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排序方式: 共有390条查询结果,搜索用时 15 毫秒
71.
As there is no effective systemic therapy for advanced hepatocellular carcinoma (HCC), we investigated the presence of receptors for somatostatin, bombesin and luteinizing hormone-releasing hormone (LHRH) in SK-Hep-1 human hepatic carcinoma and the effects of cytotoxic analogs of somatostatin (AN-238), bombesin (AN-215) and LHRH (AN-207) on the growth of this tumor. Nude mice bearing SK-Hep-1 HCCs were treated with AN-238, AN-215, AN-207 and their combination, or cytotoxic radical 2-pyrrolinodoxorubicin (AN-201). Tumor growth reduction was determined and cell proliferation characteristics and apoptosis were studied by histologic analysis. The expression of receptors for somatostatin, bombesin and LHRH was investigated by radioreceptor assays and immunohistochemistry. High-affinity binding sites for somatostatin, bombesin and LHRH were detected in SK-Hep-1 cancers. All three cytotoxic peptide analogs inhibited growth of SK-Hep-1 tumors and decreased the cell proliferation rate. Combination therapy with two or three cytotoxic analogs resulted in the strongest tumor inhibition. Receptors for somatostatin, bombesin and LHRH are expressed in SK-Hep-1 human HCC. Cytotoxic peptide analogs targeted to these receptors inhibit growth of this tumor. Targeting to multiple receptors enhances the efficacy of therapy. The results of our study encourage additional experimental investigations to permit the introduction of these cytotoxic analogs into clinical trials. 相似文献
72.
High-affinity desensitization (HAD) by nanomolar agonists was described to shape the ability of P2X(3) receptors for mediating pain sensation. These receptors are activated by micromolar ATP, but nanomolar ATP is sufficient to effectively desensitize them. The mechanism behind HAD is still obscure. It has been suggested ( J Neurosci 25: 7359-7365, 2005 ) that HAD can happen only if the receptor has previously been activated and desensitized by high agonist concentrations. It was not clear, however, whether the high-affinity site was different from the conventional binding site and which mechanism led to its exposure during desensitization. A subsequent article ( Mol Pharmacol 70: 373-382, 2006 ) argued that HAD could also occur without preceding desensitization, because even resting receptors expose high-affinity binding sites. To support this hypothesis, a kinetic model was proposed that could reproduce all major phenomena observed experimentally. We attempted to improve this model and used it to simulate the agonist-induced formation of the high-affinity binding site. We collected electrophysiological data using HEK 293 cells expressing human P2X(3) receptors and fitted simulated currents to experimentally acquired currents. A simple allosteric kinetic model in which only triliganded receptors could open failed to reproduce receptor behavior; introduction of an additional diliganded open state was necessary. Simulation with this model gave results that were in good agreement with experimental data. By using simulations and experiments, we analyzed the process of high-affinity binding site formation upon agonist exposure and propose an explanation, which helps to resolve the apparent conflict regarding the mechanism of HAD. 相似文献
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Philippa J. Karoly Juan Romero Mark J. Cook Dean R. Freestone Daniel M. Goldenholz 《Epilepsia》2019,60(9):e99-e103
Individual seizure rates are highly volatile, with large fluctuations from month‐to‐month. Nevertheless, changes in individual mean seizure rates are used to measure whether or not trial participants successfully respond to treatment. This study aims to quantify the challenges in identifying individual treatment responders in epilepsy. A power calculation was performed to determine the trial duration required to detect a significant 50% decrease in seizure rates (P < .05) for individuals. Seizure rate simulations were also performed to determine the number of people who would appear to be 50% responders by chance. Seizure rate statistics were derived from long‐term seizure counts recorded during a previous clinical trial for an implantable seizure monitoring device. We showed that individual variance in monthly seizure rates can lead to an unacceptably high false‐positive rate in the detection of individual treatment responders. This error rate cannot be reduced by increasing the trial population; however, it can be reduced by increasing the duration of clinical trials. This finding suggests that some drugs may be incorrectly evaluated as effective; or, conversely, that helpful drugs could be rejected based on 50% response rates. It is important to pursue more nuanced approaches to measuring individual treatment response, which consider the patient‐specific distributions of seizure rates. 相似文献
76.
