Ecay, M. (Margarita)

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    Síntesis simplificada de 11C-(+)-α-dihidrotetrabenazina para su utilización como radioligando PET de los transportadores vesiculares de monoaminas
    (Elsevier, 2008) Areses, P. (P.); Marti-Climent, J.M. (Josep María); Obeso, J.A. (José A.); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Quincoces, G. (Gemma); Richter, J.A. (José Ángel); Ecay, M. (Margarita); Blesa, J. (Javier); Martino, E. (E.); Álvarez, L. (Lluis)
    La dihidrotetrabenazina (2-hidroxi-3-isobutil-9,10-dimetoxi-1,3,4,6,7-hexahidro-11bH-benzo[a]-quinolizina, DTBZ) se ha convertido en el ligando ideal de los transportadores presinápticos de monoaminas (VMAT2) debido a su elevada afinidad de unión y su lipofilicidad. Objetivo. Desarrollar un procedimiento de síntesis automático para el marcaje con carbono-11 de la DTBZ para utilizarla como marcador en el estudio in vivo mediante tomografía por emisión de positrones de pérdidas neuronales en modelos animales de enfermedad de Parkinson. Material y métodos. Se ha diseñado un nuevo método de síntesis totalmente automatizado para la obtención de 11C-(+)DTBZ. La reacción de metilación del precursor ­(+)desmetildihidrotetrabenazina­ se lleva a cabo a temperatura ambiente, a partir de la obtención de 11CH3I que utilizamos como precursor primario, en presencia de dimetilsulfóxido e hidróxido de potasio. Para los procesos de purificación se han utilizado cartuchos de extracción en fase sólida alúmina y los disolventes residuales del producto final se eliminaron mediante evaporación bajo flujo de helio. Resultados. De las 54 síntesis realizadas se han obtenido, con un tiempo de bombardeo de 5 minutos, y 6 minutos de síntesis tras la obtención de 11CH3I, unas producciones medias de 1,94 ± 0,13 GBq de 11C-(+)DTBZ, estéril, apirógeno y con una pureza radioquímica > 99 %. Conclusiones. Este nuevo procedimiento de síntesis es rápido y simple, ya que para la purificación final se han optimizado técnicas que permitieran la eliminación de los disolventes residuales basándonos en su polaridad y es aplicable a otras síntesis automáticas para la obtención de otros compuestos marcados mediante reacciones de metilación.
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    18F-FDG metabolism in a rat model of chronic infarction: a 17-sector semiquantitative analysis
    (SCHATTAUER, 2007) Marti-Climent, J.M. (Josep María); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Gavira, J.J. (Juan José); Richter, J.A. (José Ángel); Barba, J. (Joaquín); Garcia-Velloso, M. J. (María José); Ecay, M. (Margarita); Mazo, M. (Manuel); Garcia-Rodriguez, A. (Alba); Garcia-de-Jalon, J.A. (José A.); Prosper-Cardoso, F. (Felipe); Abizanda-Sarasa, G. (Gloria)
    Strategies to establish the functional benefit of cell therapy in cardiac regeneration and the potential mechanism are needed. Aims: Development of a semi-quantitative method for non invasive assessment of cardiac viability and function in a rat model of myocardial infarction (MI) based on the use of microPET. Animals, methods: Ten rats were subjected to myocardial imaging 2, 7, 14, 30, 60 and 90 days after left coronary artery ligation. Intravenous 18F-fluoro-2-deoxy-2-D-glucose (18F-FDG) was administered and regional 18F activity concentrations per unit area were measured in 17 regions of interest (ROIs) drawn on cardiac polar maps. By comparing the differences in 18F uptake between baseline and each of the follow up time points, parametric polar maps of statistical significance (PPMSS) were calculated. Left ventricular ejection fraction (LVEF) was blindly assessed echocardiographically. All animals were sacrificed for histopathological analysis after 90 days. Results: The diagnostic quality of 18F-FDG microPET images was excellent. PPMSS demonstrated a statistically significant decrease in 18F concentrations as early as 48 hours after MI in 4 of the 17 ROIs (segments 7, 13, 16 and 17; p <0.05) that persisted throughout the study. Semi-quantitative analysis of 18F-FDG uptake correlated with echocardiographic decrease in LVEF (p <0.001). Conclusion: The use of PPMSS based on 18F-FDG-microPET provides valuable semi-quantitative information of heart glucose metabolism allowing for non-invasive follow up thus representing a useful strategy for assessment of novel therapies in cardiac regeneration.
