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21.
A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells
Alessia Garufi Daniela Trisciuoglio Manuela Porru Carlo Leonetti Antonella Stoppacciaro Valerio D’Orazi Maria Laura Avantaggiati Alessandra Crispini Daniela Pucci Gabriella D’Orazi 《Journal of experimental & clinical cancer research : CR》2013,32(1):72
Background
Mutations of the p53 oncosuppressor gene are amongst the most frequent aberration seen in human cancer. Some mutant (mt) p53 proteins are prone to loss of Zn(II) ion that is bound to the wild-type (wt) core, promoting protein aggregation and therefore unfolding. Misfolded p53 protein conformation impairs wtp53-DNA binding and transactivation activities, favouring tumor growth and resistance to antitumor therapies. Screening studies, devoted to identify small molecules that reactivate mtp53, represent therefore an attractive anti-cancer therapeutic strategy. Here we tested a novel fluorescent curcumin-based Zn(II)-complex (Zn-curc) to evaluate its effect on mtp53 reactivation in cancer cells.Methods
P53 protein conformation was examined after Zn-curc treatment by immunoprecipitation and immunofluorescence assays, using conformation-specific antibodies. The mtp53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The intratumoral Zn-curc localization was evaluated by immunofluorescence analysis of glioblastoma tissues of an ortothopic mice model.Results
The Zn-curc complex induced conformational change in p53-R175H and -R273H mutant proteins, two of the most common p53 mutations. Zn-curc treatment restored wtp53-DNA binding and transactivation functions and induced apoptotic cell death. In vivo studies showed that the Zn-curc complex reached glioblastoma tissues of an ortothopic mice model, highlighting its ability to crossed the blood-tumor barrier.Conclusions
Our results demonstrate that Zn-curc complex may reactivate specific mtp53 proteins and that may cross the blood-tumor barrier, becoming a promising compound for the development of drugs to halt tumor growth. 相似文献22.
Stela Vujosevic M. Margarita Parra M. Elizabeth Hartnett Louise OToole Alessia Nuzzi Celeste Limoli Edoardo Villani Paolo Nucci 《Eye (London, England)》2023,37(2):203
The retina and the optic nerve are considered extensions of the central nervous system (CNS) and thus can serve as the window for evaluation of CNS disorders. Spectral domain optical coherence tomography (OCT) allows for detailed evaluation of the retina and the optic nerve. OCT can non-invasively document changes in single retina layer thickness and structure due to neuronal and retinal glial cells (RGC) modifications in systemic and local inflammatory and neurodegenerative diseases. These can include evaluation of retinal nerve fibre layer and ganglion cell complex, hyper-reflective retinal spots (HRS, sign of activated microglial cells in the retina), subfoveal neuroretinal detachment, disorganization of the inner retinal layers (DRIL), thickness and integrity of the outer retinal layers and choroidal thickness. This review paper will report the most recent data on the use of OCT as a non invasive imaging biomarker for evaluation of the most common systemic neuroinflammatory and neurodegenerative/neurocognitive disorders in the adults and in paediatric population. In the adult population the main focus will be on diabetes mellitus, multiple sclerosis, optic neuromyelitis, neuromyelitis optica spectrum disorders, longitudinal extensive transverse myelitis, Alzheimer and Parkinson diseases, Amyotrophic lateral sclerosis, Huntington’s disease and schizophrenia. In the paediatric population, demyelinating diseases, lysosomal storage diseases, Nieman Pick type C disease, hypoxic ischaemic encephalopathy, human immunodeficiency virus, leukodystrophies spinocerebellar ataxia will be addressed.Subject terms: Retina, Prognostic markers, Retinal diseases, Predictive markers 相似文献
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Emmanuel de Billy Marsha Pellegrino Domenico Orlando Giulia Pericoli Roberta Ferretti Pietro Businaro Maria Antonietta Ajmone-Cat Sabrina Rossi Lucia Lisa Petrilli Nicola Maestro Francesca Diomedi-Camassei Marco Pezzullo Cristiano De Stefanis Paola Bencivenga Alessia Palma Rossella Rota Francesca Del Bufalo Luca Massimi Gerrit Weber Chris Jones Andrea Carai Simona Caruso Biagio De Angelis Ignazio Caruana Concetta Quintarelli Angela Mastronuzzi Franco Locatelli Maria Vinci 《Neuro-oncology》2022,24(7):1150
BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG. 相似文献
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Yasmin R. Mohseni Adeel Saleem Sim L. Tung Caroline Dudreuilh Cameron Lang Qi Peng Alessia Volpe George Adigbli Amy Cross Joanna Hester Farzin Farzaneh Cristiano Scotta Robert I. Lechler Fadi Issa Gilbert O. Fruhwirth Giovanna Lombardi 《European journal of immunology》2021,51(10):2522-2530
Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation. 相似文献
26.
Cinzia Maria Chinnici Giovanna Russelli Matteo Bulati Vitale Miceli Alessia Gallo Rosalia Bus Rosaria Tinnirello Pier Giulio Conaldi Gioacchin Iannolo 《World journal of gastroenterology : WJG》2021,27(17):1905-1919
Due to their immunomodulatory potential and release of trophic factors that promote healing, mesenchymal stromal cells (MSCs) are considered important players in tissue homeostasis and regeneration. MSCs have been widely used in clinical trials to treat multiple conditions associated with inflammation and tissue damage. Recent evidence suggests that most of the MSC therapeutic effects are derived from their secretome, including the extracellular vesicles, representing a promising approach in regenerative medicine application to treat organ failure as a result of inflammation/fibrosis. The recent outbreak of respiratory syndrome coronavirus, caused by the newly identified agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has forced scientists worldwide to use all available instruments to fight the infection, including the inflammatory cascade caused by this pandemic disease. The use of MSCs is a valid approach to combat organ inflammation in different compartments. In addition to the lungs, which are considered the main inflammatory target for this virus, other organs are compromised by the infection. In particular, the liver is involved in the inflammatory response to SARS-CoV-2 infection, which causes organ failure, leading to death in coronavirus disease 2019 (COVID-19) patients. We herein summarize the current implications derived from the use of MSCs and their soluble derivatives in COVID-19 treatment, and emphasize the potential of MSC-based therapy in this clinical setting. 相似文献
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Rocco Spagnuolo Alessandro Corea Mariantonietta Blumetti Alessia Giovinazzo Massimiliano Serafino Caterina Pagliuso Raffaele Pagnotta Grazia Curto Cristina Cosco Vincenzo Cosco Rosellina Margherita Mancina Pietro Garieri Anna Papaleo Laura Grande Anna Barilaro Eugenio Garofalo Andrea Bruni Patrizia Doldo 《Journal of advanced nursing》2020,76(11):2993-3002
29.
La Paglia Giuliana Maria Concetta Sanchez-Pernaute Olga Alunno Alessia Martínez-Becerra Maria José Romero-Bueno Fredeswinda Recuero Sheila Borges Pablo Eder Mahillo-Fernández Ignacio Garrido Jesús Gerli Roberto Herrero-Beaumont Gabriel Naredo Esperanza 《Clinical rheumatology》2020,39(4):1207-1215
Clinical Rheumatology - This study aims to investigate ultrasound (US) findings on salivary glands (SG) in patients with Sjögren syndrome (SS) vs. other connective tissue diseases (CTDs) and... 相似文献
30.