Suchergebnisse

Tools for automatic evaluation of Web accessibility are fast and responsive, but in order to ascertain the degree of actual compliance with design recommendations, they must be complemented with the personal opinion of an expert. What is required is a methodology combining manual and automatic techniques to assess accurately the level of accessibility of Web platforms. This metric should be thorough in order to follow the Web Accessibility Initiative guidelines, precise, and unambiguous. This article deals with a new questionnaire for experts offering greater objectivity and clarity in the formulation of variables, which will provide a more realistic assessment of Web accessibility and be geared to legislative requirements. Finally, it will be implemented to validate its consistency. ; Las herramientas de evaluación automática de la accesibilidad Web son un método rápido y oportuno; pero para conocer el grado de cumplimiento real de las recomendaciones de diseño es necesario complementarlo con el juicio personal de un experto. Se requiere una propuesta metodológica que combine técnicas manuales y automáticas para evaluar fidedignamente el nivel de accesibilidad de las plataformas Web. Esta métrica debe ser exhaustiva, ya que debe introducir las pautas que contempla la Web Accessibility Initiative, precisa y carente de ambigüedad. En el presente artículo, se abordará el planteamiento de un nuevo cuestionario dirigido a expertos, dotado de mayor objetividad y claridad en la formulación de las variables, que permitirá aportar una valoración más real de la accesibilidad Web y acorde con la normativa legislativa exigida. Finalmente, será implementado para ratificar su validez y consistencia.

© The Author(s). ; [Background]: Trastuzumab-based therapies are the therapeutic option for HER2 positive (HER2+) breast cancer. HER2 amplification is the only biomarker validated for trastuzumab-based therapies. However, a proportion of tumors become refractory during treatment course. For this reason, the finding of new biomarkers beyond HER2 overexpression to identify patients who would benefit most from trastuzumab regimens is of outstanding importance. ; [Methods]: Models of trastuzumab-resistant or hypersensitive cells were generated by exposure to trastuzumab. Cell surface, total HER2, and analyses of proteins involved in cell cycle or apoptosis were analyzed by western blotting. Cell proliferation was analyzed by cell counting, cell cycle and apoptosis was evaluated by FACS. Transcriptomic characterization of the cellular models was performed using bioinformatic online tools, and clinico-genomic analyses were performed using the PAMELA clinical trial data. ; [Results]: Besides differing in sensitivities to trastuzumab, the different cellular models also showed distinct response to other anti-HER2 drugs (lapatinib, neratinib, pertuzumab and T-DM1) used in the clinic. That differential effect was not due to changes in cell surface, total or activated HER2. Trastuzumab caused important induction of cell death in hypersensitive cells but not in parental or resistant cells. Transcriptomic analyses of these cellular models together with querying of online databases allowed the identification of individual genes and gene signatures that predicted prognosis and trastuzumab response in HER2+ breast cancer patients. ; [Conclusion]: The identification of trastuzumab response biomarkers may be used to select patients particularly sensitive to facilitate the use of trastuzumab-based therapies and refine follow-up guidelines in patients with HER2+ tumors. ; A Pandiella: Ministry of Economy and Competitiveness of Spain (BFU2015–71371-R), the Junta de Castilla y León (CSI146P20), the Instituto de Salud Carlos III through CIBERONC, the Scientific Foundation of the Spanish Association Against Cancer (AECC), ALMOM, ACMUMA and the CRIS Cancer Foundation. LDG is recipient of a predoctoral contract of the Consejería de Educación of the Castilla y León Autonomous Government. Work carried out in our laboratory receives support from the European Community through the Regional Development Funding Program (FEDER). FBM: Fundación Científica Asociación Española Contra el Cáncer AECC_Postdoctoral17–1062

8 páginas, 4 figuras, 4 tablas. ; [Background]: Breast cancer is the most common neoplasia in women. Even though advances in its treatment have improved disease outcome, some patients relapse. Therefore, attempts to better define the molecular determinants that drive breast cancer cell proliferation may help in defining potential therapeutic targets. Mitogen-activated protein kinases (MAPK) play important roles in tumorigenesis. One of them, Erk5, has been linked to the proliferation of breast cancer cells in vitro. Here we have investigated the expression and prognostic value of Erk5 in human breast cancer. ; [Methodology/Principal Findings]: Animal and cellular models were used to study Erk5 expression and function in breast cancer. In 84 human breast tumours the expression of Erk5 was analyzed by immunohistochemistry. Active Erk5 (pErk5) was studied by Western blotting. Correlation of Erk5 with clinicopathological parameters and with disease-free survival in early stage breast cancer patients was analyzed. Expression of Erk5 was detected in most patients, and overexpression was found in 20%. Active Erk5 was present in a substantial number of samples, as well as in tumours from an animal breast cancer model. Overexpression of Erk5 was associated with a decrease in disease-free survival time, which was independent of other clinicopathological parameters of prognosis. Transient transfection of a short hairpin RNA (shRNA) targeting Erk5, and a stable cell line expressing a dominant negative form of Erk5 (Erk5AEF), were used to investigate the influence of Erk5 on drugs used in the clinic to treat breast tumours. We found that inhibition of Erk5 decreased cancer cell proliferation and also sensitized these cells to the action of anti-HER2 therapies. ; [Conclusions/Significance]: Overexpression of Erk5 is an independent predictor of disease-free survival in breast cancer, and may represent a future therapeutic target. ; This work was supported by a grant from the Ministry of Science and Education of Spain (BFU2006-01813/BMC to AP), the Instituto de Salud Carlos III (PI061552), and by the Castilla y Leon Autonomous Government (to AEO). ; Peer reviewed

© 2021 by the authors. ; [Background]: Tribbles pseudokinase 3 (TRIB3) has been proposed to both promote and restrict cancer generation and progression. However, the precise mechanisms that determine this dual role of TRIB3 in cancer remain to be understood. In this study we aimed to investigate the role of TRIB3 in luminal breast cancer, the most frequent subtype of this malignancy. [Methods]: We genetically manipulated TRIB3 expression in a panel of luminal breast cancer cell lines and analyzed its impact on cell proliferation, and the phosphorylation, levels, or subcellular localization of TRIB3 and other protein regulators of key signaling pathways in luminal breast cancer. We also analyzed TRIB3 protein expression in samples from luminal breast cancer patients and performed bioinfor-matic analyses in public datasets. Results: TRIB3 enhanced the proliferation and AKT phosphoryla-tion in luminal A (HER2-) but decreased them in luminal B (HER2+) breast cancer cell lines. TRIB3 negatively regulated the stability of HER2 in luminal B breast cancer cell lines. TRIB3 expression was associated with increased disease-free survival and a better response to therapy in luminal breast cancer patients. [Conclusions]: Our findings support the exploration of TRIB3 as a potential biomarker and therapeutic target in luminal breast cancer. ; This work was funded by the Instituto de Salud Carlos III (ISCIII) and confounded by the European Regional Development Fund (ERDF), "A way to make Europe", grant number PI18/00442 integrated into the State Plan for R & D + I 2017-2020; by the European Commission through the Horizon 2020 European Training Networks program, grant number H2020-MSCA-ITN308 2016 721532; and by the Breast Cancer Now (formerly Breast Cancer Campaign) foundation, grant number 2012NovSP033. Alba Orea-Soufi was supported by a predoctoral FPU contract from Spanish Government. Work in SC-L group is supported by a MINECO/FEDER research grant RTI2018-094130-B-100.