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    Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction
    (Oxford University Press, 2008-05) Joffre, C. (Carine); Cemborain, A. (A.); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Gavira, J.J. (Juan José); Planat-Benard, V. (Valérie); Boisson, M. (M.); Laharrague, P. (Patrick); Leobon, B. (Bertrand); Casteilla, L. (L.); Barba, J. (Joaquín); Ecay, M. (Margarita); Mazo, M. (Manuel); Prosper-Cardoso, F. (Felipe); Pelacho, B. (Beatriz); Penicaud, L. (Luc); Abizanda-Sarasa, G. (Gloria)
    Aims: To determine the effect of transplantation of undifferentiated and cardiac pre-differentiated adipose stem cells compared with bone marrow mononuclear cells (BM-MNC) in a chronic model of myocardial infarction. Methods: Ninety-five Sprague–Dawley rats underwent left coronary artery ligation and after 1month received by direct intramyocardial injection either adipose derived stem cells (ADSC), cardiomyogenic cells (AD-CMG) or BM-MNC from enhanced-Green Fluorescent Protein (eGFP) mice. The control group was treated with culture medium. Heart function was assessed by echocardiography and 18F-FDG microPET. Cell engraftment, differentiation, angiogenesis and fibrosis in the scar tissue were also evaluated by (immuno)histochemistry and immunofluorescence. Results: One month after cell transplantation, ADSC induced a significant improvement in heart function (LVEF 46.3±9.6% versus 27.7±8% pre-transplant) and tissue viability (64.78±7.2% versus 55.89±6.3% pre-transplant). An increase in the degree of angiogenesis and a decrease in fibrosis were also detected. Although transplantation of AD-CMG or BM-MNC also had a positive, albeit smaller, effect on angiogenesis and fibrosis in the infarcted hearts, this benefit did not translate into a significant improvement in heart function or tissue viability. Conclusion: These results indicate that transplantation of adipose derived cells in chronic infarct provides a superior benefit to cardiac pre-differentiated ADSC and BM-MNC.
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    Assessment of metabolic patterns and new antitumoral treatment in osteosarcoma xenograft models by [18F]FDG and sodium [18F]fluoride PET
    (2018) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Marrodán, L. (Lucía); Garcia-Velloso, M. J. (María José); Ecay, M. (Margarita)
    BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children and young adults that produces aberrant osteoid. The aim of this study was to assess the utility of 2-deoxy-2-[18F-] fluoro-D-glucose ([18F] FDG) and sodium [18F] Fluoride (Na [18F] F) PET scans in orthotopic murine models of osteosarcoma to describe the metabolic pattern of the tumors, to detect and diagnose tumors and to evaluate the efficacy of a new treatment based in oncolytic adenoviruses. METHODS: Orthotopic osteosarcoma murine models were created by the injection of 143B and 531MII cell lines. [18F]FDG and Na [18F] F PET scans were performed 30 days (143B) and 90 days (531MII) post-injection. The antitumor effect of two doses (107 and 108 pfu) of the oncolytic adenovirus VCN-01 was evaluated in 531 MII model by [18F] FDG PET studies. [18F] FDG uptake was quantified by SUVmax and Total Lesion Glycolysis (TLG) indexes. For Na [18F] F, the ratio tumor SUVmax/hip SUVmax was calculated. PET findings were confirmed by histopathological techniques. RESULTS: The metabolic pattern of tumors was different between both orthotopic models. All tumors showed [18F] FDG uptake, with a sensitivity and specificity of 100%. The [18F] FDG uptake was significantly higher for the 143B model (p < 0.001). Sensitivity for Na [18F] F was around 70% in both models, with a specificity of 100%. 531MII tumors showed a heterogeneous Na [18F] F uptake, significantly higher than 143B tumors (p < 0.01).
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    High value of 64Cu as a tool to evaluate the restoration of physiological copper excretion after gene therapy in Wilson's disease
    (2022) González-Aseguinolaza, G. (Gloria); Moreno-Luqui, D. (Daniel); Ferrer, V. (Verónica); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Murillo, O. (Oihana); Tamarit, B. (Blanche); Ecay, M. (Margarita); Douar, A. (Anne); Barberia, M. (Miren); Hernandez-Alcoceba, R. (Rubén); Combal, J.P. (Jean Philippe); Bénichou, B. (Bernard); Gazquez, C. (Cristina)
    Wilson's disease (WD) is an inherited disorder of copper metabolism associated with mutations in ATP7B gene. We have shown that the administration of an adeno-associated vector (AAV) encoding a mini version of human ATP7B (VTX-801) provides long-term correction of copper metabolism in a murine WD model. In preparation of a future clinical trial, we have evaluated by positron emission tomography (PET) the value of 64Cu biodistribution, excretion pattern, and blood kinetics as pharmacodynamic biomarkers of VTX-801 effects. Six-week-old WD mice were injected intravenously with increasing doses of VTX-801 and 3 weeks or 3 months later with [64Cu]CuCl2. Untreated WD and wild-type (WT) mice were included as controls. Control WD mice showed increased hepatic 64Cu retention, reduced fecal excretion of the radiotracer, and altered 64Cu blood kinetics (BK) compared with WT mice. VTX-801 treatment in WD mice resulted in a significant reduction of hepatic 64Cu accumulation, the restoration of fecal 64Cu excretion, and the correction of 64Cu BK. This study showed that VTX-801 restores physiological copper metabolism in WD mice, confirming the mechanism of action of VTX-801, and demonstrated the translational potential of [64Cu]CuCl2-PET to explore VTX-801 pharmacodynamics in a minimally invasive and sensitive manner in WD patients.
