Quimioembolización en el hepatocarcinoma. Análisis de supervivencia en 37 pacientes en el HCU Lozano Blesa

Objetivo: Valorar la supervivencia de los pacientes con hepatocarcinoma (HCC) tratado mediante 1, 2 o más de 2 sesiones de quimioembolización transarterial (transarterial chemoembolization, TACE) en el Hospital Clínico Universitario (HCU) Lozano Blesa (febrero 2010 - mayo 2015). Materiales y Métodos: Se realizó una revisión bibliográfica del HCC y de la TACE, así como revisión de la base de datos del HCU de 38 pacientes con HCC tratados con TACE, valorando la supervivencia en función del número de sesiones realizadas y la respuesta al tratamiento mediante pruebas de imagen. Resultados: El número mínimo de sesiones de TACE fue 1 y un 50 % de los pacientes habían recibido terapia complementaria a la TACE. Tras la segunda TACE, se valoró la respuesta al tratamiento mediante los criterios mRECIST (modified Response Evaluation Criteria in Solid Tumors), contando con un total de 33 pacientes, obteniéndose en un 45 % una respuesta completa. En aquellos pacientes que recibieron más de 2 TACEs (27), se produjo respuesta completa en el 41 %. La supervivencia fue mayor en aquellos pacientes que recibieron 2 o más de 2 TACEs respecto a los que recibieron 1 sola sesión. Se apreciaron diferencias estadísticamente significativas en la supervivencia de los pacientes que se sometieron a TACE como tratamiento único o TACE más TOH (Trasplante Ortotópico Hepático); sin embargo no se detectaron diferencias significativas en los pacientes que recibieron TACE junto con tratamiento ablativo respecto a los que recibieron TACE. Conclusiones: La TACE mejora la supervivencia de los pacientes en estadio B de la BCLC (Barcelona Clinic Liver Cancer) o estadio A no candidatos a cirugía ni ablación y ayuda a evitar la progresión de la enfermedad en aquellos que se encuentran en lista de espera para TOH

Limitations in conventional identification of filamentous morphotype Nostocoida limicola II in activated sludges

[EN] Excessive growth of filamentous bacteria causes bulking and foaming in activated sludge wastewater treatment plants (WWTP). One of the most common bacterial group responsible of these operational problems is known as Nostocoida limicola morphotype. The different ecophysiology of bacteria that represent N. limicola, especially those that are found within N. limicola II, suggests that the measures corrective to control the exccesive growth can be different. Therefore, the conventional identification might place lead to a wrong decision in the WWTP. The main aim of this study was to identify and estimate the abundance of the different species of N. limicola II in three WWTP from the Comunidad Valenciana (Spain) using the fluorescence in situ hybridization technique (FISH). The results have enabled us to determine their frequency depending on the different variables of the process control, suggesting that the identification of N. limicola II with the conventional technique would be unsuitable for further decision making in the WWTP, being the most appropriate the FISH technique.[ES] El crecimiento excesivo de bacterias filamentosas en fangos activos origina episodios de bulking y foaming en las estaciones depuradoras de aguas residuales (EDAR). Entre las bacterias más comunes causantes de dichos episodios se encuentran aquellas denominadas bajo el morfotipo Nostocoida limicola. La diversa ecofisiología de las bacterias que representan N. limicola, especialmente aquellas que se engloban dentro de N. limicola II, sugiere que las medidas correctoras a tomar pueden ser distintas y, por tanto, la identificación convencional llevar a una incorrecta toma de decisiones en la EDAR. Por ello, el objetivo principal de este estudio ha sido identificar y valorar la abundancia de las distintas especies de N. limicola II en tres EDAR de la Comunidad Valenciana, empleando para ello la técnica de hibridación in situ con sondas 16S/23S rDNA marcadas con fluoróforos (FISH). Los resultados han permitido determinar su frecuencia de aparición en función de las distintas variables de control del proceso, sugiriendo que la identificación de N. limicola II a través de la técnica convencional sería inadecuada para la posterior toma de decisiones en la EDAR, siendo la técnica FISH la más adecuada en estos casos.Este estudio forma parte del proyecto de investigación 'Estudio integrado del proceso de fangos activos', financiado por la Entidad Pública de Saneamiento de Aguas Residuales de la Comunidad Valenciana (EPSAR). Los autores agradecen la colaboración de las empresas de explotación AvsaEgevasa, DAM, Facsa y OMS-Sacede.Calvo Garcia, S.; Zornoza-Zornoza, AM.; Alonso Molina, JL. (2016). Limitaciones en la identificación convencional del morfotipo filamentoso Nostocoida limicola II en fangos activos. Tecnoaqua. 18:40-49. http://hdl.handle.net/10251/98070S40491

Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP.

Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk.We thank Miguel Sánchez for text editing. We thank Erika R. Geisbrecht, Kenneth Irvine, and Ariberto Fassati for kindly providing reagents. This study was supported by grants from the Spanish Ministry of Science and Innovation (MICIIN)/Agencia Estatal de Investigación (AEI)/European Regional Development Fund (ARDF/FEDER) “A way to make Europe” (PID2020-118658RB-I00, SAF2017-83130-R, IGP-SO grant MINSEV1512-07-2016, CSD2009-0016 and BFU2016-81912-REDC), Comunidad Autónoma de Madrid (Tec4Bio-CM, S2018/NMT¬4443), Fundació La Marató de TV3 (201936-30-31), “La Caixa” Foundation (HR20-00075) and AECC (PROYE20089DELP) all to M.A.d.P. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 641639. M.G.G. and L.S. are sponsored by FPU fellowships (FPU15/ 03776 and FPU18/05394, respectively). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MICIIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence CEX2020- 001041-S.S

CD44 Modulates Cell Migration and Invasion in Ewing Sarcoma Cells

The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1low cells present a migratory and invasive phenotype, while EWSR1::FLI1high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells.This project was funded by Instituto de Salud Carlos III, grant numbers PI20CIII/00020, DTS18CIII/00005, Asociación Pablo Ugarte, grant numbers TRPV205/18; Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, grant numbers TVP333-19, TVP-1324/15; ASION, grant number TVP141/17. Enrique Fernández-Tabanera is supported by Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, Saint T. Cervera is supported by Asociación Pablo Ugarte and Raquel M. Melero is supported by a CIBERER contract.S

EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma

Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.FC-A, LG-G, JCL, AS, PG-M, SEL-P, SM and JA are supported by Asociación Pablo Ugarte and Miguelañez SA, ASION-La Hucha de Tomás, Fundación La Sonrisa de Alex and Instituto de Salud Carlos III (PI12/00816 and Spanish Cancer Network RTICC RD12/0036/0027). TGPG is supported by a grant from ‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)’, the Daimler and Benz Foundation in cooperation with the Reinhard Frank Foundation, by LMU Munich’s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the Fritz Thyssen Foundation (FTH-40.15.0.030MN) and by the German Cancer Aid (DKH-111886 and DKH-70112257). The ‘Genetics and Biology of Cancers’ team (TGPG, DS and OD) is supported by grants from the Ligue Nationale Contre Le Cancer (Equipe labellisée). This work was also supported by the European PROVABES, ASSET and EEC FP7 grants. We also thank the following associations for their invaluable support: the Société Française des Cancers de l’Enfant, Courir pour Mathieu, Dans les pas du Géant, Olivier Chape, Les Bagouzamanon, Enfants et Santé and les Amis de Claire. We thank Dr S Navarro (University of Valencia, Valencia, Spain) and Dr TJ Triche (Children’s Hospital Los Angeles, Los Angeles, USA) for providing us with Ewing sarcoma cell lines A4573 and TTC-466, respectively.S

Diagnostic procedures of Nuclear Medicine in thyroid pathology: relationship with TI-RADS groups and Bethesda cytology

