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排序方式: 共有480条查询结果,搜索用时 15 毫秒
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Truninger K Menigatti M Luz J Russell A Haider R Gebbers JO Bannwart F Yurtsever H Neuweiler J Riehle HM Cattaruzza MS Heinimann K Schär P Jiricny J Marra G 《Gastroenterology》2005,128(5):1160-1171
BACKGROUND & AIMS: Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs. METHODS: Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene. RESULTS: An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene. CONCLUSIONS: PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed. 相似文献
54.
Daniela Di Paolo D. Yang Fabio Pastorino Laura Emionite Michele Cilli Antonio Daga Elisa Destefanis Annarita Di Fiore Francesca Piaggio Chiara Brignole Xiaobao Xu Chris Liang James Gibbons Mirco Ponzoni Patrizia Perri 《Oncotarget》2015,6(30):28774-28789
Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients.We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models.X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner.In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents.Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors. 相似文献
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The precursor of endothelin-1, big endothelin-1, can be hydrolyzed by chymase to generate endothelin-1 (1-31) in vitro. In the present study, we explored the processes involved in the production of endothelin-1 (1-31) as well as its pharmacodynamic characteristics in the rabbit in vivo. Endothelin-1 (1-31) (1 nmol/kg, injected into the left cardiac ventricle) induced a monophasic increase of mean arterial blood pressure similarly to big endothelin-1 (1-38), whereas endothelin-1 induces a biphasic response. Phosphoramidon, a dual neutral endopeptidase and endothelin-converting enzyme inhibitor, blocked both pressor responses to endothelin-1 (1-31) and big endothelin-1 but not those afforded by endothelin-1. Thiorphan, a neutral endopeptidase inhibitor, markedly inhibited the response to endothelin-1 (1-31) but only weakly reduced that of big endothelin-1. In contrast, CGS 35066, an endothelin-converting enzyme inhibitor, was significantly more efficient against the pressor response to big endothelin-1 than to endothelin-1 (1-31). Furthermore, injection of big endothelin-1 concomitantly with phosphoramidon induced an increase in endothelin-1 (1-31) plasma levels. Finally, intracardiac-administered endothelin-1 (1-31) induced an increase of endothelin-1 plasma levels, which are markedly reduced by phosphoramidon and thiorphan but not by CGS 35066. Our results thus demonstrate that endothelin-1 (1-31) is an alternate intermediate in the production of endothelin-1 after big endothelin-1 administration in the rabbit in vivo. 相似文献
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Martin Buchelt Bodo Schlangmann Stephan Schmolke Werner Siebert 《Lasers in surgery and medicine》1995,16(2):179-183
Background and Objective: As the Ho:YAG laser gained increasing importance in recent experimental and clinical investigations, this study was performed to investigate the effect of power on ablation rates and temperature during disc ablation with a high power Ho:Yag laser under simulated clinical conditions. Study Design/Materials and Methods: A high power Ho:YAG laser was used to investigate the influence of increasing power from 10 to 32 Watt on ablation rate (mg) and temperature (°C). Ablation weight was measured by a precision scale calculating the difference of the pre- and postlasing weight of the specimen after application of total energies of 1,000, 1,500, and 2,000 J. Temperatures were measured by thermoprobes, which were connected via a thermomodule to an amplifier and the signal was plotted by a computer with appropriate software. Results: Whereas ablation rate rose almost linearly with total energy, increasing power above 20 W did not essentially improve ablation rate. Temperatures reached their highest values after application of a total energy of 500 J and did not rise further, whereas increasing power did not induce a rise in temperature. Conclusions: Regarding the chosen experimental setting, maximum temperatures are reached after application of 500 J, and increasing power does not induce a rise in temperature. © 1995 Wiley-Liss, Inc. 相似文献
58.
M. Magerl J. Schmolke M. Metz T. Zuberbier F. Siebenhaar M. Maurer 《Clinical and experimental dermatology》2009,34(5):e137-e140
In dermographic urticaria (DU), shearing forces on the skin result in weals and itching. Second-generation antihistamines are recommended as the first-line treatment, but to date only a few have ever been tested for this condition. The objective of this pilot study was to assess the safety and efficacy of ebastine in preventing symptoms of DU. Seven adult patients with DU participated in a double-blind cross-over trial of ebastine 20 mg. Safety was assessed using a sensitive psychometric battery, testing cognitive performance and mood. Efficacy was assessed by rating weals, erythema, pruritus and burning after challenge. Ebastine had no negative effective on cognitive performance or mood. Weals, pruritus and burning were greatly reduced for most subjects. This pilot study suggests that ebastine is safe and effective in preventing the symptoms of DU and should be tested on a larger scale. 相似文献
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M. Schmolke W. E. Zimmermann K. F. Kilian L. Koslowski G. Hoffmann 《Langenbeck's archives of surgery / Deutsche Gesellschaft fur Chirurgie》1965,313(1):1032-1035
Ohne ZusammenfassungVortragender:M. Schmolke-Freiburg i. Br. 相似文献