首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   10314篇
  免费   457篇
  国内免费   78篇
耳鼻咽喉   89篇
儿科学   277篇
妇产科学   82篇
基础医学   1446篇
口腔科学   276篇
临床医学   628篇
内科学   2812篇
皮肤病学   211篇
神经病学   815篇
特种医学   281篇
外科学   1537篇
综合类   30篇
预防医学   249篇
眼科学   110篇
药学   953篇
中国医学   44篇
肿瘤学   1009篇
  2023年   37篇
  2022年   23篇
  2021年   124篇
  2020年   66篇
  2019年   110篇
  2018年   149篇
  2017年   108篇
  2016年   150篇
  2015年   161篇
  2014年   236篇
  2013年   307篇
  2012年   540篇
  2011年   555篇
  2010年   327篇
  2009年   301篇
  2008年   605篇
  2007年   692篇
  2006年   624篇
  2005年   686篇
  2004年   696篇
  2003年   684篇
  2002年   723篇
  2001年   156篇
  2000年   128篇
  1999年   182篇
  1998年   184篇
  1997年   134篇
  1996年   141篇
  1995年   151篇
  1994年   156篇
  1993年   159篇
  1992年   142篇
  1991年   128篇
  1990年   123篇
  1989年   124篇
  1988年   99篇
  1987年   96篇
  1986年   78篇
  1985年   90篇
  1984年   65篇
  1983年   62篇
  1982年   65篇
  1981年   64篇
  1980年   47篇
  1979年   45篇
  1978年   35篇
  1977年   27篇
  1976年   38篇
  1975年   29篇
  1974年   26篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
1.
2.
Lessons Learned
  • Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
  • It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.
BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.  相似文献   
3.
Motor imagery is defined as an act wherein an individual contemplates a mental action of motor execution without apparent action. Mental practice executed by repetitive motor imagery can improve motor performance without simultaneous sensory input or overt output. We aimed to investigate cerebral hemodynamics during motor imagery and motor execution of a self-feeding activity using chopsticks. This study included 21 healthy right-handed volunteers. The self-feeding activity task comprised either motor imagery or motor execution of eating sliced cucumber pickles with chopsticks to examine eight regions of interest: pre-supplementary motor area, supplementary motor area, bilateral prefrontal cortex, premotor area, and sensorimotor cortex. The mean oxyhemoglobin levels were detected using near-infrared spectroscopy to reflect cerebral activation. The mean oxyhemoglobin levels during motor execution were significantly higher in the left sensorimotor cortex than in the supplementary motor area and the left premotor area. Moreover, significantly higher oxyhemoglobin levels were detected in the supplementary motor area and the left premotor area during motor imagery, compared to motor execution. Supplementary motor area and premotor area had important roles in the motor imagery of self-feeding activity. Moreover, the activation levels of the supplementary motor area and the premotor area during motor execution and motor imagery are likely affected by intentional cognitive processes. Levels of cerebral activation differed in some areas during motor execution and motor imagery of a self-feeding activity. This study was approved by the Ethical Review Committee of Nagasaki University(approval No. 18110801) on December 10, 2018.  相似文献   
4.
International Journal of Clinical Oncology - The role of pembrolizumab in the treatment of poor performance status (PS) patients remains unclear. We conducted a phase II trial to investigate the...  相似文献   
5.
Objective: The recognition of fluid retention is critical in treating heart failure (HF). Bioelectrical impedance analysis (BIA) is a well-known noninvasive method; however, data on its role in managing patients with congenital heart disease (CHD) are limited. Here, we aimed to clarify the correlation between BIA and HF severity as well as the prognostic value of BIA in adult patients with CHD.
Design: This prospective single-center study included 170 patients with CHD admitted between 2013 and 2015. We evaluated BIA parameters (intra- and extracellular water, protein, and mineral levels, edema index [EI, extracellular water-to-total body water ratio]), laboratory values, and HF-related admission prevalence.
Results: Patients with New York Heart Association (NYHA) functional classes III-IV had a higher EI than those with NYHA classes I-II (mean ± SD, 0.398 ± 0.011 vs 0.384 ± 0.017, P < .001). EI was significantly correlated with brain natriuretic peptide level (r = 0.51, P < .001). During the mean follow-up period of 7.1 months, KaplanMeier analysis showed that a discharge EI > 0.386, the median value in the present study, was significantly associated with a future increased risk of HF-related admission (HR = 4.15, 95% CI = 1.70-11.58, P < .001). A body weight reduction during hospitalization was also related to EI reduction.
Conclusions: EI determined using BIA could be a useful marker for HF severity that could predict future HF-related admissions in adult patients with CHD.  相似文献   
6.
