Treatment of obesity in children and adolescents. How nutrition can work?

Overweight appears when persistent positive energy imbalances occur for long periods of time. Knowledge of dietary risk factors during childhood and adolescence is needed in order to design preventive measures against the increase in the prevalence of obesity and its consequences but is, however, largely missing. Longitudinal studies in children have not found clear causal associations between energy intake or diet composition and overweight development. Research has been ongoing to develop effective intervention studies for obese children but it is not clear which intervention is the most effective in assisting overweight/obese children to improve body composition without affecting growth rates. The objective of this article is to review the available knowledge on dietary risk factors for the development of childhood obesity, to discuss different dietary treatment strategies, and to propose an evidence-based approach to treat obese adolescents

Dietary total antioxidant capacity and obesity in children and adolescents

Dietary antioxidant intake has been suggested to protect against oxidative damage and related clinical complications. The aim of this study was to assess the potential relationships between the dietary total antioxidant capacity (TAC) and obesity-related features in children and adolescents. Anthropometric variables from 369 children and adolescents were measured (184 obese and 185 control). A validated food-frequency questionnaire was used to calculate the TAC and the daily nutrient and energy intake. Dietary TAC showed positive associations with fiber, folic acid, magnesium, and vitamins A, C and E. BMI, SDS-BMI and total body fat were inversely associated with dietary TAC only in obese subjects. These data suggest that dietary TAC may be a potential indicator of the risk to develop obesity-related features and could be considered as a useful method in assessing antioxidant intake

Impact of prophylactic TNF blockade in the dual PD-1 and CTLA-4 immunotherapy efficacy and toxicity

The TNF blockade therapy is currently a well-established treatment option for a variety of autoimmune diseases such as rheumatoid arthritis (RA), psoriasis or Crohn's disease, given the proinflammatory role of TNF in the course of these diseases. Importantly, TNF neutralization is also used for the treatment of corticosteroid-refractory immune-related adverse events (irAEs) induced by the combined anti-PD-1 and anti-CTLA-4 immunotherapy. The manifestation of these toxicities is an important limiting factor for the successful implementation of the inhibitory checkpoint blockade therapy (ICB), restraining its anti-tumor efficacy. In our recent study (Perez-Ruiz et al., Nature 569(7756): 428-432.), we analyzed the potential impact of prophylactic TNF neutralization therapy in the anti-PD1/CTLA-4 efficacy. Through several mouse models, we demonstrated that TNF neutralization ameliorated ICB-exacerbated colitis in addition to improving ICB-dependent anti-tumor efficacy. Similar results were obtained after prophylactic TNF blockade in graft vs host xenografted mouse models with human immune cells, which showed a reduction in colitis and hepatitis. Importantly, there was a preservation of the immunotherapeutic control of xenografted tumors after ICB treatment. Moreover, TNF and TNF-dependent gene expression is upregulated in the colon mucosa from patients affected by colitis as a side effect of ipilimumab and nivolumab. Our results, thus, provide evidence of the successful combination of prophylactic TNF neutralization with ICB therapy strategy to ameliorate toxicities, while keeping or even ameliorating anti-tumor efficacy. The prophylactic TNF blockade strategy is clinically feasible since excellent TNF inhibitors have been approved for the treatment of autoimmunity and are used for the immune-related serious adverse events in immunotherapy

Influencia del polimorfismo -866 G/A del gen de la UCP2 en población infantil obesa

