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81.
Qiang Fu Le Xu Yiwei Wang Qi Jiang Zheng Liu Junyu Zhang Quan Zhou Han Zeng Shanyou Tong Tao Wang Yangyang Qi Baoying Hu Hangcheng Fu Huyang Xie Lin Zhou Yuan Chang Yu Zhu Bo Dai Jiejie Xu 《European urology》2019,75(5):752-763
Background
Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities.Objective
To seek a potential therapeutic target in glutamine-addicted ccRCC.Design, setting, and participants
Tumors from ccRCC patients from a Shanghai cohort and ccRCC tumor data from The Cancer Genome Atlas (TCGA) cohort were analyzed. In vivo and in vitro studies were conducted with fresh human ccRCC tumors and murine tumor cells.Outcome measurements and statistical analysis
Immune cell numbers and functions were analyzed by flow cytometry. Glutamine and cytokine concentrations were determined. Survival was compared between different subpopulations of patients using Kaplan-Meier and Cox regression analyses.Results and limitations
We found that in ccRCC, high interleukin (IL)-23 expression was significantly associated with poor survival in both TCGA (overall survival [OS] hazard ratio [HR] = 2.04, cancer-specific survival [CSS] HR = 2.95; all p < 0.001) and Shanghai (OS HR = 2.07, CSS HR = 3.92; all p < 0.001) cohorts. IL-23 blockade prolongs the survival of tumor-bearing mice, promotes T-cell cytotoxicity in in vitro cultures of human ccRCC tumors, and augments the therapeutic benefits of anti-PD-1 antibodies. Mechanistically, glutamine consumption by ccRCC tumor cells results in the local deprivation of extracellular glutamine, which induces IL-23 secretion by tumor-infiltrating macrophages via the activation of hypoxia-inducible factor 1α (HIF1α). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor β expression, thereby suppressing tumor cell killing by cytotoxic lymphocytes. The positive correlations between glutamine metabolism, IL-23 levels, and Treg responses are confirmed in both TCGA cohort and tumors from Shanghai ccRCC patients. Study limitations include the unclear impacts of glutamine deprivation and IL-23 on other immune cells.Conclusions
Macrophage-secreted IL-23 enhanced Treg functions in glutamine-addicted tumors; thus, IL-23 is a promising target for immunotherapy in ccRCC.Patient summary
In this study, we analyzed the immune components in glutamine-addicted clear cell renal cell carcinoma (ccRCC) tumors from two patient cohorts and conducted both in vitro and in vivo studies. We found that ccRCC tumor cell-intrinsic glutamine metabolism orchestrates immune evasion via interleukin (IL)-23, and IL-23–high patients had significantly poorer survival than IL-23–low patients. IL-23 should thus be considered a therapeutic target in ccRCC, either alone or in combination with immune checkpoint inhibitors. 相似文献82.
83.
Béla Nagy Zsolt Bene Zsolt Fejes Sonya L. Heltshe David Reid Nicola J. Ronan Yvonne McCarthy Daniel Smith Attila Nagy Elizabeth Joseloff György Balla János Kappelmayer Milan Macek Scott C. Bell Barry J. Plant Margarida D. Amaral István Balogh 《Journal of cystic fibrosis》2019,18(2):271-277
Background
We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy.Methods
In this retrospective clinical study, 3 independent CF patient cohorts (US-American: 29, Australian: 12 and Irish: 19 cases) were enrolled carrying at least one Class III CFTR CF-causing mutation (p.Gly551Asp) and being treated with CFTR potentiator ivacaftor. Plasma HE4 was measured by immunoassay before treatment (baseline) and 1–6?months after commencement of ivacaftor, and were correlated with FEV1 (% predicted), sweat chloride, C-reactive protein (CRP) and body mass index (BMI).Results
After 1?month of therapy, HE4 levels were significantly lower than at baseline and remained decreased up to 6?months. A significant inverse correlation between absolute and delta values of HE4 and FEV1 (r?=??0.5376; P?<?.001 and r?=??0.3285; P?<?.001), was retrospectively observed in pooled groups, including an independent association of HE4 with FEV1 by multiple regression analysis (β?=??0.57, P?=?.019). Substantial area under the receiver operating characteristic curve (ROC-AUC) value was determined for HE4 when 7% mean change of FEV1 (0.722 [95% CI 0.581–0.863]; P?=?.029) were used as classifier, especially in the first 2?months of treatment (0.806 [95% CI 0.665–0.947]; P?<?.001).Conclusions
This study shows that plasma HE4 levels inversely correlate with lung function improvement in CF patients receiving ivacaftor. Overall, this potential biomarker may be of value for routine clinical and laboratory follow-up of CFTR modulating therapy. 相似文献84.
85.
86.
87.
