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   1662篇
  免费   102篇
  国内免费   8篇
耳鼻咽喉   6篇
儿科学   105篇
妇产科学   35篇
基础医学   170篇
口腔科学   40篇
临床医学   227篇
内科学   312篇
皮肤病学   21篇
神经病学   182篇
特种医学   321篇
外科学   129篇
综合类   23篇
预防医学   44篇
眼科学   10篇
药学   72篇
中国医学   6篇
肿瘤学   69篇
  2023年   8篇
  2022年   11篇
  2021年   21篇
  2020年   15篇
  2019年   18篇
  2018年   38篇
  2017年   23篇
  2016年   26篇
  2015年   36篇
  2014年   45篇
  2013年   45篇
  2012年   54篇
  2011年   45篇
  2010年   56篇
  2009年   76篇
  2008年   51篇
  2007年   39篇
  2006年   40篇
  2005年   35篇
  2004年   37篇
  2003年   44篇
  2002年   38篇
  2001年   45篇
  2000年   36篇
  1999年   45篇
  1998年   55篇
  1997年   61篇
  1996年   79篇
  1995年   54篇
  1994年   47篇
  1993年   60篇
  1992年   35篇
  1991年   23篇
  1990年   34篇
  1989年   54篇
  1988年   47篇
  1987年   36篇
  1986年   43篇
  1985年   36篇
  1984年   20篇
  1983年   17篇
  1982年   28篇
  1981年   23篇
  1980年   13篇
  1979年   10篇
  1978年   8篇
  1977年   16篇
  1976年   17篇
  1975年   17篇
  1973年   3篇
排序方式: 共有1772条查询结果,搜索用时 15 毫秒
51.
Pentraxin 3 (PTX3) is a soluble pattern recognition receptor that binds with high affinity and selectivity to fibroblast growth factor‐2 (FGF2), thus inhibiting its pro‐angiogenic activity. Here we investigated the effects of PTX3 on monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patient‐derived bone marrow (BM) plasma cells (PCs), endothelial cells (ECs), and fibroblasts (FBs), and assessed whether PTX3 can modulate the cross‐talk between PCs and those microenvironment cells. PTX3 and FGF2 expression was evaluated by ELISA. Functional studies, including cell viability, wound healing, chemotaxis, and Matrigel® assays, were performed on MGUS and MM ECs and FBs upon the PTX3 treatment. Through western blot PTX3‐induced modulation in FGF2/FGF receptor signalling pathways was evaluated in MGUS and MM ECs and FBs through western blot. Co‐cultures between MM ECs/FBs and human PC lines were used to evaluate possible PTX3 indirect effects on MM PCs. Adhesion molecules were studied by flow cytometry. PTX3 provides a direct time‐ and dose‐dependent apoptotic effect on MM ECs and FBs, but not on either MM primary PCs or human PC lines. PTX3 inhibits migration of MM ECs and FBs in a dose‐dependent manner, and impacts in vitro and in vivo FGF2‐mediated MM angiogenesis. Co‐cultures of PCs and ECs/FBs show that PTX3 treatment indirectly impairs PC viability and adhesion. We conclude that PTX3 is an anti‐angiogenic factor in MM and behaves as a cytotoxic molecule on MM cells by inhibiting the cross‐talk between PCs and ECs/FBs. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.  相似文献   
52.
53.
Purpose

The pentose phosphate pathway (PPP) has been shown to play an important role in the metabolism of cancer cells. The transketolase-like 1 gene (TKTL1) encodes an enzyme representing an essential component of this pathway. Its expression has been demonstrated to correlate with stage and outcome in various tumors. The aim of the present study was to assess expression patterns and the prognostic role of TKTL1 in muscle-invasive bladder cancer (MIBC).

Patients and methods

The expression of TKTL1 was assessed in a tissue microarray consisting of histopathologically benign and malign tissue of 112 patients who underwent radical cystectomy due to MIBC. Cytoplasmatic and nuclear expression were assessed by immunohistochemistry and compared separately with clinicopathologic parameters and outcome.

Results

Cytoplasmatic expression of TKTL1 was exclusively present in tumor tissue. In contrast, the proportion of nuclei positive for TKTL1 was higher in histopathologically benign tissue compared with malign tissue. No correlation was observed between cytoplasmatic or nuclear TKTL1 expression and tumor stage, grade or the presence of metastases. Patients with lymph node involvement showed a decreased frequency of cytoplasmatic expression compared with node-negative patients (p = 0.01). However, no further correlation was observed between the expression of TKTL1 and clinical outcome of patients.

Conclusions

The present study shows that the cytoplasmatic expression of TKTL1 is specific for MIBC tissue compared with histopathologically benign urothelium. This specific expression is present in a subgroup of MIBC potentially identifying patients with activated PPP suitable for a targeted inhibition of sugar metabolism. In contrast to other malignancies, TKTL1 shows no prognostic significance in MIBC.