Recently, there has been increased attention on the analysis of circulating tumor cells (CTCs), also known as liquid biopsy, owing to its potential benefits in cancer diagnosis and treatment. Circulating tumor cells are released from primary tumor lesions into the blood stream and eventually metastasize to distant body organs. However, a major hurdle with CTC analysis is their natural scarcity. Existing methods lack sensitivity, specificity, or reproducibility required in CTC characterization and detection. Here, we report untargeted molecular profiling of single CTCs obtained from gastric cancer and colorectal cancer patients, using live single cell mass spectrometry integrated with microfluidics‐based cell enrichment techniques. Using this approach, we showed the difference in the metabolomic profile between CTCs originating from different cancer groups. Moreover, potential biomarkers were putatively annotated to be specific to each cancer type.  相似文献   
7.
Inactivation of the Adenomatous polyposis coli (APC) gene is an initiating and the most relevant event in most sporadic cases of colorectal cancer, providing a rationale for using Apc‐mutant mice as the disease model. Whereas carcinogenesis has been observed only at the organism level, the recent development of the organoid culture technique has enabled long‐term propagation of intestinal stem cells in a physiological setting, raising the possibility that organoids could serve as an alternative platform for modeling colon carcinogenesis. Indeed, it is demonstrated in the present study that lentivirus‐based RNAi‐mediated knockdown of Apc in intestinal organoids gave rise to subcutaneous tumors upon inoculation in immunodeficient mice. Reconstitution of common genetic aberrations in organoids resulted in development of various lesions, ranging from aberrant crypt foci to full‐blown cancer, recapitulating multi‐step colorectal tumorigenesis. Due to its simplicity and utility, similar organoid‐based approaches have been applied to both murine and human cells in many investigations, to gain mechanistic insight into tumorigenesis, to validate putative tumor suppressor genes or oncogenes, and to establish preclinical models for drug discovery. In this review article, we provide a multifaceted overview of these types of approaches that will likely accelerate and advance research on colon cancer.  相似文献   
8.
9.
Hematopoietic stem cells (HSCs) depend on the bone marrow (BM) niche for their maintenance, proliferation, and differentiation. The BM niche is composed of nonhematopoietic and mature hematopoietic cells, including megakaryocytes (Mks). Thrombopoietin (Thpo) is a crucial cytokine produced by BM niche cells. However, the cellular source of Thpo, upon which HSCs primarily depend, is unclear. Moreover, no specific molecular pathway for the regulation of Thpo production in the BM has been identified. Here, we demonstrate that the membrane protein C-type lectin-like receptor-2 (CLEC-2) mediates the production of Thpo and other factors in Mks. Mice conditionally deleted for CLEC-2 in Mks (Clec2MkΔ/Δ) produced lower levels of Thpo in Mks. CLEC-2–deficient Mks showed down-regulation of CLEC-2–related signaling molecules Syk, Lcp2, and Plcg2. Knockdown of these molecules in cultured Mks decreased expression of Thpo. Clec2MkΔ/Δ mice exhibited reduced BM HSC quiescence and repopulation potential, along with extramedullary hematopoiesis. The low level of Thpo production may account for the decline in HSC potential in Clec2MkΔ/Δ mice, as administration of recombinant Thpo to Clec2MkΔ/Δ mice restored stem cell potential. Our study identifies CLEC-2 signaling as a novel molecular mechanism mediating the production of Thpo and other factors for the maintenance of HSCs.Maintenance of hematopoietic stem cells (HSCs) within the adult BM is crucial for the healthy production of hematopoietic cells (Orkin and Zon, 2008). HSCs reside in a specialized microenvironment in the BM called the niche (Schofield, 1978). Along with cell-intrinsic programs, the niche influences the cell fate of HSCs, which in turn govern the homeostasis of the hematopoietic system (Nakamura-Ishizu et al., 2014a). The HSC niche is chiefly composed of nonhematopoietic cells, including immature osteoblasts (OBLs; Arai and Suda, 2007), endothelial cells (ECs; Butler et al., 2010; Ding et al., 2012), perivascular cells (Sugiyama et al., 2006; Ding et al., 2012), mesenchymal stem cells (MSCs; Méndez-Ferrer et al., 2010), sympathetic nervous cells (Katayama et al., 2006), adipocytes (Naveiras et al., 2009), and nonmyelinating Schwann cells (Yamazaki et al., 2011). Nonetheless, mature hematopoietic cells such as macrophages/monocytes (Chow et al., 2011), osteoclasts (Kollet et al., 2006), and regulatory T cells (Fujisaki et al., 2011) also regulate HSCs, albeit mainly in an