ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology

Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5–KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology.This work has been supported with Grant RTI2018-094093-B-I00 funded by MCIN/AEI/10.13039/501100011033, “ERDF A way of making Europe” to RSP. Also supported with funds from Fundación Leticia Castillejo Castillo, Roche España and ACEPAIN to RSP and MJRH. RSP and MJRH’s Research Institute and the work carried out in their laboratory, received partial support from the European Community through the FEDER. JJ and EAL hold a predoctoral research contract cofounded by the European Social Fund and UCLM. OR holds a contract for accessing the Spanish System of Science, Technology, and Innovation (SECTI) funded by the University of Castilla-La Mancha (UCLM) and received partial support from the European Social Fund (FSE) through its Operative Program for Castilla-La Mancha (2007–2013

CHK1 expression in gastric cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response

This work is licensed under a Creative Commons Attribution 4.0 International License.-- et al.Radiation has a limited but relevant role in the adjuvant therapy of gastric cancer (GC) patients. Since Chk1 plays a critical function in cellular response to genotoxic agents, we aimed to analyze the role of Chk1 in GC as a biomarker for radiotherapy resistance. We analyzed Chk1 expression in AGS and MKN45 human GC cell lines by RT-QPCR and WB and in a small cohort of human patient's samples. We demonstrated that Chk1 overexpression specifically increases resistance to radiation in GC cells. Accordingly, abrogation of Chk1 activity with UCN-01 and its expression with shChk1 increased sensitivity to bleomycin and radiation. Furthermore, when we assessed Chk1 expression in human samples, we found a correlation between nuclear Chk1 accumulation and a decrease in progression free survival. Moreover, using a luciferase assay we found that Chk1's expression is controlled by p53 and RB/E2F1 at the transcriptional level. Additionally, we present preliminary data suggesting a posttranscriptional regulation mechanism, involving miR-195 and miR-503, which are inversely correlated with expression of Chk1 in radioresistant cells. In conclusion, Chk1/microRNA axis is involved in resistance to radiation in GC, and suggests Chk1 as a potential tool for optimal stratification of patients susceptible to receive adjuvant radiotherapy after surgery.This work was supported by Instituto de Salud Carlos III–Fondo de Investigación Sanitaria (PS09/1988 to ISP; PI11-00949, pI014-1495 and Feder Funds to RP); Comunidad Autónoma de Madrid-Universidad Autónoma de Madrid (CCG10-UAM/BIO-5871 to ISP); Fundación Leticia Castillejo Castillo and Ministerio de Ciencia e Innovación (SAF2012-30862 to RSP), Spain. JBI was supported by a fellowship from Catedra Isaac Costero, funded by Banco Santander UAM and is a doctoral student from a double doctorate program in Molecular Biosciences (UAM) and in Biomedical Sciences, (UNAM) and received fellowship CVU:607546 from CONACYT.Peer Reviewe

Implication of VHL, ERK5, and HIF-1alpha in clear cell renal cell carcinoma: Molecular basis

Objectives: To determine the expression status of several proteins related to VHL gene function and its relationship with common clinicopathological parameters. Material and methods: Observational, analytical, cross-sectional study with 50 patients diagnosed with clear cell renal cell carcinoma. The study analyzed VHL mutations and hypermethylation as well as protein expression of VHL, CA-IX, HIF-1alpha, VEGF, ERK1/2, and ERK5, relating them to clinical variables. A bivariate and multivariate descriptive logistical regression analysis was performed, using the presence of metastasis at diagnosis as dependent variable. Results: The study identified 13 (26%) VHL mutations related to nuclear grade (P = 0.036). VHL hypermethylation was found in 20% of cases. VHL expression was associated with the presence of mutations (P = 0.013), and the absence of expression was associated with nuclear grade and the presence of metastasis (P<0.05). HIF-1alpha was negative in only 5 cases. Vascular endothelial growth factor (VEGF) was positive in 31 of 47 cases and was associated with Fuhrman nuclear grade, presence of metastasis, and stage (P<0.05). ERK5 expression was increased in 58% of cases and associated with the presence of metastasis and more advanced stages (P<0.05). In the logistic regression analysis, the only variable remaining in the model was VEGF expression (P = 0.014). Conclusions: VEGF has prognostic value in clear cell renal cell carcinoma, and ERK5 may be a new prognostic marker in this type of tumor owing to its relationship with metastasis and more advanced stages

p38MAPK and Chemotherapy: We always need to hear both Sides of the Story

The p38MAPK signaling pathway was initially described as a stress response mechanism. In fact, during previous decades, it was considered a pathway with little interest in oncology especially in comparison with other MAPKs such as ERK1/2, known to be target of oncogenes like Ras. However, its involvement in apoptotic cell death phenomena makes this signaling pathway more attractive for many cancer research laboratories. This apoptotic role allows to establish a link between p38MAPK and regular chemotherapeutic agents such as Cisplatin or base analogs (Cytarabine, Gemcitabine or 5-Fluorouracil) which are currently used in hospitals across the world. In fact, and more recently, p38MAPK has also been connected with targeted therapies like tyrosine kinase inhibitors (vg. Imatinib, Sorafenib) and, to a lesser extent, with monoclonal antibodies. In addition, the oncogenic or tumor suppressor potential of this signaling pathway has aroused the interest of the scientific community in evaluating p38MAPK as a novel target for cancer therapy. In this review, we will summarize the role of p38MAPK in chemotherapy as well as the potential that p38MAPK inhibition can bring to cancer therapy. All the evidences suggest that p38MAPK could be a double-edged sword and that the search for the most appropriate candidate patients, depending on their pathology and treatment, will lead to a more rational use of this new therapeutic tool