  相似文献   
54.
Brentuximab vedotin (BV) shows a high overall response rate (ORR) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) after autologous transplant (ASCT). The aim of this multicenter study, conducted in nine Hematology Departments of Rete Ematologica Pugliese, was to retrospectively evaluate the efficacy and safety of BV as salvage therapy and as bridge regimen to ASCT or allogeneic transplant (alloSCT) in R/R HL patients. Seventy patients received BV. Forty-five patients (64%) were treated with BV as bridge to transplant:16 (23%) patients as bridge to ASCT and 29 (41%) as bridge to alloSCT. Twenty-five patients (36%), not eligible for transplant, received BV as salvage treatment. The ORR was 59% (CR 26%). The ORR in transplant naïve patients was 75% (CR 31%). In patients treated with BV as bridge to alloSCT, the ORR was 62% (CR 24%). In a multivariate analysis, the ORR was lower in refractory patients (p?<?0.005). The 2y-OS was 70%. The median PFS was 17 months. Ten of the 16 (63%) naïve-transplant patients received ASCT, with 50% in CR before ASCT. In the 29 patients treated with BV as bridge to alloSCT, 28 (97%) proceeded to alloSCT with 25% in CR prior to alloSCT. The most common adverse events were peripheral neuropathy (50%), neutropenia (29%) and anemia (12%). These data suggest that BV is well tolerated and very effective in R/R HL, producing a substantial level of CR. BV may also be a key therapeutic agent to achieve good disease control before transplant, improving post- transplant outcomes, also in refractory and heavily pretreated patients, without significant overlapping toxicities with prior therapies.  相似文献   
55.
Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the resulting promyelocytic myeloid leukemia/retinoic acid receptor alpha (PML/RAR alpha) fusion proteins. To date APL is the only AML that is sufficiently sensitive to all-trans retinoic acid's (ATRA) differentiating effect. In vivo ATRA alone achieves complete remission in most APL patients. However, failure or partial responses are observed and the molecular basis of the absence of ATRA response in these patients has not been determined. To gain insights in the cell growth and differentiation of APL cells, expression of hematopoietic growth factors (HGF) shown to be produced by leukemic cells (interleukin-1 beta [IL-1 beta], IL-6, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor [G-CSF], granulocyte- macrophage colony-stimulating factor [GM-CSF], and IL-3) was studied in 16 APL samples. Twelve APL cases expressed IL-1 beta, IL-6, and TNF alpha, but not G-CSF, GM-CSF, and IL-3. These cases achieved complete remission with ATRA therapy. The four remaining patients (either TNF alpha negative or G-CSF, GM-CSF or IL-3 positive) did not achieve complete remission with ATRA. In all cases, in vivo response to ATRA therapy was correlated to the in vitro differentiation effect of all- trans retinoic acid 10(-6) mol/L. Thus, ATRA differentiation induction was strongly correlated to the HGF expression (P < .0001). These results suggest that the presence or absence of HGF's expression by APL cells may contribute to the therapeutic effect of ATRA in this disease.  相似文献   
56.
57.
Platelet glycoproteins IIb and IIIa as a calcium channel in liposomes   总被引:3,自引:0,他引:3  
Rybak  ME; Renzulli  LA; Bruns  MJ; Cahaly  DP 《Blood》1988,72(2):714-720
Human platelet membrane glycoproteins IIb and IIIa (GPIIb and IIIa) were incorporated into phospholipid vesicles by the reverse-phase technique to assess the ability of GPIIb and IIIa to function as a Ca2+ channel. Movement of Ca2+ across the lipid bilayer was quantitated by injection of proteoliposomes with encapsulated Fura-2 into Ca2+ buffers and measurement of Fura-2 fluorescence as an indicator of Ca2+ influx. Reciprocally, to assess the function of proteins in an inside-out orientation, Ca2+-loaded vesicles were injected into Ca2+-free buffer and Ca2+ efflux monitored by a calcium electrode. Incorporation of the IIb-IIIa complex produced significant facilitation of Ca2+ movement across the lipid bilayer. No net transmembrane Ca2+ movement was seen with dissociated IIb and IIIa. Movement of Ca2+ was proportional to the transmembrane Ca2+ gradient. Ca2+ movement into the vesicles was inversely proportional to extravesicular NaCl from 25 to 150 mmol/L, analogous to several studies in the intact platelet. Adenosine triphosphate had no effect on Ca2+ movement into or out of the vesicles. Specific inhibition of a Ca2+ shift into the vesicles was seen with M148, a monoclonal antibody to IIb/IIIa, while no inhibition was observed with a panel of other anti-IIb/IIIa monoclonal antibodies. This suggests that a specific site on the complex or orientation of the complex is essential for calcium channel function. These data demonstrate that the GPIIb/IIIa complex can serve as a passive Ca2+ channel across a phospholipid bilayer and has the potential to play a role in Ca2+ flux across the platelet plasma membrane.  相似文献   
58.
59.
60.
The plasma membrane of cardiac myocytes presents complex invaginations known as the transverse-axial tubular system (TATS). Despite TATS's crucial role in excitation-contraction coupling and morphological alterations found in pathological settings, TATS's electrical activity has never been directly investigated in remodeled tubular networks. Here we develop an ultrafast random access multiphoton microscope that, in combination with a customly synthesized voltage-sensitive dye, is used to simultaneously measure action potentials (APs) at multiple sites within the sarcolemma with submillisecond temporal and submicrometer spatial resolution in real time. We find that the tight electrical coupling between different sarcolemmal domains is guaranteed only within an intact tubular system. In fact, acute detachment by osmotic shock of most tubules from the surface sarcolemma prevents AP propagation not only in the disconnected tubules, but also in some of the tubules that remain connected with the surface. This indicates that a structural disorganization of the tubular system worsens the electrical coupling between the TATS and the surface. The pathological implications of this finding are investigated in failing hearts. We find that AP propagation into the pathologically remodeled TATS frequently fails and may be followed by local spontaneous electrical activity. Our findings provide insight on the relationship between abnormal TATS and asynchronous calcium release, a major determinant of cardiac contractile dysfunction and arrhythmias.  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