Synthesis and Pharmacological Evaluation of New N-Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout

NLRP3 is involved in the pathophysiology of several inflammatory diseases. Therefore, there is high current interest in the clinical development of new NLRP3 inflammasome small inhibitors to treat these diseases. Novel N-sulfonylureas were obtained by the replacement of the hexahydroindacene moiety of the previously described NLRP3 inhibitor MCC950. These new derivatives show moderate to high potency in inhibiting IL-1β release in vitro. The greatest effect was observed for compound 4b, which was similar to MCC950. Moreover, compound 4b was able to reduce caspase-1 activation, oligomerization of ASC, and therefore, IL-1β processing. Additional in silico predictions confirmed the safety profile of compound 4b, and in vitro studies in AML12 hepatic cells confirmed the absence of toxicological effects. Finally, we evaluated in vivo anti-inflammatory properties of compound 4b, which showed a significant anti-inflammatory effect and reduced mechanical hyperalgesia at 3 and 10 mg/kg (i.p.) in an in vivo mouse model of gout.J.E. thanks Fondo de Investigaciones Sanitarias (ISCIII/ FEDER) (Programa Miguel Servet: CP19/00005 and PI19/ 00082) and Fundación Mutua Madrileñ a. D.D.-I. thanks the Spanish Ministry of Science, Innovation, and Universities for predoctoral FPU grant

Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens

Altres ajuts: This work was carried out at the Esther Koplowitz Center, Barcelona. Genmab and Janssen pharmaceuticals funded this research. Additional grants that contributed to this work included: [...], and CIBERONC (CB16/12/00334 and CB16/12/00225).CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a three-dimensional (3D) lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of MCL and FL, and shows comparable activity to rituximab in a disseminated in vivo model of blastic MCL. Moreover, daratumumab improves overall survival (OS) in a mouse model of transformed CD20 FL, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development

Medios de comunicación y derecho a la información en Jalisco 2013

En el primer apartado, dedicado al sistema de medios en general, se presentan tres artículos: “Nuevos medios de comunicación en Jalisco”, “c7 ¿medio público o vocero del gobierno?” y “Réquiem por un ombudsman”. El segundo apartado está dedicado al tema de la libertad de expresión; se presentan aquí dos textos: “La vulnerabilidad en un ambiente de cambio. Los ataques a los medios de comunicación en Jalisco durante el año” y “Violaciones a la libertad de expresión de periodistas y trabajadores de medios en Jalisco, 1995-2013”. En el apartado “Derecho a la información, comunicación y política” se ofrecen cuatro textos de índole muy diversa: “La estrategia de comunicación del Gobierno del Estado”, “Diálogos públicos: la discusión de una nueva ley de transparencia para Jalisco”, “Cuando un niño desaparece, el peor enemigo es el tiempo…”, sobre la alerta Amber, y “2013: un año marcado por despidos en diversos periódicos de Guadalajara”. En la sección “Los que se fueron” se presenta la semblanza de Felipe Vicencio. Y en el apartado de “La investigación del observatorio de medios” se comparten los resultados de un trabajo sobre los columnistas de opinión jaliscienses que escriben en la prensa local.ITESO, A.C

Habitat filtering and inferred dispersal ability condition across-scale species turnover and rarity in Macaronesian island spider assemblages

