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Treatment of T1D via optimized expansion of antigen-specific Tregs induced by IL-2/anti-IL-2 monoclonal antibody complexes and peptide/MHC tetramers

  • Izquierdo, Cristina
  • Zarama Ortiz, Angela
  • Presa, Maximiliano
  • Malo, Sara
  • Montoya, Anna
  • Garabatos, Nahir
  • Mora Giral, Concepció
  • Verdaguer Autonell, Joan
  • Stratmann, Thomas
Type 1 diabetes can be overcome by regulatory T cells (Treg) in NOD mice yet an efficient method to generate and maintain antigen-specific Treg is difficult to come by. Here, we devised a combination therapy of peptide/MHC tetramers and IL-2/anti-IL-2 monoclonal antibody complexes to generate antigen-specific Treg and maintain them over extended time periods. We first optimized treatment protocols conceived to obtain an improved islet-specific Treg/effector T cell ratio that led to the in vivo expansion and activation of these Treg as well as to an improved suppressor function. Optimized protocols were applied to treatment for testing diabetes prevention in NOD mice as well as in an accelerated T cell transfer model of T1D. The combined treatment led to robust protection against diabetes, and in the NOD model, to a close to complete prevention of insulitis. Treatment was accompanied with increased secretion of IL-10, detectable in total splenocytes and in Foxp3− CD4 T cells. Our data suggest that a dual protection mechanism takes place by the collaboration of Foxp3+ and Foxp3− regulatory cells. We conclude that antigen-specific Treg are an important target to improve current clinical interventions against this disease.
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A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-β in mouse endometrium

  • Eritja Sánchez, Núria
  • Felip, Isidre
  • Dosil Garcia, Maria Alba
  • Vigezzi, Lucia
  • Mirantes Barbeito, Cristina
  • Yeramian Hakim, Andree
  • Navaridas Fernández de Bobadilla, Raúl
  • Santacana Espasa, Maria
  • Llobet Navàs, David
  • Yoshimura, Akihiko
  • Nomura, Masatoshi
  • Encinas Martín, Mario
  • Matias-Guiu, Xavier
  • Dolcet Roca, Xavier
The TGF-β/Smad and the PI3K/AKT signaling pathways are important regulators of proliferation and apoptosis, and their alterations lead to cancer development. TGF-β acts as a tumor suppressor in premalignant cells, but it is a tumor promoter for cancerous cells. Such dichotomous actions are dictated by different cellular contexts. Here, we have unveiled a PTEN-Smad3 regulatory loop that provides a new insight in the complex cross talk between TGF-β/Smad and PI3K/AKT signaling pathways. We demonstrate that TGF-β triggers apoptosis of wild-type polarized endometrial epithelial cells by a Smad3-dependent activation of PTEN transcription, which results in the inhibition of PI3K/AKT signaling pathway. We show that specific Smad3 knockdown or knockout reduces basal and TGF-β-induced PTEN expression in endometrial cells, resulting in a blockade of TGF-β-induced apoptosis and an enhancement of cell proliferation. Likewise Smad3 deletion, PTEN knockout prevents TGF-β-induced apoptosis and increases cell proliferation by increasing PI3K/AKT/mTOR signaling. In summary, our results demonstrate that Smad3-PTEN signaling axis determine cellular responses to TGF-β.
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Coexpression of p-IGF-1R and MMP-7 modulates panitumumab and cetuximab efficacy in RAS Wild-Type metastatic colorectal cancer patients

  • Alonso, Vicente
  • Escudero, Pilar
  • Fernández-Martos, Carlos
  • Salud Salvia, Maria Antonieta
  • Méndez, Miguel
  • Gallego, Javier
  • Rodriguez, Jose-R.
  • Martín-Richard, Marta
  • Fernández-Plana, Julen
  • Manzano, Hermini
  • Méndez, José-Carlos
  • Zanui, Monserrat
  • Falcó, Esther
  • Gil-Raga, Mireia
  • Rojo, Federico
  • Cuatrecasas, Miriam
  • Feliu, Jaime
  • García-Albéniz, Xabier
  • Maurel, Joan
INTRODUCTION: The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS: We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as >70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS: We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95%CI: 0.11-0.52; P=.0004) and with shorter OS in POSIBA (adjusted HR: 1.67; 95%CI: 0.96-2.90; P=.07). CONCLUSION: A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP.
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Reciprocal effects of antiretroviral drugs used to treat HIV infection on the fibroblast growth factor 21/β-Klotho System