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    Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells
    (2020) Gil-Bazo, I. (Ignacio); Pio, R. (Rubén); Román, M. (Marta); Puyalto, A. (Ander); Collantes, M. (María); Lozano-Moreda, T. (Teresa); Vicent, S. (Silvestre); Garcia-Ros, D. (David); Villalba-Esparza, M. (María); Caglevic, C. (Christian); Ecay, M. (Margarita); Rodríguez-Remírez, M. (M.); Alignani, D. (Diego); Rolfo, C. (Christian); Guruceaga, E. (Elizabeth); Moreno, H. (Haritz); Andrea, C.E. (Carlos Eduardo) de; Ortiz-Espinosa, S. (Sergio); Vilalta, A. (Anna); Torregrosa, M.S. (María Soledad); Baraibar-Argota, I. (Iosune); Lopez, I. (Inés); Calvo-González, A. (Alfonso); Ajona, D. (Daniel); Oliver, A. (Ana); Lasarte, J.J. (Juan José)
    The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.
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    Estilo comportamental al inicio del segundo año de vida:estudio retrospectivo en escolares afectados de trastorno por deficit de atencion e hiperactividad
    (Elsevier España, 2009) Narbona, J. (Juan); Magallon-Recalde, S. (Sara); Ecay, M. (Margarita); Crespo-Eguilaz, N. (Nerea); Poch-Olive, M.L. (M.L.)
    OBJECTIVES: To study the relationship between behavioural profile of children suffering from Attention Deficit Hyperactivity Disorder (ADHD) and the previous behavioural style of these patients as toddlers. SUBJECTS AND METHODS: We asked the parents of 50 schoolchildren with ADHD, and those of 30 controls, to fill in a Spanish version of the Toddler Behaviour Questionnaire (TBQ) from their retrospective perception of their children's behaviour as toddlers. TBQ items were grouped by factor analysis; t-Student between the scores of both groups and a multiple correlation analysis of TBQ and DSM-IV-ADHD-RS in each of the groups were used. RESULTS: Children in the ADHD group were reported by parents to have had a different toddler behavioural profile in comparison to that of control children (P<0.05). These differences were associated with adapting to new environments, mood, regularity and stability of play behaviour. A correlation was found between behavioural profile in DSM-IV-ADHD- RS and TBQ. CONCLUSIONS: The results of this study should be interpreted with caution. However, they suggest that in the fifth trimester of life a particular behavioural style as regards regularity, stability of play, and mood, could indicate a risk of developing ADHD in the future. This behavioural style should be taken into consideration in rearing and early education prospective studies.
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    Monoaminergic PET imaging and histopathological correlation in unilateral and bilateral 6-hydroxydopamine lesioned rat models of Parkinson's disease: a longitudinal in-vivo study
    (Elsevier, 2015-02-12) Delgado, M. (Mercedes); Quiroga-Varela, A. (Ana); Juri, C. (Carlos); Obeso, J.A. (José A.); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Prieto-Azcárate, E. (Elena); Molinet-Dronda, F. (Francisco); Gago, B. (Belén); Ecay, M. (Margarita); Iglesias, E. (Elena); Marin, C. (Concepció)
    Carbon-11 labeled dihydrotetrabenazine (11C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with Parkinson's disease. Here, we applied 11C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague–Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. bilateral lesion by injection of 6-OHDA in the third ventricle, and 3. vehicle injection in either site. 11C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6 weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new 11C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT). 11C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th weeks post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between 11C-DTBZ PET SB and striatal DAT immunostaining values (r = 0.95, p < 0.001). The data presented here indicate that 11C-DTBZ PET may be used to ascertain changes occurring in-vivo throughout the evolution of nigro-striatal dopaminergic neurodegeneration, mainly in the unilateral 6-OHDA lesion rat.
