499 research outputs found

    p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer.

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    Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. The expression of P-gp is associated in vitro and in vivo with cross-resistance to several anti-cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug resistance. Interestingly, in vitro experiments have shown that mutant p53 can activate the promoter of the MDR1 gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in primary breast cancer cells and analysed the impact of the co-expression on patients prognosis. Immunohistochemistry was used to investigate P-gp expression (JSB-1, C219) and nuclear p53 accumulation (DO-7) in 20 operable chemotherapy untreated and 30 locally advanced breast cancers undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. Double immunostaining showed that P-gp expression and nuclear p53 accumulation often occur concomitantly in the same tumour cells. A correlation between p53 and P-gp expression was found in all 50 breast cancers (P = 0.003; Fisher's exact test). P-gp expression, nuclear p53 accumulation, and co-expression of p53 and P-gp were more frequently observed in locally advanced breast cancers than in operable breast cancers (P = 0.0004, P = 0.048; P = 0.002 respectively. Fisher's exact test). Co-expression of p53 and P-gp was the strongest prognostic factor for shorter survival by multivariate analysis (P = 0.004) in the group of locally advanced breast cancers (univariate analysis: P = 0.0007). Only 3 out of 13 samples sequentially taken before and after chemotherapy displayed a change in P-gp or p53 staining. In conclusion, nuclear p53 accumulation is often associated with P-gp expression in primary breast cancer, and simultaneous expression of p53 and P-gp is associated with shorter survival in locally advanced breast cancer patients. Co-expression of P-gp and mutant p53 belong to a series of molecular events resulting in a more aggressive phenotype, drug resistance and poor prognosis

    Proximity Dimensions and Scientific Collaboration among Academic Institutions in Europe: The Closer, the Better?

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    The main objective of this paper is to examine the effect of various proximity dimensions (geographical, cognitive, institutional, organizational, social and economic) on academic scientific collaborations (SC). The data to capture SC consists of a set of co-authored articles published between 2006 and 2010 by universities located in EU-15, indexed by the Science Citation Index (SCI Expanded) of the ISI Web of Science database. We link this data to institution-level information provided by the EUMIDA dataset. Our final sample consists of 240,495 co-authored articles from 690 European universities that featured in both datasets. Additionally, we also retrieved data on regional R&D funding from Eurostat. Based on the gravital equation, we estimate several econometrics models using aggregated data from all disciplines as well as separated data for Chemistry & Chemical Engineering, Life Sciences and Physics & Astronomy. Our results provide evidence on the substantial role of geographical, cognitive, institutional, social and economic distance in shaping scientific collaboration, while the effect of organizational proximity seems to be weaker. Some differences on the relevance of these factors arise at discipline level

    Pre-approval and post-approval availability of evidence and clinical benefit of conditionally approved cancer drugs in Europe: a comparison with standard approved cancer drugs

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    Aims: Cancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post-approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown. Methods: We identified all CMA cancer indications converted to SMA in 2006ā€“2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post-approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses. Results: We included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post-approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P =.31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57ā€“3.4). Conclusion: While CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA

    An Assessment of the UKā€™s Trade with Developing Countries under the Generalised System of Preferences

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    The European Union (EU) Generalised System of Preferences (GSP Scheme) grants preferential treatment to 88 eligible countries. There are, however, concerns that the restrictive features (such as Rules of Origin, Low Preference Margin and Low Coverage) of the existing scheme indicate gravitation towards commercial trade agenda to which efficiency imperatives appear subordinated. Whether these concerns are genuine is an empirical question whose answer largely determines whether, after Brexit, the UK continues with the existing specifics of the EU scheme or develops a more inclusive UK-specific GSP framework. This study quantitatively examines the efficiency of the EU GSP as it relates to UK beneficiaries from 2014 to 2017. We draw on the descriptive efficiency estimation (The utilisation Rate, Potential Coverage Rate, and the Utility Rate) using import data across 88 beneficiary countries and agricultural products of the Harmonised System Code Chapter 1 to 24. Asides the Rules of Origin that, generally, harm the uptake of GSP, low preference margin is found to cause low utilisation rates in a non-linear manner. Essentially, a more robust option (such that allows ā€œglobal Cumulationā€ or broader product coverage) could, substantially, lower the existing barriers to trade and upsurge the efficiency of the GSP scheme
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