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   3343篇
  免费   205篇
  国内免费   19篇
耳鼻咽喉   38篇
儿科学   95篇
妇产科学   159篇
基础医学   542篇
口腔科学   71篇
临床医学   234篇
内科学   901篇
皮肤病学   58篇
神经病学   215篇
特种医学   59篇
外科学   378篇
综合类   26篇
预防医学   278篇
眼科学   44篇
药学   190篇
中国医学   6篇
肿瘤学   273篇
  2023年   24篇
  2022年   39篇
  2021年   116篇
  2020年   50篇
  2019年   113篇
  2018年   80篇
  2017年   73篇
  2016年   82篇
  2015年   84篇
  2014年   111篇
  2013年   145篇
  2012年   234篇
  2011年   210篇
  2010年   102篇
  2009年   101篇
  2008年   201篇
  2007年   189篇
  2006年   220篇
  2005年   185篇
  2004年   158篇
  2003年   151篇
  2002年   141篇
  2001年   87篇
  2000年   86篇
  1999年   80篇
  1998年   34篇
  1997年   23篇
  1996年   18篇
  1995年   26篇
  1994年   22篇
  1993年   18篇
  1992年   42篇
  1991年   42篇
  1990年   22篇
  1989年   41篇
  1988年   32篇
  1987年   19篇
  1986年   24篇
  1985年   28篇
  1984年   19篇
  1983年   18篇
  1982年   15篇
  1981年   6篇
  1980年   8篇
  1978年   4篇
  1977年   6篇
  1974年   7篇
  1973年   4篇
  1972年   5篇
  1966年   4篇
排序方式: 共有3567条查询结果,搜索用时 15 毫秒
1.
Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.  相似文献   
2.
3.
Background  Nonmelanoma skin cancer (NMSC) has been linked to cutaneous human papillomaviruses of the genus beta (betaPV).
Objectives  We sought to assess the presence of betaPV in NMSC biopsies from a group of Scottish skin cancer patients, both immunocompetent (IC) patients and immunosuppressed (IS) organ transplant recipients.
Methods  One hundred and twenty-one paraffin-embedded skin tumours (27 actinic keratosis, 41 intraepidermal carcinoma, 53 squamous cell carcinoma) and 11 normal skin samples were analysed for the presence of betaPV by a polymerase chain reaction–reverse hybridization assay designed to detect the presence of the 25 known betaPV genotypes.
Results  In IC patients, betaPV was detected in 30 of 59 (51%) tumours and two of 11 (18%) normal skin samples ( P  =   0·046). In IS patients, betaPV was found in 27 of 62 (44%) tumours; no normal skin samples were available for comparison. The most frequently found genotypes were HPV-24, HPV-15 and HPV-38. Of those tumours infected with betaPV, 28 of 57 (49%) were infected with more than one genotype (range 2–8). Tumours from IS patients were from a younger age group (mean age 57·4 years) than IC patients (mean age 73·8 years). Multiple infections were more common in tumours from IC patients (21 of 30; 70%) compared with those from IS patients (seven of 27; 26%) ( P  <   0·001). In the IC group, age did not appear to influence the distribution of single and multiple infections whereas in IS patients the proportion of multiple infections to single infections increased with age. There were no multiple infections in normal skin.
Conclusions  A wide spectrum of betaPV types was detected in our samples. Further characterization of betaPV in vivo is needed in order to determine the mechanisms by which the virus contributes to cutaneous carcinogenesis.  相似文献   
4.
The effect of thyrotrophin-releasing hormone (TRH) on intracellular free Ca2+ concentration, [Ca2+)i, was investigated with the fluorescent dye fura-2 in cell suspensions obtained from 13 human growth hormone-secreting adenomas and 6 adrenocorticotrophin-secreting adenomas. Preoperatively, 9 out of 13 acromegalic patients showed a positive growth hormone response to TRH administration while none of the 6 patients with Cushing's disease had a plasma adrenocorticotrophin increase after TRH injection. In all the growth hormone-secreting adenomas the addition of TRH (100 nM) caused a significant rise in [Ca2+]i (from a resting level of 133±40 (±SD) to a value of 284±119 nM at 100 nM TRH, n = 42; P<0.001). The transient induced by TRH was found to have a dual origin, one due to Ca2+ mobilization from intracellular stores which was maintained in presence of EGTA (3mM) and verapamil (10 μM) and a plateau phase due to Ca2+ influx from the extracellular media. Somatostatin (0.1 μM) lowered both resting [Ca2+]i and TRH-induced transients. The effect of gonadotrophin-releasing hormone on [Ca2+]i was evaluated on cell suspensions obtained from 6 growth hormone-secreting adenomas. Gonadotrophin-releasing hormone (100 nM) caused a marked rise in [Ca2+]i (from 179±25 to 283±15nM) on the cell suspension obtained from the only in vivo responsive adenoma while it was ineffective in the remaining 5. Although TRH was ineffective in modifying plasma adrenocorticotrophin levels in all patients with Cushing's disease, in 5 out of 6 tumors the addition of 100 nM TRH caused a significant rise in [Ca2+]i (from 102.5 ± 36 to 163±66 nM, n = 22; P < 0.005). However, the effect of TRH on [Ca2+]i was significantly lower than that caused by arginine vasopressin, a physiological stimulator of adrenocorticotrophin release ([Ca2+]i values; 145±78 nM at 100 nM TRH versus 300±140 at 10 nM arginine vasopressin, n = 15; P<0.05). Moreover, the effect of arginine vasopressin on [Ca2+]i was detectable at concentrations as low as 0.1 nM while TRH was effective at concentrations higher than 1 nM. By contrast, gonadotrophin-releasing hormone was ineffective in increasing [Ca2]i in all the adrenocorticotrophin-secreting adenomas studied. Collectively, these data indicate that sensitivity to TRH is present in almost all the growth hormone- and adrenocorticotrophin-secreting adenomas independently of the responsiveness of the individual patients to the peptide.  相似文献   
5.
6.
We have examined immunohistochemically the presence of human chorionic gonadotrophin (hCG) in 29 esophageal carcinomas: 24 squamous cell carcinomas, 2 adenocarcinomas, 2 adenoid cystic carcinomas and 1 adenosquamous carcinoma. In hCG-positive tumors, the presence of human placental lactogen (hPL) and pregnancy-specific beta-1 glycoprotein (SP-1) was also assessed. HCG immunoreactive cells were found in 5 squamous cell carcinomas (21%) and in none of 5 non-squamous cell tumors. The hCG positive cells were found in the most infiltrating areas of the tumors where poorly differentiated and pleomorphic cells predominated. The positive tumors were 4 poorly differentiated (31%) and one moderately differentiated carcinoma (12%). Four out of 10 cases (40%) with lymph node metastases had hCG in the primary tumor, whereas only one out of 11 cases (9%) without metastases was hCG positive. HPL and SP-1 were found in two cases. These placental proteins were detected in similar areas than hCG but the number of hPL and SP-1 immunoreactive cells was lower than hCG positive cells. SP-1 was also seen in areas of squamous cell differentiation negative for hCG. None of these two cases showed trophoblastic differentiation.  相似文献   
7.
8.
9.
10.

Objectives  

This study was designed to assess the prevalence of adverse drug reactions (ADRs) in the internal medicine wards of two teaching Hospitals, identify the most common ADRs, the principal medications involved, and determine the risk factors implicated in the occurrence of such ADRs.  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