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    Infection-specific PET imaging with 18F-fluorodeoxysorbitol and 2-[18F]F-¿-aminobenzoic acid: An extended diagnostic tool for bacterial and fungal diseases
    (2023) Llop, J. (Jordi); Pulagam, K.R. (Krishna R.); Collantes, M. (María); Leiva, J. (José); Peñuelas-Sanchez, I. (Ivan); Rua, M. (Marta); Simón-Martínez, J.A. (Jon Ander); Pareja, F. (Félix); Pozo, J.L. (José Luis) del; Carmona-Torre, F. (Francisco de A.); Ecay, M. (Margarita); Ramos-Membrive, R. (Rocío)
    Introduction Suspected infectious diseases located in difficult-to-access sites can be challenging due to the need for invasive procedures to isolate the etiological agent. Positron emission tomography (PET) is a non-invasive imaging technology that can help locate the infection site. The most widely used radiotracer for PET imaging (2-deoxy-2[F-18] fluoro-D-glucose: [F-18]FDG) shows uptake in both infected and sterile inflammation. Therefore, there is a need to develop new radiotracers able to specifically detect microorganisms. MethodsWe tested two specific radiotracers: 2-deoxy-2-[F-18]-fluoro-D-sorbitol ([F-18]FDS) and 2-[F-18]F-rho-aminobenzoic acid ([F-18]FPABA), and also developed a simplified alternative of the latter for automated synthesis. Clinical and reference isolates of bacterial and yeast species (19 different strains in all) were tested in vitro and in an experimental mouse model of myositis infection. Results and discussionNon-lactose fermenters (Pseudomonas aeruginosa and Stenotrophomonas maltophilia) were unable to take up [F-18]FDG in vitro. [F-18]FDS PET was able to visualize Enterobacterales myositis infection (i.e., Escherichia coli) and to differentiate between yeasts with differential assimilation of sorbitol (i.e., Candida albicans vs. Candida glabrata). All bacteria and yeasts tested were detected in vitro by [F-18]FPABA. Furthermore, [F-18]FPABA was able to distinguish between inflammation and infection in the myositis mouse model (E. coli and Staphylococcus aureus) and could be used as a probe for a wide variety of bacterial and fungal species.
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    13N-Ammonia PET as a Measurement of Hindlimb Perfusion in a Mouse Model of Peripheral Artery Occlusive Disease
    (SOC NUCLEAR MEDICINE INC, 2007) Marti-Climent, J.M. (Josep María); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Uriz, M. (Maialen); Quincoces, G. (Gemma); Richter, J.A. (José Ángel); Ecay, M. (Margarita); Prosper-Cardoso, F. (Felipe); Abizanda-Sarasa, G. (Gloria); Aranguren, X.L. (Xabier L.)
    Peripheral arterial occlusive disease (PAOD) is a leading cause of mortality and morbidity in the western world. The development of noninvasive methods for assessment and comparison of the efficacy of novel therapies in animal models is of great importance. Methods: Hindlimb ischemia was induced in nude mice by ligation and excision of the left femoral artery (n = 5) or the left iliac artery (n = 10). Assessment of limb perfusion was performed by small-animal PET analysis after intravenous injection of 13N-ammonia between 24 h and 30 d after surgery using the ratio of perfusion between the left limb (ischemic) and the right limb (control). Activity concentration per area unit was calculated in regions of interest placed on 1-mm-thick images for numeric calculations, and the iliac and the femoral models were compared. In addition, histopathologic studies were performed to assess the degree of necrosis (hematoxylin–eosin) and fibrosis (sirius red). Immunohistochemistry analyses for identification of arterioles ({alpha}-smooth muscle actin) and endothelium—capillaries—(Bandeiraea simplicifolia I [BS-I] lectin) were also performed. Results: Perfusion in both hindlimbs of control animals was similar (median of the left-to-right ratio = 0.99). Twenty-four hours after ischemia, perfusion of the ischemic limb (% mean ± SD) was 33.3 ± 10.6 and 22.1 ± 9.9 in the femoral and iliac models, respectively. Spontaneous recovery of perfusion in the hindlimb that underwent surgery was significantly lower in the iliac model at day +15 (73.2 ± 15.5 vs. 51.9 ± 11.3; P < 0.01). Fibrosis increased progressively until day +30, whereas muscle necrosis was maximal at day +7 with a moderate reduction by day +30. In accordance with this positive effect, there was a statistically significant increase in the area covered with smooth muscle-coated vessels (arterioles) at day +30 in comparison with day 7 (P < 0.05). In addition, a correlation between 13N-ammonia uptake and the amount of necrosis (r = –0.73; P = 0.06) and fibrosis (r = –0.67; P = 0.05) at day +30 was found. Conclusion: 13N-Ammonia imaging allows semiquantitative evaluation of hindlimb perfusion in surgical mouse models of acute hindlimb ischemia. Although spontaneous perfusion recovery is observed in both models, the iliac model shows a substantially lower recovery and is hence better suited for assessment of new therapeutic strategies for acute hindlimb