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High-risk neuroblastoma, a predominantly TP53 wild-type (wt) tumour, is incurable in >50% patients supporting the use of MDM2 antagonists as novel therapeutics. Idasanutlin (RG7388) shows in vitro synergy with chemotherapies used to treat neuroblastoma. This is the first study to evaluate the in vivo efficacy of the intravenous idasanutlin prodrug, RO6839921 (RG7775), both alone and in combination with temozolomide in TP53 wt orthotopic neuroblastoma models. Detection of active idasanutlin using liquid chromatography-mass spectrometry and p53 pathway activation by ELISA assays and Western analysis showed peak plasma levels 1 h post-treatment with maximal p53 pathway activation 3–6 h post-treatment. RO6839921 and temozolomide, alone or in combination in mice implanted with TP53 wt SHSY5Y-Luc and NB1691-Luc cells showed that combined RO6839921 and temozolomide led to greater tumour growth inhibition and increase in survival compared to vehicle control. Overall, RO6839921 had a favourable pharmacokinetic profile consistent with intermittent dosing and was well tolerated alone and in combination. These preclinical studies support the further development of idasanutlin in combination with temozolomide in neuroblastoma in early phase clinical trials.  相似文献   
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Digestive Diseases and Sciences - Inadequate bowel preparation (IBP) is associated with reduced adenoma detection. However, limited research has examined the impact of different commercial bowel...  相似文献   
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Cyclooxygenase‐2 (COX‐2) and its metabolic product prostaglandin E2 (PGE2) are induced in response to growth factors, inflammatory cytokines, tumor promoters, activated oncogenes, and, in the skin, ultraviolet (UV) radiation. Accumulating evidence suggests a role for the COX‐2/PGE2 pathway in tumorigenesis in various tissue types including cutaneous squamous cell carcinoma. There is also strong evidence for a role in the development of actinic keratoses (AKs) — common dysplastic lesions of the skin associated with UV radiation overexposure — considered as part of a continuum with skin cancer. Non‐steroidal anti‐inflammatory drugs (NSAIDs) exert their anti‐inflammatory, analgesic, and antipyretic effects by reversibly or irreversibly acetylating COX isoforms, inhibiting downstream prostaglandins, and may have a chemopreventive role in malignancies, including skin cancer. Topical treatment of AK lesions with the NSAID diclofenac sodium 3% in combination with hyaluronic acid 2.5% has been shown to be effective and well tolerated, although the mechanism of action remains to be elucidated.  相似文献   
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R. Higgins  F. Murphy  P. Hogg 《Radiography》2021,27(2):539-545
IntroductionAs part of the BSc (Hons) Diagnostic Radiography programme students learn and undertake research relevant to their development as first post radiographers (dose optimisation and image quality) within the Research-Informed Teaching experience (RiTe). Due to the COVID-19 pandemic, the delivery of RiTe to our year 2 students was moved to an online format using Microsoft Teams and Blackboard Collaborate and focused on a key area of current practice - COVID-19 and chest X-ray imaging. Within RiTe students are placed into collaborative enquiry-based learning (CEBL) groups to share tasks, but to also support and learn from one another.MethodsAn online survey was used to explore the year 2 student cohort task value and self-efficacy of this online version of RiTe.ResultsA 73% (32/44) response rate was achieved. Students found the online version of RiTe to be a positive learning and development experience. There was strong agreement that they not only found it relevant to their area of practice (task-value), but also strongly agreed that they understood and could master the skills taught (self-efficacy).ConclusionThis online version of RiTe was effectively structured to help scaffold student learning and development of research data analysis skills despite the lack of face-to-face teaching. The students also valued the topic area (COVID-19 and chest X-ray imaging). A blended learning approach with RiTe will be used next year with a combination of collaborative online teaching and physical data collection and analysis in the university-based X-ray imaging laboratory. Further evaluation and data collection will also be undertaken.Implications for practiceUniversity-based empirical work in groups to learn about research can be replaced by an online mechanism whilst still maintaining task-value and acceptable self-efficacy.  相似文献   
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