Pansuriya TC Oosting J Verdegaal SH Flanagan AM Sciot R Kindblom LG Hogendoorn PC Szuhai K Bovée JV 《Genes, chromosomes & cancer》2011,50(9):673-679
Ollier disease and Maffucci syndrome are rare, nonhereditary skeletal disorders characterized by the presence of multiple enchondromas with (Maffucci) or without (Ollier) co-existing multiple hemangiomas of soft tissue. Enchondromas can progress toward central chondrosarcomas. PTH1R mutations are found in a small subset of Ollier patients. The genetic deficit in Maffucci syndrome is unknown. Here, we report the first genome-wide analysis using Affymetrix SNP 6.0 array on Maffucci enchondromas (n = 4) and chondrosarcomas (n = 2) from four cases. Results were compared to a previously studied cohort of Ollier patients (n = 37). We found no loss of heterozygosity (LOH) or common copy number alterations shared by all enchondromas, with the exception of some copy number variations. As expected, chondrosarcomas were found to have multiple genomic imbalances. This is similar to conventional solitary and Ollier-related enchondromas and chondrosarcomas and supports the multistep genetic progression model. Expression profiling using Illumina BeadArray-v3 chip revealed that cartilaginous tumors in Maffucci patients are more similar to such tumors in Ollier patients than to sporadic cartilage tumors. Point mutations in a single gene or other copy number neutral genomic changes might play a role in enchondromagenesis. 相似文献
77.
Kálmán Toth István Barna György Nagy Karoly Wellinger Gyöngyi Horvath Tamas Bender 《Clinical rheumatology》2011,30(4):537-540
The goal of this study is to determine and compare the β-endorphin levels in the synovial fluid of patients with different
joint disorders (avascular necrosis, AVN; osteoarthritis, OA; and rheumatoid arthritis, RA of the hip or knee). Eighty-seven
patients were involved in our study with an average age of 62 years. Thirty-three patients had AVN (18 hips, 15 knees). Twenty-three
patients were diagnosed with OA (14 hips, 9 knees), and 31 patients suffered from RA (12 hips, 19 knees). We measured the
β-endorphin levels of the synovial fluids -harvested from surgery—with radioimmunoassay. No significant difference was found
in the β-endorphin levels of the synovial fluid from AVN comparing to OA and RA, however β-endorphin level was significantly
higher in RA group than among patients with OA (p = 0.01). Synovial β-endorphin level was slightly lower in knee comparing to hip joint p = (0.06). When examining the different joints separately in compliance with diagnoses, we concluded that the synovial β-endorphin
level from AVN was between the values of OA and RA without significant difference, whereas it was significantly higher in
the knee of RA, than of OA groups (p = 0.05 knee, p = 0.2 hip). Our results confirmed those experiments which stated that there is a significant increase in synovial β-endorphin
level in patients with inflammatory autoimmune diseases (e.g., RA), comparing to the level measured in degenerative conditions
(e.g., OA). 相似文献
78.
Adult hippocampal slice cultures were used in the modeling of apoptotic aspects of neurodegeneration. Slice viability was determined by the use of trypan blue (TB) staining, and apoptosis was assessed by caspase-3 immunohistochemistry. A large number of pyramidal cells showed signs of degeneration 30 min after sectioning (58.4% of the total number of pyramidal cells), as they exhibited TB uptake, and about 71.6% of these neurons became stained by the third day in culture, when patches in the stratum oriens also demonstrated distinct TB staining. By the sixth day of culturing, almost all cells in the pyramidal cell layer became TB positive (88.4%). The caspase-3 immunoreactivity displayed a different pattern, as the most intense immunoreactivity, detected mainly in the pyramidal cells, peaked 6 h after culturing, and then decreased steadily. The present data show that in adult hippocampal slices a large number of pyramidal cells initiate apoptotic processes as a result of irreparable damage sustained during slice preparation and culture maintenance, and support the notion that apoptosis is an integral part of the neurodegenerative processes not only in vivo but also in vitro. Elucidation of mechanisms for the apoptotic processes in adult hippocampal slice cultures could lead to the development of new therapeutic strategies; moreover, the utilization of adult hippocampal slice cultures could be a viable alternative technique to in vivo experiments in studying the mechanisms responsible for neurodegeneration. 相似文献
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