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51.
Larsson R Mongan NP Johansson M Shcherbina L Abrahamsson PA Gudas LJ Sterner O Persson JL 《Current medicinal chemistry》2011,18(29):4440-4453
Recurrent prostate cancer (PCa) remains a major clinical challenge. Invasive and metastatic PCa lesions often exhibit a partial and time-limited response to therapy before the cancer progresses and the patient succumbs to the disease. Despite recent advances in early diagnosis and treatment, approximately one-third of treated patients will relapse and become resistant to currently available treatments. In this review we evaluate current treatment practices and recent advances in therapy for localized prostate malignancy and advanced, metastatic prostate cancer. Some of the promising new drugs for PCa treatment include MDV3100, an androgen receptor (AR) antagonist that prevents androgens from binding to the AR and nuclear translocation and co-activator recruitment of the ligand-receptor complex; abiraterone, an orally administered drug that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17; and several newer cytotoxic drugs (epothilones, satraplatin). Key new insights are that cancer stem cells play a role in PCa and that PCa cells are dependent on the AR for proliferation, even in the hormone refractory state of the disease. We also discuss potential molecular targets for new drug candidates for the treatment of metastatic PCa. 相似文献
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Kevin A David Nigel P Mongan Christopher Smith Lorraine J Gudas David M Nanus 《Cancer biology & therapy》2010,9(9):678-684
Retinoic acid derivatives have shown their greatest benefit in acute promyelocytic leukemia, but have also demonstrated pre-clinical anti-cancer effects in some solid tumors. Histone deacetylase inhibitors, by upregulating gene expression, are able to limit cancer cell proliferation and induce apoptosis. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid has been previously studied in hematologic malignancies. We conducted a Phase I two-step dose escalation trial of the liposomal ATRA analog ATRA-IV and divalproex sodium (Depakote®) in nine patients with advanced solid tumors refractory to prior therapy. Side effects attributed to therapy had a severity ≤grade 2 and included skin toxicity and thrombocytopenia. The best disease response seen was disease stabilization in one patient. Expression of cellular retinoic acid binding protein-2 in peripheral blood mononuclear cells was detected as a marker of drug effect. The maximum tolerated dose (MTD) of both drugs in combination could not be established due to early closure of the trial resulting from a halt in the commercial availability of ATRA-IV.Key words: ATRA, valproic acid, Phase I trial, histone deacetylase inhibitors, cancer 相似文献
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Retinoic acid, a natural derivative of vitamin A (retinol), induces mouse F9 teratocarcinoma stem cells to differentiate into nontumorigenic parietal endoderm cells. The mouse cellular retinoic acid binding protein (CRABP) has been implicated in the mechanism of action of retinoic acid (RA), since a mutant F9 cell line, RA-3-10, which possesses less than 5% of the wild type level of [3H]RA:CRABP binding activity, fails to differentiate in response to RA. In order to study the CRABP in this RA-induced differentiation process, we have cloned and sequenced the full-length mouse CRABP complementary DNA and have characterized its expression in wild type F9 and mutant cells. The mouse CRABP mRNA is a single, low abundant mRNA approximately 800 bases in length. The steady state level of the CRABP mRNA was measured in untreated stem cells and after the addition of RA alone, dibutyryl cyclic AMP plus theophylline (CT), or retinoic acid, dibutyryl cyclic AMP and theophylline (RACT) to F9 wild type and the mutant RA-3-10 cells. The CRABP mRNA was present in wild type F9 stem cells, and the level of its expression was changed by RA. When RA was added to F9 wild type cells, the steady state level of CRABP mRNA decreased 2- to 3-fold. When RACT was added to wild type cells, the level of CRABP mRNA increased and then decreased, resulting in a peak of CRABP mRNA expression between 24 and 48 h. In contrast, untreated mutant RA-3-10 cells had a lower level of CRABP mRNA than wild type stem cells, and the mutant cells responded quite differently to the addition of RA and RACT. The addition of RA caused an impressive 60-fold increase in the steady state level of CRABP mRNA in RA-3-10 cells by 120 h. One interpretation of this result is that there is negative regulation of CRABP mRNA expression, mediated directly or indirectly by the wild type functional CRABP protein, and that this regulation is aberrant in the RA-3-10 cells. 相似文献
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Lorraine J. Gudas Amos Cohen Buddy Ullman David W. Martin Jr. 《Somatic Cell and Molecular Genetics》1978,4(2):201-219
Using the S49 T-cell lymphoma system for the study of immunodeficiency diseases, we characterized several variants in purine salvage and transport pathways and studied their responses to the cytotoxic action of adenosine (5–20 M) in the presence of adenosine deaminase (ADA) inhibitors. Both an adenosine transport deficient mutant and a mutant lacking adenosine (ado) kinase activity are resistant to the cytotoxic effects of adenosine up to 15 M. Variants lacking hypoxanthine-guanine phosphoribosyl transferase or adenine phosphoribosyltransferase are sensitive to the killing action of adenosine. We monitored the intracellular concentrations of purine and pyrimidine nucleotides, orotate, and PPribose P in mutant and wild-type cells following the addition of adenosine and an ADA inhibitor. We conclude that at low concentrations, adenosine must be phosphorylated to deplete the cell of pyrimidine nucleotides and PPribose P and to promote the accumulation of orotate. These alterations account for one mechanism of adenosine toxicity. 相似文献
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Challita-Eid PM Morrison K Etessami S An Z Morrison KJ Perez-Villar JJ Raitano AB Jia XC Gudas JM Kanner SB Jakobovits A 《Cancer research》2007,67(12):5798-5805
Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a novel cell surface protein highly expressed in primary prostate cancer, with restricted expression in normal tissues. In this report, we show STEAP-1 expression in prostate metastases to lymph node and bone and in the majority of human lung and bladder carcinomas. We identify STEAP-1 function in mediating the transfer of small molecules between adjacent cells in culture, indicating its potential role in tumor cell intercellular communication. The successful generation of two monoclonal antibodies (mAb) that bind to cell surface STEAP-1 epitopes provided the tools to study STEAP-1 susceptibility to naked antibody therapy. Both mAbs inhibited STEAP-1-induced intercellular communication in a dose-dependent manner. Furthermore, both mAbs significantly inhibited tumor growth in mouse models using patient-derived LAPC-9 prostate cancer xenografts and established UM-UC-3 bladder tumors. These studies validate STEAP-1 as an attractive target for antibody therapy in multiple solid tumors and provide a putative mechanism for mAb-induced tumor growth inhibition. 相似文献
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Identification of Ethanol and 4‐Nitroquinoline‐1‐Oxide Induced Epigenetic and Oxidative Stress Markers During Oral Cavity Carcinogenesis 下载免费PDF全文
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