Publisher Copyright: © 2021 The Authors. Journal of Biogeography published by John Wiley & Sons Ltd.Aim: Habitat diversity has been linked to the diversity and structure of island communities, however, little is known about patterns and processes within habitats. Here we aim to determine the contributions of habitat type and inferred dispersal frequency to the differences in taxonomic structure between assemblages in the same island habitat. Location: The Macaronesian archipelagos (Azores, Madeira, the Canary Islands and Cabo Verde). Taxon: Spiders (Araneae). Methods: We established forest and dry habitat sites (each with five plots) on two islands per archipelago. We collected spiders using standardised sampling protocols. We tested the differences in beta diversity separately for each habitat and for each inferred category of ballooning (an aerial dispersal strategy) frequency across geographic scales through nested non-parametric permutational multivariate analyses of variance. We then tested whether ballooning and habitat influenced heterogeneity in species composition (dispersion in beta diversity) in the two habitat types. We analysed the effects of habitat and ballooning on species abundance distribution (SAD) and rarity by fitting Gambin models and evaluating the contribution of ballooning categories to SAD. Results: Communities of the same archipelago and habitat were taxonomically more similar, and beta diversity increased with geographic scale, being greater in dry habitats. There was greater species replacement among assemblages in dry habitats than in forests, with greater differences for rare ballooners. There were no differences in SAD between habitats although dry habitat sites seemed to harbour more species with low abundances (rare species) than forests. Main conclusions: Habitat type does not only condition the differences between spider assemblages of the same habitat but also the scale at which they occur. These differences may be determined by the heterogeneity in the physical structure of each habitat as well as how much this structure facilitates aerial dispersal (ballooning), and should be considered in theories/hypotheses on island community assembly as well as in conservation strategies.Peer reviewe

Código Cáncer: resultados preliminares

Antecedentes: Los retrasos en la atención de personas con cáncer impactan negativamente su calidad de vida y aumentan los costos al sistema de salud. / Objetivo: Describir las fases del proyecto Código Cáncer y sus resultados preliminares. / Métodos: Se organizaron siete grupos de investigación para: a) entender las causas de los retrasos que enfrentan las personas con cáncer en México, sus trayectorias y costos asociados; b) conocer los mecanismos de referencia formales e informales que constituyen su trayectoria en el sistema de salud, y c) entender la infraestructura existente y la necesaria para responder a las necesidades epidemiológicas del país. / Resultados: Estos resultados sientan las bases para la implementación de un programa de referencia rápida de pacientes. / Conclusión: Las políticas de diagnóstico y tratamiento oportuno del cáncer basadas en la evidencia son imprescindibles para atender los retrasos en la atención. Código Cáncer representa un proyecto innovador para lograr este objetivo en México

Factores de riesgo para trastornos de la alimentación en los alumnos de la Universidad de Manizales

ResumenObjetivo: Determinar la frecuencia de los factores de riesgo para trastornos de la alimentación en estudiantes de la Universidad de Manizales. Materiales y métodos: De 3,610 estudiantes regulares de la Universidad  de Manizales se tomó una muestra de 165 estudiantes, quienes respondieron un cuestionario integrado compuesto por variables demográficas, las escalas de Zung para ansiedad o depresión,el Eating Disorderrs Inventory (EDI2) y el Apgar familiar; además se tomaron las medidas de peso, talla, índice de masa corporal y pliegue en el antebrazo. Resultado: Un12.7% de la población presentó factor de riesgo positivo para trastornos de la conducta alimentaría, 17.3% de la población femenina y el 3.8% de la población masculina; las personas con mayor factor de riesgo fueron las mujeres en la facultad de Comunicación Social y Periodismo (24.1%). Se determinó una  relación significativa entre la variable impulso por la delgadez con la ansiedad o depresión. El mayor índice de masa corporal y de porcentaje de grasa está asociado con un aumentoen la variable impulso por la delgadez. Conclusiones:Se encontraron factores de riesgo asociados con trastornos de la alimentación. La frecuencia del factor de riesgo según EDI2 en este estudio fue más baja que la encontrada en estudios realizados en Medellín y Bogotá.[Cano AA, Castaño JJ, Corredor DA, García AM, González M, Lloreda OL, et al. Factores de riesgo para trastornos de la alimentación en los alumnos de la Universidad de Manizales. MedUNAB 2007; 10:187-194].Palabras claves: Trastornos de la conducta alimentaria, factores de riesgo; Anorexia nerviosa, Bulimia

Impact of mediterranean diet promotion on environmental sustainability: a longitudinal analysis

[EN]This article aims to estimate the differences in environmental impact (greenhouse gas [GHG] emissions, land use, energy used, acidification and potential eutrophication) after one year of promoting a Mediterranean diet (MD). Methods Baseline and 1-year follow-up data from 5800 participants in the PREDIMED-Plus study were used. Each participant's food intake was estimated using validated semi-quantitative food frequency questionnaires, and the adherence to MD using the Dietary Score. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The association between MD adherence and its environmental impact was calculated using adjusted multivariate linear regression models.SIPublicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL

