administration) approved the first anti-angiogenic drug (bevacizumab) for treatment of metastatic colorectal cancer. Other angiogenic inhibitors have since been approved or are in different stages of clinical trials. However, continued clinical and preclinical investigations have identified major drawbacks associated with the application of this class of agents, including inherent/acquired resistance and induction of tumor invasiveness. In addition, lack of thoroughly validated predictive biomarkers has been one of the major hurdles to stratify cancer patients and to monitor tumor progression and response to the therapy. Investigations in clinic and preclinical models have provided some molecular and cellular mechanisms for the above challenges. This review aims to provide a concise update from recent findings. 相似文献
32.
目的 观察重组人血管内皮抑制素(恩度)与化疗联合治疗晚期结直肠癌的有效性和安全性。方法 自2006年8月至2009年5 月,5 例初治转移性结直肠癌患者和18 例复治转移性结直肠癌患者接受恩度联合细胞毒药物治疗。恩度15mg/d,加人生理盐水500ml 静脉滴注,连用14 天。同时8 例患者采用FOLFIRI 方案化疗,2 例患者采用CAPIRI 方案化疗,9 例患者采用GLF 方案化疗,4 例患者采用FOLFOX4 或XELOX 方案化疗。分别按照RECIST 1.0 和NCI-CTC 3.0 评价疗效和毒性。结果23 例可评价毒性,21 例可评价疗效。在4 例初治患者中,2 例SD, 2 例PD。在17 例复治患者中,8 例SD, 9 例PD,疾病控制率(DCR)为47.1%。全组中位肿瘤进展时间(mTTP)为5 个月(95 % CI: 2.2~7.8 个月),中位总生存时间(mOS)为12 个月(95% CI: 10.5~13.5 个月)。复治患者的mTTP 和mOS 分别为4 个月(95% CI: 1.7~6.3 个月)和11.5 个月(95 %CI: 8.5~14.5 个月)。主要不良反应为血液学毒性、恶心呕吐,考虑主要与化疗相关。轻度心血管系统毒性考虑与恩度相关。结论恩度联合细胞毒药物治疗转移性结直肠癌安全性好,恩度未增加化疗药物的毒性。对复治患者有延长疾病控制时间的趋势,值得进一步研究。 相似文献
33.
Yi Xie Martin J. Hicks Stephen M. Kaminsky Malcolm A.S. Moore Ronald G. Crystal Arash Rafii 《Gynecologic oncology》2014
Rationale
Anti-angiogenesis therapies such as bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), have been used against ovarian cancer, but transient and low peritoneal drug levels are likely a factor in treatment failure. We hypothesized that a single administration of adeno-associated virus (AAV)-mediated intraperitoneal expression of bevacizumab would direct persistent expression and suppress growth and metastasis of ovarian cancer.Methods
AAVrh.10BevMab, a rhesus serotype 10 adeno-associated viral vector coding for bevacizumab, was evaluated for the capacity of a single intraperitoneal administration to persistently suppress peritoneal tumor growth in an intraperitoneal model of ovarian carcinomatosis with human ovarian cancer cells in nude immunodeficient mice.Results
The data demonstrates that AAVrh10.BevMab mediates persistent and high levels of bevacizumab in the peritoneal cavity following a single intraperitoneal administration in mice. In AAVrh10.BevMab treated A2780 human ovarian cancer-bearing mice, tumor growth was significantly suppressed (p < 0.05) and the area of blood vessels in the tumor was decreased (p < 0.04). Survival of mice with A2780 xenografts or SK-OV3 xenografts was greatly prolonged in the presence of AAVrh10.BevMab (p < 0.001). Administration of AAVrh10.BevMab 4 days after A2780-luciferase cell implantation reduced tumor growth (p < 0.01) and increased mouse survival (p < 0.0001). Combination of AAVrh10.BevMab with cytotoxic reagents paclitaxel or topotecan proved to be more effective in increasing survival than treatment with cytotoxic reagent alone.Conclusion
A single administration of AAVrh10.BevMab provides sustained and high local expression of bevacizumab in the peritoneal cavity, and significantly suppresses peritoneal carcinomatosis and increases survival in an ovarian cancer murine model. 相似文献34.
Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in several malignancies, including cervical cancer. Chemotherapy doublets combined with the fully humanized monoclonal antibody, bevacizumab, now constitute first-line therapy for women struggling with recurrent/metastatic cervical carcinoma. Regulatory approval for this indication was based on the phase III randomized trial, GOG 240, which demonstrated a statistically significant and clinically meaningful improvement in overall survival when bevacizumab was added to chemotherapy: 17.0 vs 13.3?months; HR 0.71; 98% CI, 0.54–0.95; p?=?.004. Incorporation of bevacizumab resulted in significant improvements in progression-free survival and response. These benefits were not accompanied by deterioration in quality of life. GOG 240 identified vaginal fistula as a new adverse event associated with bevacizumab use. All fistulas occurred in women who had received prior pelvic radiotherapy, and none resulted in emergency surgery, sepsis, or death. Final protocol-specified analysis demonstrated continued separation of the survival curves favoring VEGF inhibition: 16.8 vs 13.3?months; HR 0.77; 95% CI, 0.62–9.95; p?=?.007. Post-progression survival was not significantly different between the arms in GOG 240.Moving forward, immunotherapy has now entered the clinical trial arena to address the high unmet clinical need for effective and tolerable second line therapies in this patient population. Targeting the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway using checkpoint inhibitors to break immunologic tolerance is promising. The immunologic landscape involving human papillomavirus-positive head and neck carcinoma and cutaneous squamous cell carcinoma can be informative when considering feasibility of checkpoint blockade in advanced cervical cancer. Phase II studies using anti-PD-1 molecules, nivolumab and pembrolizumab are ongoing, and GOG 3016, the first phase III randomized trial of a checkpoint inhibitor (cemiplimab) in cervical cancer, recently activated. Important considerations in attempts to inhibit the inhibitors include pseudoprogression and post-progression survival, abscopal effects, and immune-related adverse events, including endocrinopathies. 相似文献
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36.
背景与目的: 5-氟尿嘧啶(5-fluorouracil,5-FU)是胃癌化疗的骨架药物,传统大剂量5-FU常导致严重不良反应及耐药。低剂量5-FU节拍化疗在不影响疗效的前提下可明显降低药物毒性,但何种给药节拍可达到最佳抗肿瘤作用尚不清楚。本研究旨在探索5-FU的最佳节拍化疗模式,并研究其对胃癌免疫微环境的影响。方法: 建立SGC-7901胃癌细胞系的BALB/c裸小鼠皮下移植瘤模型,成瘤后随机分成4组:最大耐受剂量(maximum tolerated dose,MTD)组、每日节拍化疗(daily metronomic chemotherapy,MET-qd)组、隔日节拍化疗(every other day metronomic chemotherapy,MET-qod)组和每周2次节拍化疗(twice-weekly metronomic chemotherapy,MET-biw)组。21 d为1个疗程,共2个疗程。治疗期间观测裸小鼠的一般状况,每周称重并测量瘤体,绘制肿瘤生长曲线。采用流式细胞术检测裸小鼠外周血内皮祖细胞(circulating endothelial progenitors,CEP),瘤体及脾脏内浸润的B细胞、自然杀伤(natural killer,NK)细胞、肿瘤相关巨噬细胞(tumor-associated macrophage,TAM)、髓源性抑制细胞(myeloid-derived suppressor cell,MDSC)。采用免疫组织化学染色法检测瘤体内CD11c和CD163蛋白的表达。采用酶联免疫吸附法(enzyme-linked immunosorbent assay,ELISA)检测裸小鼠外周血中血管内皮生长因子(vascular endothelial growth factor,VEGF)、血小板源性生长因子(platelet derived growth factor,PDGF)、白细胞介素(interleukin,IL)-10和IL-12的表达。采用白细胞计数及H-E染色等评价肝、肺、肾和心脏毒性。结果: 5-FU的3种节拍化疗模式均显示出与MTD组类似的抑制裸小鼠移植瘤生长效应,其中MET-qod组的抗肿瘤效应最明显(P<0.05)。与MTD组(45.3%±4.3%)相比,5-FU的3种节拍化疗模式均可明显降低裸小鼠外周血的CEP数量,其中MET-qd组降低最明显(14.8%±3.8%)。外周血中VEGF在MET-qod组中下降最明显(P<0.001),而在MET-biw组中则明显升高(P<0.001)。PDGF的表达与VEGF趋势基本一致。5-FU的3种节拍化疗模式与MTD组相比均可导致裸小鼠脾脏和瘤体内浸润的M1与M2型TAM比值增加,MET-qod组中该比值增加最显著(脾脏1.78±0.21 vs 1.19±0.07;瘤体0.57±0.11 vs 0.14±0.09;P<0.001)。外周血中代表M2型TAM的IL-10在MET-qod中的表达量最少(P<0.001),代表M1型TAM的IL-12则相对高表达(P<0.001)。与节拍化疗组相比,MTD组裸小鼠体重减轻、外周血白细胞及血小板绝对值明显减少(P<0.001),而3个节拍治疗组之间差异无统计学意义。MTD组裸小鼠的肺间质明显增厚和慢性炎症改变,类似表现在节拍化疗组中未见。结论: 在不同的5-FU给药模式中,MET-qod节拍给药方式显示出最佳的抗肿瘤效应,且不增加不良反应。除抗血管生成外,还可通过调节TAM极化发挥抑瘤作用。 相似文献
37.