Introduction and objectives: Since its beginning, nuclear medicine has played an important role in the study and treatment of thyroid pathology. The finding of a thyroid nodule is a very frequent situation in daily clinical practice. Today, the development of new techniques including high-resolution ultrasound and fine-needle aspiration puncture has led to an important progress in diagnosis and management of the disease. These procedures have enable the development of classification systems that allow to categorise the nodules by its ultrasound characteristics (TI-RADS) and its cytological characteristics (Bethesda), providing guidance on the attitude to follow in each case. The aim of this work is to conduct a review of the guidelines and recommendations for thyroid scintigraphy as well as to establish its relationship with the TI-RADS groups and the Bethesda cytology. Synthesis: Because iodine plays an important role in the physiology and pathophysiology of the thyroid gland, iodine radiopharmaceuticals or its analogues are very suitable for the study of thyroid imaging. Despite the development of new and very precise techniques for the study of the thyroid nodule, thyroid scintigraphy remains the only technique capable of correlating thyroid anatomy and thyroid function and, therefore, it is the only test capable of demonstrating the presence of autonomous thyroid nodules, which rarely result in malignancy. Furthermore, images with specific tracers such as sestamibi-99mTc and 18F-fluorodeoxyglucose can provide information on the biological behavior of cytologically indeterminate nodules. Conclusion: Thyroid scintigraphy is the only diagnostic method that provides information on the functional state of the gland. Its integration into the TIRADS and Bethesda groups is of the utmost importance to avoid unnecessary biopsies. In addition, the use of specific radiopharmaceuticals, including positron emission tomography, provides useful information in the case of nodules cytologically indeterminate.Introducción y objetivo: La medicina Nuclear, desde sus inicios, ha tenido un papel importante en el estudio y tratamiento de la patología tiroidea. El hallazgo de un nódulo tiroideo es una situación muy frecuente en la práctica clínica diaria. En la actualidad, el desarrollo de nuevas técnicas como son la ecografía de alta resolución y la punción por aspiración con aguja fina ha originado un importante avance en el diagnóstico y manejo de ésta patología. Estos procedimientos han facilitado el desarrollo de sistemas de clasificación según las características ecográficas de los nódulos (TI-RADS) y según sus características citológicas (Bethesda) que orientan sobre la actitud a seguir en los diferentes casos. EL objetivo de este trabajo es realizar una revisión de las indicaciones y recomendaciones de la gammagrafía tiroidea y establecer su relación con los grupos TI-RADS y la citología Bethesda. Síntesis: Debido a que el iodo juega un rol importante en la fisiología y fisiopatología de la glándula tiroides, los radiofármacos del iodo o sus análogos son muy adecuados para el estudio de imágenes tiroideas. A pesar del desarrollo de nuevas técnicas muy precisas para el estudio del nódulo tiroideo, la gammagrafía de tiroides sigue siendo la única técnica capaz de correlacionar anatomía y función tiroidea y, por tanto, es el único examen capaz de demostrar la presencia de nódulos tiroideos autónomos, que raramente conllevan malignidad. Además, imágenes con trazadores específicos como el sestamibi-99mTc y 18F-fluorodeoxyglucosa pueden suministrar información del comportamiento biológico de nódulos citológicamente indeterminados. Conclusión: La gammagrafía de tiroides es el único método diagnóstico que proporciona información del estado funcional de la glándula. Su integración en los grupos TIRADS y Bethesda es de suma importancia para evitar biopsias innecesarias. Además, el uso de radiofármacos específicos, incluyendo la tomografía por emisión de positrones, proporcionan una información útil en el caso de nódulos citológicamente indeterminados

Vascular and cognitive effects of cocoa-rich chocolate in postmenopausal women: a study protocol for a randomised clinical trial

Introduction The intake of polyphenols has certain health benefits. This study will aim to assess the effect of adding a daily amount of chocolate high in cocoa content and polyphenols to the normal diet on blood pressure, vascular function, cognitive performance, quality of life and body composition in postmenopausal women. Methods and analysis Here we plan a randomised clinical trial with two parallel groups involving a total of 140 women between 50 and 64 years in the postmenopausal period, defined by amenorrhoea of at least 12 consecutive months. The main variable will be the change in blood pressure. Secondary variables will be changes in vascular function, quality of life, cognitive performance and body composition. The intervention group will be given chocolate containing 99% cocoa, with instructions to add 10 g daily to their normal diet for 6 months. The daily nutritional contribution of this amount of chocolate is 59 kcal and 65.4 mg of polyphenols. There will be no intervention in the control group. All variables will be measured at the baseline visit and 3 and 6 months after randomisation, except cognitive performance and quality of life, which will only be assessed at baseline and at 6 months. Recruitment is scheduled to begin on 1 June 2018, and the study will continue until 31 May 2019. Ethics and dissemination This study was approved by the Clinical Research Ethics Committee of the Health Area of Salamanca, Spain (‘CREC of Health Area of Salamanca’), in February 2018. A SPIRIT checklist is available for this protocol. The clinical trial has been registered at ClinicalTrials. gov provided by the US National Library of Medicine, number NCT03492983. The results will be disseminated through open access peer-reviewed journals, conference presentations, broadcast media and a presentation to stakeholders.Gerencia Regional de Castilla y León (GRS 1583/B/1

Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition

Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them to fulfil their own energy needs and deliver metabolic intermediates to local synapses. These glial cells should be, therefore, metabolically adaptable to swap different substrates. However, in vitro and in vivo studies consistently show that astrocytes are primarily glycolytic, suggesting glucose is their main metabolic precursor. Notably, transcriptomic data and in vitro studies reveal that mouse astrocytes are capable of mitochondrially oxidizing fatty acids and that they can detoxify excess neuronal-derived fatty acids in disease models. Still, the factual metabolic advantage of fatty acid use by astrocytes and its physiological impact on higher-order cerebral functions remain unknown. Here, we show that knockout of carnitine-palmitoyl transferase-1A (CPT1A)—a key enzyme of mitochondrial fatty acid oxidation—in adult mouse astrocytes causes cognitive impairment. Mechanistically, decreased fatty acid oxidation rewired astrocytic pyruvate metabolism to facilitate electron flux through a super-assembled mitochondrial respiratory chain, resulting in attenuation of reactive oxygen species formation. Thus, astrocytes naturally metabolize fatty acids to preserve the mitochondrial respiratory chain in an energetically inefficient disassembled conformation that secures signalling reactive oxygen species and sustains cognitive performance.We acknowledge the technical assistance of M. Resch, M. Carabias-Carrasco, L. Martin and E. Prieto-Garcia, from the University of Salamanca. This work was funded by the European Regional Development Fund, Agencia Estatal de Investigación (grant nos. PID2019-105699RB-I00/AEI/10.13039/501100011033 and RED2018‐102576‐T to J.P.B. and SAF2017-90794-REDT to A.A.), Instituto de Salud Carlos III (grant nos. CB16/10/00282 to J.P.B. and PI18/00285 and RD16/0019/0018 to A.A.), Junta de Castilla y León (grant no. CS/151P20) and Escalera de Excelencia (grant no. CLU-2017-03 to J.P.B. and A.A.)

RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression.

We thank Dr. Shiva Malek and her colleagues (Genentech Inc.) for sharing their results with us before publication. We also thank M. San Roman, R. Villar, M.C. Gonzalez, A. Lopez, N. Cabrera, P. Villanueva, J. Condo, O. Dominguez, and S. Ortega for excellent technical support. This work was supported by grants from the European Research Council (ERC-2015-AdG/695566, THERACAN); the Spanish Ministry of Science, Innovation, and Universities (RTC-2017-6576-1 and RTI2018094664-B-I00) and the Autonomous Community of Madrid (B2017/BMD-3884 iLUNG-CM) to M.B., as well as by a grant from the Spanish Ministry of Science, Innovation and Universities (RTI2018-094664-B-I00) to M.B. and M.M. M.B. is a recipient of an Endowed Chair from the AXA Research Fund. M.S., P.N., and F.F.-G. were supported by FPU fellowships from the Spanish Ministry of Education. L.E.-B. was a recipient of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness. S.G.-A. is a recipient of a postdoctoral fellowship from the Asociacion Espanola Contra el Cancer (AECC).S

Low transmission of SARS-CoV-2 derived from children in family clusters: An observational study of family households in the Barcelona Metropolitan Area, Spain

Background: Family clusters offer a good opportunity to study viral transmission in a stable setting. We aimed to analyze the specific role of children in transmission of SARS-CoV-2 within households. Methods: A prospective, longitudinal, observational study, including children with documented acute SARS-CoV-2 infection attending 22 summer-schools in Barcelona, Spain, was performed. Moreover, other patients and families coming from other school-like environments that voluntarily accessed the study were also studied. A longitudinal follow-up (5 weeks) of the family clusters was conducted to determine whether the children considered to be primary cases were able to transmit the virus to other family members. The household reproduction number (Re*) and the secondary attack rate (SAR) were calculated. Results: 1905 children from the summer schools were screened for SARS-CoV-2 infection and 22 (1.15%) tested positive. Moreover, 32 additional children accessed the study voluntarily. Of these, 37 children and their 26 households were studied completely. In half of the cases (13/26), the primary case was considered to be a child and secondary transmission to other members of the household was observed in 3/13, with a SAR of 14.2% and a Re* of 0.46. Conversely, the SAR of adult primary cases was 72.2% including the kids that gave rise to the contact tracing study, and 61.5% without them, and the estimated Re* was 2.6. In 4/13 of the paediatric primary cases (30.0%), nasopharyngeal PCR was persistently positive > 1 week after diagnosis, and 3/4 of these children infected another family member (p<0.01). Conclusions: Children may not be the main drivers of the infection in household transmission clusters in the study population. A prolonged positive PCR could be associated with higher transmissibility.Peer ReviewedObjectius de Desenvolupament Sostenible::3 - Salut i BenestarPostprint (published version