Robert J. Motzer MD Bernard Escudier MD Saby George MD Hans J. Hammers MD PhD Sandhya Srinivas MD Scott S. Tykodi MD PhD Jeffrey A. Sosman MD Elizabeth R. Plimack MD Giuseppe Procopio MD David F. McDermott MD Daniel Castellano MD Toni K. Choueiri MD Frede Donskov MD PhD Howard Gurney MD Stéphane Oudard MD Martin Richardet MD PhD Katriina Peltola MD PhD Ajjai S. Alva MD Michael Carducci MD John Wagstaff MD Christine Chevreau MD Satoshi Fukasawa MD Yoshihiko Tomita MD PhD Thomas C. Gauler MD Christian K. Kollmannsberger MD Fabio A. Schutz PhD James Larkin MD PhD David Cella PhD M. Brent McHenry PhD Shruti Shally Saggi BEng Nizar M. Tannir MD 《Cancer》2020,126(18):4156-4167
88.
Atsushi Hata Takahiro Nakajima Keisuke Matsusaka Masaki Fukuyo Junichi Morimoto Takayoshi Yamamoto Yuichi Sakairi Bahityar Rahmutulla Satoshi Ota Hironobu Wada Hidemi Suzuki Hisahiro Matsubara Ichiro Yoshino Atsushi Kaneda 《International journal of cancer. Journal international du cancer》2020,146(2):388-399
89.
《Clinical Lymphoma, Myeloma & Leukemia》2020,20(5):324-328
BackgroundBone marrow fibrosis (BMF), a poor prognostic factor in myelodysplastic syndromes (MDS), in the context of new risk stratifications of MDS has not been fully explored. We examined the relationship between BMF in MDS and survival outcomes, and explored the landscape of somatic gene mutations in the setting of BMF.Patients and MethodsWe retrospectively evaluated 2624 MDS patients for BMF who were divided into 2 groups: grade 0-2 BMF (96%) and severe/grade 3 BMF (4%) based on analysis presented. Commonly MDS tested acquired somatic mutations were also compared between those 2 groups of patients with available next-generation sequencing data.ResultsOnly grade 3 BMF was associated with worse overall survival independent from the Revised International Prognostic Scoring System (IPSS-R) (hazard ratio = 1.6; 95% confidence interval, 1.2-1.9; P < .005). More patients with severe BMF were classified as MDS-EB1 and -EB2 by the World Health Organization 2016 classification, a higher-risk International Prognostic Scoring System score, and a high/very high IPSS-R risk category than patients with grade 0-2 BMF. A complex karyotype, higher bone marrow myeloblasts, lower platelets, and higher rate of elevated lactate dehydrogenase were observed more often in patients with severe BMF. No differences in response to hypomethylating agents or lenalidomide were observed. Among somatic gene mutations tested in MDS, TP53 mutation and SETBP1 were more frequent in patients with grade 3 BMF.ConclusionThe presence of grade 3 BMF is associated with reduced overall survival independent from IPSS-R; however, BMF grade did not affect response to hypomethylating agent or lenalidomide treatment. TP53 and SETBP1 mutations occurred with greater frequency among patients with severe fibrosis. 相似文献
90.
桑根酮C对博莱霉素诱导小鼠肺纤维化改善作用及机制研究 总被引:1,自引:0,他引:1
目的观察桑根酮C对博莱霉素诱导的小鼠肺纤维化的影响,并探讨其可能的作用机制。方法 C57BL/6小鼠随机分为4组,即假手术组、模型组和桑根酮C(100、50 mg/kg)组,每组20只。假手术组小鼠气管内注射生理盐水,模型组小鼠气管内注射博莱霉素诱导肺纤维化模型。术后第4天开始给药,连续给药28d后检测小鼠呼吸功能;检测肺内羟脯氨酸含量;HE染色观察肺内炎症表现;Masson染色观察肺内胶原活性;免疫组化法检测肺内转化生长因子-β1(TGF-β1)蛋白表达量;免疫蛋白印迹法检测肺内α平滑肌肌动蛋白(α-SMA)、核转录因子-κB p65(NF-κB p65)、磷酸化的核转录因子-κB p65(p-NF-κB p65)、Ⅰ型胶原和Ⅲ型胶原表达量。结果与模型组比较,桑根酮C能够改善经博莱霉素诱导形成肺纤维化后小鼠的呼吸功能,能够明显降低肺内羟脯氨酸含量,明显减轻肺内炎症和胶原沉积,肺内TGF-β1、α-SMA、NF-κBp65、p-NF-κBp65、Ⅰ型胶原和Ⅲ型胶原蛋白表达量明显降低。结论桑根酮C能够明显改善博莱霉素诱导小鼠肺纤维化,改善呼吸功能,其机制可能与抑制TGF-β1过表达和降低炎症转录因子NF-κB及磷酸化表达有关。 相似文献