38.
A Phase II Clinical Trial of Apatinib in Pretreated Advanced Non-squamous Non–small-cell Lung Cancer
Fengying Wu Shijia Zhang Anwen Xiong Guanghui Gao Wei Li Weijing Cai Chunxia Su Xiaoxia Chen Fei Zhou Jing Zhao Shengxiang Ren Caicun Zhou 《Clinical lung cancer》2018,19(6):e831-e842
Objectives
Apatinib exhibits broad-spectrum antitumor activities by selectively inhibiting vascular endothelial growth factor receptor-2. This study evaluated the efficacy and safety of apatinib in patients with advanced non-squamous non–small-cell lung cancer who were heavily pretreated or not suitable to receive standard second-line chemotherapy.Patients and Methods
This was an open-label, single-arm phase II clinical trial (ClinicalTrials.govNCT02515435). Patients received 500 or 750 mg apatinib daily until progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was the objective response rate. The secondary endpoints included disease control rate, progression-free survival, overall survival, and side effects. Apatinib administration was allowed beyond disease progression.Results
Between March 2015 and August 2016, 40 patients were enrolled. Among them, 6 (15.0%), 16 (40.0%), and 18 (45.0%) received apatinib as the second-, third-, and fourth-line or beyond treatment, respectively. The mean dosage of apatinib was 477.0 ± 85.3 mg/day. Thirty-eight patients were available for response evaluation; the objective response rate and disease control rate were 13.2% and 63.2%, respectively. The median progression-free survival was 3.06 months (95% confidence interval [CI], 2.20-4.14 months). The median overall survival was 7.69 months (95% CI, 5.36 months to not estimable). The most common treatment-related adverse events were hand-foot-skin reaction (30.0%), proteinuria (27.5%), oral mucositis (22.5%), fatigue (20.0%), and hypertension (17.5%). Nine patients received apatinib after progression, and the median duration of apatinib therapy beyond progression was 5.13 months (95% CI, 4.27-7.82 months).Conclusion
Apatinib shows promising efficacy and manageable toxicity in patients with advanced non-squamous non–small-cell lung cancer. Apatinib therapy beyond progression could provide further benefits in specific subpopulations. 相似文献39.
目的: 检测IFN-α体内外对人脐静脉血管内皮细胞(HUVECs)的抑制作用,探讨IFN-α抑制肝癌血管生成的机制。方法: 运用细胞增殖抑制试验、MTT试验、管样结构形成试验、移动抑制试验以及裸鼠体内移植瘤生长和血管密度测定探讨IFN-α对HUVECs的抑制作用。结果: IFN-α对HUVECs的细胞增殖、移动和管样结构形成试验有明显的抑制作用,体内实验提示试验组移植瘤直径明显小于对照组,微血管密度(MVD)亦明显低于对照组。结论: IFN-α可以通过抑制肿瘤的血管新生,起到抑制肿瘤生长的作用。 相似文献
40.
《Clinical lung cancer》2019,20(2):134-138
Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has demonstrated a significant survival benefit over platinum-based chemotherapy in a first-line setting in advanced non–small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion. In addition, we and other groups have shown there to be favorable progression-free survival (PFS) outcomes, with acceptable toxicity profiles, with bevacizumab and first-generation EGFR-TKI combination therapy. On the basis of the above, we hypothesized that a combination of bevacizumab and afatinib could potentially improve efficacy. In our phase 1 study, a daily 30 mg dose of afatinib and 15 mg/kg intravenous bevacizumab every 3 weeks was well tolerated and was defined as the recommended dose. We have initiated a randomized phase 2 trial comparing afatinib (30 mg daily) and bevacizumab (15 mg/kg every 3 weeks) with afatinib (40 mg daily) alone for nonsquamous NSCLC harboring EGFR common mutations as a first-line therapy. A total of 100 patients will be enrolled onto this study and randomized in a 1:1 ratio. Patients will continue to receive treatment until disease progression or unacceptable toxicity. The primary end point is PFS, and the secondary end points are overall survival, tumor response, and time to treatment failure. The power is greater than 50% under the assumptions of a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group (2-sided α = 0.05). We hypothesize that the combination therapy will be more efficacious than standard therapies for EGFR-mutant NSCLC patients. 相似文献