Objetivo: En el presente estudio se pretende evaluar la prevalencia de la mutación -866 G/A del gen de la UCP2 y conocer su influencia sobre el fenotipo de los niños (11- 12 años) navarros obesos. Antecedentes y ámbito del estudio: La obesidad es una enfermedad de origen multifactorial, que puede estar relacionada con la presencia de mutaciones y polimorfismos en diversos genes candidatos. El gen de la proteína desacoplante UCP2 es uno de los más estudiados en relación con la obesidad porque parece participar en el control de la composición corporal y de diversos procesos metabólicos. Se han descrito tres polimorfismos en este gen: una inserción/deleción de 45 nucleótidos, un cambio del nucleótido guanina por adenina en la posición -866 y otro que origina un reemplazo de alanina por valina en el aminoácido 55. Según diferentes estudios, el alelo - 866G está relacionado con un mayor riesgo de desarrollar obesidad, aunque en la literatura aparecen resultados contradictorios en cuanto a esta asociación. Sujetos: El estudio se llevó a cabo en 125 niños (52% varones) obesos de 11-12 años de edad, seleccionados a través de los Servicios de Endocrinología Pediátrica de la Clínica Universitaria y del Hospital Virgen del Camino (Pamplona), obteniendo el consentimiento informado de acuerdo con la declaración de Helsinki. Intervenciones: Tras verificar el cumplimiento de los criterios de inclusión se tomaron medidas antropométricas (peso, talla, IMC, pliegue tricipital y subescapular) y se determinó el porcentaje de masa grasa por medio de impedancia bioeléctrica. Además se midieron los niveles plasmáticos de colesterol total, glucosa, insulina y leptina. Se procedió también a la extracción del ADN de las células sanguíneas de la serie blanca para determinar el genotipo mediante la técnica de PCR seguida de una digestión con BstUI y posterior visualización en un gel de agarosa con un 2% de bromuro de etidio. Resultados: El análisis genético reveló una frecuencia del alelo A de 0,404, con un porcentaje de individuos G/G, G/A, y A/A del 40,0%, 39,2% y 20,8%, respectivamente. Los portadores del alelo A presentaron un valor significativamente mayor de la suma de los pliegues tricipital y subescapular (p=0,034). No se observaron diferencias significativas entre los sujetos mutados y los no mutados en cuanto a las variables bioquímicas estudiadas. Conclusiones: Los sujetos portadores del polimorfismo presentan valores más altos para los pliegues tricipital y subescapular frente a los no mutados lo que podría indicar una relación entre la presencia del alelo A en niños obesos y niveles mayores de grasa subcutánea

TV watching modifies obesity risk linked to the 27Glu polymorphism of the ADRB2 gene in girls

OBJECTIVE: A matched case-control study was conducted in a population of Spanish children and adolescents (5-18 years old), to assess the interaction between the Gln27Glu polymorphism of the ADRB2 and television (TV) watching on obesity risk. PATIENTS: Obese (n=165) and control subjects (n=165) matched by sex and age were recruited and classified according to Spanish reference data. Results. Using conditional logistic regression, we calculated the obesity risk linked to the polymorphism. A statistically significant association was found for 27Glu carrier allele girls (OR = 1.95; 95% CI = 1.02-3.70), but no association was apparent among boys. In the fully adjusted model, the odds ratio for obesity linked to the genotype Glu27Glu in the female population rose to 4.84 (95% CI = 1.37-17.10). Moreover, we found a significant negative interaction between hours of TV watching and the Gln27Glu polymorphism for obesity risk in girls. Surprisingly, among 27Glu carrier subjects, even girls with a low level of TV watching ( < 12.5 h/week) had a high obesity risk (OR = 4.60; 95% CI = 1.01-20.02), which was not very different to the odds ratio values for sedentary girls carrying the 27 Glu allele watching TV more than 12.5 h/week (OR = 6.05; 95% CI = 1.31-27.71). Conclusion. A higher risk of obesity was found for girls carrying the 27Glu allele of the ADRB2 gene even when they spent less than 12.5 h/week watchi

Cytokines in clinical cancer immunotherapy

Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials

A novel mutation Thr162Arg of the melanocortin 4 receptor gene in a Spanish children and adolescent population

Objective  The melanocortin 4 receptor gene (MC4R) is involved in body weight regulation. While many studies associated MC4R mutations with childhood obesity, information on MC4R mutations in Spanish children and adolescents is lacking. Our objective was to screen a population of children and adolescents from the north of Spain (Navarra) for MC4R mutations and to study the phenotypes of carriers and their families. In addition, functional assays were performed for a novel MC4R mutation. Methods  The study was composed of 451 Spanish children and adolescents (49% boys), aged 5–18 year. According to the International Obesity Task Force (IOTF) criteria, the groups included 160 obese, 132 overweight and 159 normal-weight control subjects. Results  One novel (Thr162Arg) and three known nonsynonymous mutations in the MC4R gene (Ser30Phe, Thr150Ile, Ala244Glu) were detected heterozygously. The MC4R mutations were found in three male (one obese and two overweight) and two female subjects (one obese and one overweight). The novel mutation did not appear to lead to an impaired receptor function. An unequivocal relationship of MC4R mutations with obesity in pedigrees together with an impaired function of the encoded receptor could not be established for any of the mutations. Conclusions  The presence of heterozygous MC4R mutations in obese and overweight subjects indicates that these mutations may be a susceptibility factor for obesity development, but lifestyle factors, such as exercise or sedentary activities, may modify their effect

Asociación entre los macronutrientes de la dieta y la obesidad en la infancia y adolescencia; un estudio de casos y controles