Multicore fiber scenarios supporting power over fiber in radio over fiber systems

We propose the integration of power over fiber in the next generation 5G radio access network front-haul solutions based on spatial division multiplexing with multicore fibers. The different architectures in both shared- and dedicated- core scenarios for power over fiber delivery and data signals are described. The maximum power to be delivered depending on the efficiencies of the different components is addressed as well as the limits of the delivered energy to avoid fiber fuse and non-linear effects. It is shown how those limits depend on high power laser linewidth, fiber attenuation, link length and fiber core effective area. The impairments related to non-linear effects, multicore fiber crosstalk and temperature are also theoretically analyzed. Experiments show there is no degradation of signal quality for feeding powers of several hundreds of milliwatts for both scenarios in 4-core multicore fibers. This study helps in designing future power by light delivery solutions in Radio over Fiber systems with multicore fibers.This work was supported in part by the Spanish Ministry of Science, Innovation and Universities, Directorate for Research and Innovation at Madrid region, and H2020 European Union programme under Grant RTI2018-094669-B-C32 and Grant Y2018/EMT-4892, and in part by FSE and 5G PPP Bluespace project Grant 762055

Fiber-Optic Pyrometer with Optically Powered Switch for Temperature Mesurements

We report the experimental results on a new infrared fiber-optic pyrometer for very localized and high-speed temperature measurements ranging from 170 to 530 degrees C using low-noise photodetectors and high-gain transimpedance amplifiers with a single gain mode in the whole temperature range. We also report a shutter based on an optical fiber switch which is optically powered to provide a reference signal in an optical fiber pyrometer measuring from 200 to 550 degrees C. The tests show the potential of remotely powering via optical means a 300 mW power-hungry optical switch at a distance of 100 m, avoiding any electromagnetic interference close to the measuring point.This work was supported by the Spanish Ministry of Economy and Competitiveness and FEDER program under grants TEC2015-63826-C3-2-R and by Comunidad de Madrid under grant S2013/MIT-2790

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ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

© 2021 The Authors.Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5-dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.This work was supported by grants from Fundación Leticia Castillejo Castillo, Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-094093-B-I00) to RSP and MJRH. OR holds a contract for accessing the Spanish System of Science, Technology, and Innovation (SECTI) funded by the University of Castilla-La Mancha (UCLM) and received partial support from the European Social Fund (FSE) through its Operative Program for Castilla-La Mancha (2007–2013). RSP and MJRH's Research Institute, and the work carried out in their laboratory, received partial support from the European Community through the FEDER. RPS and EAL hold a research predoctoral contract cofounded by the European Social Fund and UCLM. The Spanish Ministry of Economy and Competitiveness (MINECO, Project RTI2018-096724-B-C21) and the Generalitat Valenciana (PROMETEO/2016/006) support work in the Encinar´s laboratory. Authors are grateful to Dr.G- Ferrer Mayorga for her assistance in the transwell assays, and to the ‘Centro de Computación Científica’ (CCC-UAM) for letting us to take advantage of the computer cluster Cibeles (https://www.ccc.uam.es/) and for providing computing facilities

Sistema de consulta de proyecciones regionalizadas de cambio climático para México

Los modelos de circulación general acoplados permiten proyectar el clima futuro, pero no hay un modelo único, por lo que se recurre a ensambles de varios modelos. En este trabajo se utilizó un método estadístico para obtener un ensamble usando 23 modelos de circulación general mediante el algoritmo de fiabilidad de ensamble ponderado que considera dos criterios de fiabilidad: el desempeño del modelo para reproducir el clima actual y la convergencia de los cambios proyectados entre los modelos seleccionados. Se regionalizaron los datos de precipitación, y temperaturas máxima y mínima de superficie, con los escenarios SRES-A1B y SRES-A2 para elsiglo XXI, y se incrementó su resolución espacial a una malla regular de 0.5 × 0.5° sobre México. Para facilitar el manejo de estos resultados se desarrolló un sistema, Sedepecc, que contiene las proyecciones generadas en una base de datos y las presenta a través de una interfaz amigable. El análisis de las anomalías proyectadas para el presente siglo en México indica un incremento general en temperatura y un decremento en precipitación. Los resultados indican que el cambio de la temperatura será mayor para el verano que para el invierno, acentuándose para las últimas tres décadas del presente siglo, donde los valores se proyectan por arriba de los 5 °C para algunas regiones del centro del país. Como caso de aplicación del sistema, se generaron las proyecciones de cambio climático para el distrito de riego 075, localizado en el norte del estado de Sinaloa, México