Isotemporal substitution of inactive time with physical activity and time in bed: cross-sectional associations with cardiometabolic health in the PREDIMEDPlus study

Background: This study explored the association between inactive time and measures of adiposity, clinical parameters, obesity, type 2 diabetes and metabolic syndrome components. It further examined the impact of reallocating inactive time to time in bed, light physical activity (LPA) or moderate-to-vigorous physical activity (MVPA) on cardio-metabolic risk factors, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Methods: This is a cross-sectional analysis of baseline data from 2189 Caucasian men and women (age 55-75 years, BMI 27-40 Kg/m2) from the PREDIMED-Plus study (http://www.predimedplus.com/). All participants had ≥3 components of the metabolic syndrome. Inactive time, physical activity and time in bed were objectively determined using triaxial accelerometers GENEActiv during 7 days (ActivInsights Ltd., Kimbolton, United Kingdom). Multiple adjusted linear and logistic regression models were used. Isotemporal substitution regression modelling was performed to assess the relationship of replacing the amount of time spent in one activity for another, on each outcome, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Results: Inactive time was associated with indicators of obesity and the metabolic syndrome. Reallocating 30 min per day of inactive time to 30 min per day of time in bed was associated with lower BMI, waist circumference and glycated hemoglobin (HbA1c) (all p-values < 0.05). Reallocating 30 min per day of inactive time with 30 min per day of LPA or MVPA was associated with lower BMI, waist circumference, total fat, visceral adipose tissue, HbA1c, glucose, triglycerides, and higher body muscle mass and HDL cholesterol (all p-values < 0.05). Conclusions: Inactive time was associated with a poor cardio-metabolic profile. Isotemporal substitution of inactive time with MVPA and LPA or time in bed could have beneficial impact on cardio-metabolic health

Dietary intake of polychlorinated dibenzo-p-dioxins and furans, adiposity and obesity status

Introduction: The principal source of exposure to Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) in humans comes from food intake. PCDD/Fs, are a family of potential endocrine disruptors and have been associated with different chronic diseases such as diabetes and hypertension. However, studies assessing the relationship between dietary exposure to PCDD/Fs and adiposity or obesity status in a middle-aged population are limited. Objective: To assess cross-sectionally and longitudinally the associations between estimated dietary intake (DI) of PCDD/Fs and body mass index (BMI), waist circumference, and the prevalence/incidence of obesity and abdominal obesity in a middle-aged population. Methods: In 5899 participants aged 55-75 years (48% women) living with overweight/obesity from the PREDIMED-plus cohort, PCDD/Fs DI was estimated using a 143-item validated food-frequency questionnaire, and the levels of food PCDD/F expressed as Toxic Equivalents (TEQ). Consequently, cross-sectional and prospective associations between baseline PCDD/Fs DI (in pgTEQ/week) and adiposity or obesity status were assessed at baseline and after 1-year follow-up using multivariable cox, logistic or linear regression models. Results: Compared to participants in the first PCDD/F DI tertile, those in the highest tertile presented a higher BMI (β-coefficient [confidence interval]) (0.43kg/m2 [0.22; 0.64]; P-trend <0.001), a higher waist circumference (1.11 cm [0.55; 1.66]; P-trend <0.001), and a higher prevalence of obesity and abdominal obesity (1.05 [1.01; 1.09] and 1.02 [1.00; 1.03]; P-trend = 0.09 and 0.027, respectively). In the prospective analysis, participants in the top PCDD/F DI baseline tertile showed an increase in waist circumference compared with those in the first tertile after 1-year of follow-up (β-coefficient 0.37 cm [0.06; 0.70]; P-trend = 0.015). Conclusion: Higher DI of PCDD/Fs was positively associated with adiposity parameters and obesity status at baseline and with changes in waist circumference after 1-year of follow-up in subjects living with overweight/obesity. Further large prospective studies using a different population with longer follow-up periods are warranted in the future to strengthen our results. Keywords: Abdominal obesity; Adiposity; Endocrine disrupting chemicals; Obesity; Polychlorinated dibenzo-p-furans (PCDD/F)