Introducción: La alta de prevalencia de obesidad infantil en España y sus posibles consecuencias hacen de esta enfermedad un problema prioritario de salud pública. Objetivo: Valorar, mediante un estudio epidemiológico analítico de casos y controles, la asociación entre la composición en macronutrientes de la dieta y la obesidad en una muestra de niños y adolescentes navarros de 5,5 a 18,8 años. Método: Se reclutaron 178 casos, niños y adolescentes obesos (índice de masa corporal > percentil 97) en Navarra. Los controles fueron emparejados individualmente según edad y sexo. Las medidas antropométricas fueron tomadas por personal entrenado utilizando métodos estandarizados. Se realizaron entrevistas individuales para recoger información sobre la frecuencia de consumo de alimentos mediante un cuestionario previamente validado a partir del que se calculó la ingesta de macronutrientes (hidratos de carbono, proteínas y grasas) y de los subtipos de grasas. Estos resultados se dividieron en quintiles de macronutrientes ajustados por ingesta energética total. Se realizó una regresión logística condicional para estimar odds ratios ajustadas de obesidad para cada uno de los cuatro quintiles superiores de consumo, usando el quintil inferior como referencia. Resultados: La composición de macronutrientes de la dieta era similar en casos y controles, excepto para las grasas poliinsaturadas, que se asociaron inversamente a la obesidad (p tendencia lineal < 0,01) con una odds ratio ajustada de 0,34 (IC 95%: 0,15 a 0,77) para el quinto quintil. Conclusiones: Nuestros resultados sugieren una asociación inversa entre una mayor ingesta de grasas poliinsaturadas y el riesgo de obesidad

Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocytedeficient mice reconstituted with human NK cells

Daratumumab is an anti-CD38 fully human IgG1 mAb approved for multiple myeloma treatment. One of the proposed mechanisms of action is the induction of antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells. NK cells acquire surface CD137 expression in the presence of solid-phase-attached daratumumab and when encountering a daratumumab-coated CD38+ tumor cell line. In this setting, addition of the agonist anti-CD137 mAb urelumab enhances NK-cell activation increasing CD25 expression and IFNɣ production. However, in vitro ADCC is not increased by the addition of urelumab both in 4h or 24h lasting experiments. To study urelumab-increased daratumumab-mediated ADCC activity in vivo, we set up a mouse model based on the intravenous administration of a luciferase-transfected multiple myeloma cell line of human origin, human NK cells and daratumumab to immuno-deficient NSG mice. In this model, intravenous administration of urelumab 24h after daratumumab delayed tumor growth and prolonged mice survival

Enhancement of antibody-dependent cellular cytotoxicity of cetuximab by a chimeric protein encompassing interleukin-15

Enhancement of antibody-dependent cellular cytotoxicity (ADCC) may potentiate the antitumor efficacy of tumor-targeted monoclonal antibodies. Increasing the numbers and antitumor activity of NK cells is a promising strategy to maximize the ADCC of standard-of-care tumor-targeted antibodies. For this purpose, we have preclinically tested a recombinant chimeric protein encompassing the sushi domain of the IL15Rα, IL-15, and apolipoprotein A-I (Sushi-IL15-Apo) as produced in CHO cells. The size-exclusion purified monomeric fraction of this chimeric protein was stable and retained the IL-15 and the sushi domain bioactivity as measured by CTLL-2 and Mo-7e cell proliferation and STAT5 phosphorylation in freshly isolated human NK and CD8+ T cells. On cell cultures, Sushi-IL15-Apo increases NK cell proliferation and survival as well as spontaneous and antibody-mediated cytotoxicity. Scavenger receptor class B type I (SR-B1) is the receptor for ApoA-I and is expressed on the surface of tumor cells. SR-B1 can adsorb the chimeric protein on tumor cells and can transpresent IL-15 to NK and CD8+ T cells. A transient NK-humanized murine model was developed to test the increase of ADCC attained by the chimeric protein in vivo. The EGFR+ human colon cancer cell line HT-29 was intraperitoneally inoculated in immune-deficient Rag2-/-γc-/- mice that were reconstituted with freshly isolated PBMCs and treated with the anti-EGFR mAb cetuximab. The combination of the Sushi-IL15-Apo protein and cetuximab reduced the number of remaining tumor cells in the peritoneal cavity and delayed tumor engraftment in the peritoneum. Furthermore, Sushi-IL15-Apo increased the anti-tumor effect of a murine anti-EGFR mAb in Rag1-/- mice bearing subcutaneous MC38 colon cancer transfected to express EGFR. Thus, Sushi-IL15-Apo is a potent tool to increase the number and the activation of NK cells to promote the ADCC activity of antibodies targeting tumor antigens