indirect manner, through the modulation of nonhematopoietic niche cells. Recently, mature megakaryocytes (Mks) were described as hematopoietic progeny that directly regulate HSC quiescence (Heazlewood et al., 2013; Bruns et al., 2014; Zhao et al., 2014; Nakamura-Ishizu et al., 2014b); one of the mechanisms underlying Mk niche function is the production of the cytokine thrombopoietin (Thpo) by Mks themselves (Nakamura-Ishizu et al., 2014b). However, among the Mk-related niche factors reported to date, no molecular mechanism that is specific to Mks has been identified.Thpo is a crucial cytokine for both the maturation of Mks and the maintenance of quiescent HSCs (Zucker-Franklin and Kaushansky, 1996; Qian et al., 2007; Yoshihara et al., 2007). Thpo is produced in multiple organs, including the liver, kidney, spleen, and muscle (Nomura et al., 1997). Baseline production of serum Thpo is thought to be maintained by the liver and regulated in response to inflammatory stress or changes in glycosylation of aged platelets (Kaser et al., 2001; Stone et al., 2012; Grozovsky et al., 2015). Serum Thpo levels also fluctuate according to circulating platelet number: platelets sequester Thpo via the myeloproliferative leukemia virus oncogene (c-Mpl), the receptor for Thpo (Kuter and Rosenberg, 1995; de Graaf et al., 2010), thereby lowering Thpo levels. Thus, platelet number is not as tightly regulated by Thpo production as erythrocyte number is by erythropoietin production (Fandrey and Bunn, 1993). It is likely that BM HSCs depend on Thpo, which is produced in the BM by niche cells. Depletion of circulating platelets by neuraminidase does not affect HSCs (Bruns et al., 2014), indicating that serum Thpo up-regulation through thrombocytopenia does not affect HSC maintenance. Moreover, HSCs reside near bone-lining OBLs and mature Mks, which both support HSCs by producing Thpo (Yoshihara et al., 2007; Nakamura-Ishizu et al., 2014b). However, the main cellular source of Thpo, upon which BM HSCs depend, and the molecular signaling pathway that mediates BM Thpo production remain elusive.Recent studies showed that signals mediated through C-type lectin-like domain-containing receptors (CLEC-4H1 and CLEC-4H2; also known as Ashwell–Morell receptor) stimulate Thpo production in hepatocytes through recognition of desialylated platelets (Grozovsky et al., 2015). Platelets and Mks express CLEC-2 (Suzuki-Inoue et al., 2006, 2007), which is among the top 25 genes specifically expressed on Mks (Senis et al., 2007). Activation of platelet CLEC-2 through binding to sialylated podoplanin is essential for the segregation of lymphatic and blood vessels during development (Bertozzi et al., 2010; Suzuki-Inoue et al., 2010). CLEC-2–podoplanin signaling also functions in maintenance of lymphocyte- and dendritic cell–related responses in the stroma of lymph nodes (Acton et al., 2012, 2014; Herzog et al., 2013).The significance of CLEC-2 expression on Mks in BM hematopoiesis, and whether it is involved in Thpo production in Mks, has not been previously explored. Here, we demonstrate that Mk-specific deficiency of CLEC-2 disrupts HSC quiescence and alters HSC potential as a result of defective Mk niche function. Moreover, we demonstrate that CLEC-2 signaling is involved in various molecular pathways for production of niche factors, including Thpo in Mks. Through the identification of CLEC-2, a novel Mk-specific factor, our data elucidate the organ-dependent production and function of Thpo and reinforce the idea that Mks contribute to a niche that regulates HSC quiescence.  相似文献   
10.
[Purpose] Strength training is recommended for children with cerebral palsy. However, it is difficult for moderately impaired children with cerebral palsy, who require crutches for ambulation, to participate in this type of training. The purpose of this study was to investigate whether whole-body vibration training is an effective method of strengthening in a moderately impaired child with cerebral palsy. [Subject and Methods] This report describes an 8-year-old Japanese boy with cerebral palsy, who was ambulatory with crutches. The subject participated in physical therapy twice a week for 5 weeks. Whole-body vibration training was selected to complement the standing practice. The patient’s crutch-walking ability, gross motor function, and spasticity were evaluated. [Results] The number of steps and walking duration were reduced in a 5-m walk test with crutches and gross motor function was improved. Further, the spasticity was reduced. [Conclusion] Whole-body vibration training is an effective physical therapy intervention in moderately impaired children with cerebral palsy, who are unable to walk without crutches.Key words: Cerebral palsy, Whole-body vibration, Walking ability  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号