  • Moure, Ricardo
  • Domingo, Pere
  • Villarroya, Joan
  • Gasa, Laura
  • Gallego-Escuredo, José M.
  • Quesada-López, Tania
  • Morón-Ros, Samantha
  • Maroto, Alberto F.
  • Mateo, Gracia M.
  • Domingo, Joan C.
  • Villarroya, Francesc
  • Giralt, Marta
Following antiretroviral therapy, HIV-infected patients show increased circulating levels of the antidiabetic hormone fibroblast growth factor 21 (FGF21). In contrast, the expression of the FGF21-obligatory coreceptor -Klotho (KLB) is reduced in target tissues. This situation is comparable to the FGF21 resistance status observed in obesity and type 2 diabetes. Here, we performed the first systematic study of the effects of distinct members of different antiretroviral drug classes on the FGF21/KLB system in human hepatic, adipose, and skeletal muscle cells. Most protease inhibitors and the nonnucleoside reverse transcriptase inhibitor efavirenz induced FGF21 gene expression. Neither nucleoside reverse transcriptase inhibitors nor the viral entry inhibitor maraviroc had any effect. Among the integrase inhibitors, elvitegravir significantly induced FGF21 expression, whereas raltegravir had minor effects only in adipose cells. In human hepatocytes and adipocytes, known target cells of FGF21 action, efavirenz, elvitegravir, and the lopinavir-ritonavir combination exerted inhibitory effects on KLB gene expression. Drug treatments that elicited FGF21 induction/KLB repression were those found to induce endoplasmic reticulum (ER) stress and oxidative stress. Notably, the pharmacological agents thapsigargin and tunicamycin, which induce these stress pathways, mimicked the effects of drug treatments. Moreover, pharmacological inhibitors of either ER or oxidative stress significantly impaired lopinavir–ritonavir-induced regulation of FGF21, but not KLB. In conclusion, the present in vitro screen study identifies the antiretroviral drugs that affect FGF21/KLB expression in human cells. The present results could have important implications for the management of comorbidities resulting from side effects of specific antiretroviral drugs for the treatment of HIV-infected patients.
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Quality Assurance of Samples and Processes in the Spanish Renal Research Network (REDinREN) Biobank

  • Calleros-Basilio, Laura
  • Cortés, María Alicia
  • García-Jerez, Andrea
  • Luengo-Rodríguez, Alicia
  • Orozco-Agudo, Ana
  • Valdivielso Revilla, José Manuel
  • Rodríguez-Puyol, Diego
  • Rodríguez-Puyol, Manuel
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Acetylsalicylic acid prevents intermittent hypoxia-induced vascular remodeling in a murine model of sleep apnea

  • Suarez-Giron, Monique C.
  • Castro-Grattoni, Anabel L.
  • Torres, Marta
  • Farré, Ramon
  • Barbé Illa, Ferran
  • Sánchez de la Torre, Manuel
  • Gozal, David
  • Picado, Cesar
  • Montserrat i Capdevila, Josep
  • Almendros, Isaac
Study objectives: Chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA), induces accelerated atherogenesis as well as aorta vascular remodeling. Although the cyclooxygenase (COX) pathway has been proposed to contribute to the cardiovascular consequences of OSA, the potential benefits of a widely employed COX-inhibitor such (acetylsalicylic acid, ASA) on CIH-induced vascular pathology are unknown. Therefore, we hypothesized that a common non-selective COX inhibitor such as ASA would attenuate the aortic remodeling induced by CIH in mice. Methods: 40 wild-type C57/BL6malemice were randomly allocated to CIH or normoxic exposures (N) and treated with daily doses of ASA or placebo for 6 weeks. At the end of the experiments, intima-media thickness (IMT), elastin disorganization (ED), elastin fragmentation (EF), length between fragmented fiber endpoints (LFF), aortic wall collagen abundance (AC) and mucoid deposition (MD) were assessed. Results: Compared to N, CIH promoted significant increases in IMT (52.58 ± 2.82μm vs. 46.07 ± 4.18μm, p < 0.003), ED (25.29 ± 14.60% vs. 4.74 ± 5.37%, p < 0.001), EF (5.80 ± 2.04 vs. 3.06 ± 0.58, p < 0.001), LFF (0.65 ± 0.34% vs. 0.14 ± 0.09%, p < 0.001), AC (3.43 ± 1.52% vs. 1.67 ± 0.67%, p < 0.001) and MD (3.40 ± 2.73 μm2 vs. 1.09 ± 0.72 μm2, p < 0.006). ASA treatment mitigated the CIH-induced alterations in IMT: 44.07 ± 2.73μm; ED: 10.57 ± 12.89%; EF: 4.63 ± 0.88; LFF: 0.25 ± 0.17% and AC: 0.90 ± 0.13% (p<0.05 for all comparisons). Conclusions: ASA prevents the CIH-induced aortic vascular remodeling, and should therefore be prospectively evaluated as adjuvant treatment in patients with OSA.
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A New Gender-Specific Formula to Estimate 24-Hour Urine Protein from Protein to Creatinine Ratio

  • Marco Mayayo, M. Paz
  • Martínez Alonso, Montserrat
  • Valdivielso Revilla, José Manuel
  • Fernández i Giráldez, Elvira
Background: The quantification of proteinuria with the protein to creatinine ratio (PCR) is influenced by the excretion of creatinine, which, in turn, varies according to muscle mass and hence, to gender. Aims: To assess the difference between urine PCR and 24-hour urine proteinuria in men and women and to provide a formula to overcome bias caused by gender. Methods: Four hundred and forty four CKD patients were randomly divided into 2 groups: 70% were used to develop the models, while the remaining 30% were reserved to validate the formula. Epidemiological data were analyzed with chi-square and Student's t tests. Association between 24-hour proteinuria and PCR was studied with Spearman coefficient in men and women separately. Multivariate analysis was used to find variables predictive of disagreement between the 24-hour urine protein and the PCR. Equations to predict 24-hour proteinuria from PCR for men and women were plotted and validated. Results: Disagreement between 24-hour proteinuria and PCR was more pronounced in men (2.16 and 1.64 g in mean, respectively) than in women (2.00 and 2.06 g in mean, respectively). Age and gender were independent predictors of disagreement. Gender-specific equations for predicting 24-hour proteinuria were: males: 24-hour proteinuria = 1.3350*exp0.9108*ln(PCR); females: 24-hour proteinuria = 1.0068*exp0.9030*ln(PCR). Conclusions: Estimation of proteinuria with the PCR improves accuracy if gender-specific equations are used. Use of the PCR without correction for gender leads to the underestimation of proteinuria in men and overestimation in women.
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Principios prácticos y funcionales en situaciones de muerte y duelo para profesionales de la educación

  • Ramos Pla, Anabel
  • Gairín Sallán, Joaquín
  • Camats Guardia, Ramon
Actualmente, la sociedad está viviendo una regresión sobre la concepción de la muerte. La idea de morir se asocia a miedo, tristeza y angustia. La presente aportación proporciona a los profesionales de la educación una serie de pautas para acompañar a los niños y adolescentes en los procesos de muerte y duelo. Se apuesta por la inclusión de la muerte en el currículum escolar como eje para la enseñanza de valores y la normalización de la muerte como un hecho que forma parte de la vida. El método utilizado para llevar a cabo la extensa búsqueda bibliográfica ha sido, principalmente, la búsqueda y el seguimiento de la temática que nos ocupa en diferentes bases de datos nacionales e internacionales. De este modo, el método utilizado para analizar las referencias bibliográficas encontradas ha sido, principalmente: la idoneidad a la temática, la calidad de la revista, el año de publicación y la importancia de la autoría. El propósito último de este estudio es concebir y tratar la muerte y el duelo desde la perspectiva sistemática que la intervención pedagógica aporta, lejos de los procesos de improvisación. Es importante remarcar que este documento no pretende ser una generalización, si no que cada profesional de la educación que quiera llevar a cabo una pedagogía de la muerte (ya sea preventiva, paliativa o ambas), debe tener en cuenta el contexto. Asimismo, la prospectiva de futuro de la pedagogía de la muerte es muy positiva, ya que es un tema emergente y necesario en el terreno pedagógico., Currently, society is experiencing a regression on the conception of death. The idea of dying is associated with fear, sadness and anguish. This contribution provides education professionals with a series of guidelines to accompany children and adolescents in the processes of death and grief. It is committed to the inclusion of death in the school curriculum as an axis for the teaching of values and the normalization of death as a fact that is part of life. The method used to carry out the extensive bibliographic search has been, mainly, the search and follow-up of the subject matter that occupies us in different national and international databases. In this way, the method used to analyse the bibliographical references found was mainly: the suitability of the subject, the quality of the journal, the year of publication and the importance of authorship. The ultimate purpose of this study is to conceive and treat death and grief from the systematic perspective that pedagogical intervention provides, far from the processes of improvisation. It is important to note that this document does not intend to be a generalization, but rather that each education professional who wants to carry out a death pedagogy (be it preventive, palliative or both), must take the context into account. Likewise, the prospective of the future of the pedagogy of death is very
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The specificity of observational studies in physical activity and sports sciences: moving forward in mixed methods research and proposals for achieving quantitative and qualitative symmetry

  • Anguera, M. Teresa
  • Camerino Foguet, Oleguer
  • Castañer Balcells, Marta
  • Sánchez-Algarra, Pedro
  • Onwuegbuzie, Anthony J.
Mixed methods studies are been increasingly applied to a diversity of fields. In this paper, we discuss the growing use—and enormous potential—of mixed methods research in the field of sport and physical activity. A second aim is to contribute to strengthening the characteristics ofmixedmethods research by showing how systematic observation offers rigor within a flexible framework that can be applied to a wide range of situations. Observational methodology is characterized by high scientific rigor and flexibility throughout its different stages and allows the objective study of spontaneous behavior in natural settings, with no external influence. Mixed methods researchers need to take bold yet thoughtful decisions regarding both substantive and procedural issues. We present three fundamental and complementary ideas to guide researchers in this respect: we show why studies of sport and physical activity that use a mixed methods research approach should be included in the field of mixed methods research, we highlight the numerous possibilities offered by observational methodology in this field through the transformation of descriptive data into quantifiable code matrices, and we discuss possible solutions for achieving true integration of qualitative and quantitative findings.
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El efecto del modelo docente y de la interacción con compañeros en las habilidades motrices creativas de la Danza. Un formato de campo para su análisis y obtención de T-patterns motrices

  • Torrents Martín, Carlota
  • Castañer Balcells, Marta
  • Dinušová Tomagová, Mária
  • Anguera, M. Teresa
En el proceso de enseñanza-aprendizaje de disciplinas relacionadas con la Danza Contemporánea, la Danza creativa y de Improvisación así como la Expresión Corporal, la elección de la consigna y la forma de impartir ésta será fundamental para la consecución de los objetivos propuestos. El objetivo de este estudio será analizar el efecto de diferentes tipos de consignas para facilitar la generación divergente de respuestas con el fin de estimular la creatividad motriz. 12 sujetos sin experiencia previa en danza fueron observados durante 17 sesiones de iniciación a la Danza Contemporánea. La presencia de un modelo cinésico por parte del docente o la interacción con compañeros fueron aleatoriamente incluidos en las tareas. En el LOM -Laboratorio de Observación de la Motricidad- hemos elaborado un formato de campo ad hoc para la observación y se ha codificado con el programa Match Vision Studio (Perea, Alday y Castellano, 2004). Los datos y los T-Patterns obtenidos (Castañer, Torrents, Anguera y Dinušová, 2007) se analizaron mediante el programa Theme (Magnuson 1996) Los resultados muestran que los sujetos intentaron generar sus propias respuestas sin copiar el modelo propuesto por el docente pero que tendieron a copiar ciertas características de éste y que la divergencia en las respuestas se dio especialmente en las categorías de ritmo y dirección espacial..
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