93 results on '"Xargay-Torrent S"'
Search Results
2. A 24-month metformin treatment study of children with obesity: Changes in circulating GDF-15 and associations with changes in body weight and visceral fat
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Carreras-Badosa G, Gómez-Vilarrubla A, Mas-Parés B, Martínez-Calcerrada JM, Xargay-Torrent S, Prats-Puig A, Puerto-Carranza E, Díaz-Roldán F, de Zegher F, Ibañez-Toda L, Bassols J, and López-Bermejo A
- Subjects
metformin ,weight loss ,visceral fat ,embryonic structures ,GDF-15 ,obesity - Abstract
BACKGROUND: Metformin treatment for 24 months in children with obesity lowers body mass index (BMI), reduces liver fat, and normalizes endocrine-metabolic parameters. OBJECTIVE: Here we study whether circulating GDF-15 levels were raised by such metformin treatment and whether they related to changes in body weight and visceral fat in children with obesity. METHODS: The study population consisted of 18 pre-pubertal/early pubertal children with obesity who had participated in a randomized double-blind clinical trial receiving metformin (850 mg/day) or placebo for 24 months. Circulating GDF-15, BMI and abdominal visceral and liver fat (magnetic resonance imaging) were assessed at 0, 6, 12 and 24 months. RESULTS: Results showed that metformin-treated children had higher GDF-15 levels at 6 and 12 months. Higher rises of circulating GDF-15 associated with more loss of body weight and visceral fat. CONCLUSION: In conclusion, the concept that GDF-15 is among the mediators of metformin's normalizing effects in individuals with obesity is herewith extended into childhood.
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- 2022
3. Catch-up growth in juvenile rats, fat expansion, and dysregulation of visceral adipose tissue
- Author
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Lizarraga-Mollinedo E, Carreras-Badosa G, Xargay-Torrent S, Remesar X, Mas-Pares B, Prats A, de Zegher F, Ibañez-Toda L, López-Bermejo A, and Bassols-Casadevall J
- Abstract
BACKGROUND: Accelerated catch-up growth following intrauterine restriction increases the risk of developing visceral adiposity and metabolic abnormalities. However, the underlying molecular mechanisms of such metabolic programming are still poorly understood. METHODS: A Wistar rat model of catch-up growth following intrauterine restriction was used. A gene expression array was performed in the retroperitoneal adipose tissue sampled at postnatal day (PD) 42. RESULTS: Five hundred and forty-six differentially expressed genes (DEGs) were identified (adjusted p value < 0.05). Gene ontology enrichment analysis identified pathways related to immune and lipid metabolic processes, brown fat cell differentiation, and regulation of PI3K. Ccl21, Npr3, Serpina3n, Pnpla3, Slc2a4, and Serpina12 were validated to be upregulated in catch-up pups (all p < 0.01) and related to several fat expansion and metabolic parameters, including body weight at PD42, postnatal body weight gain, white and brown adipose tissue mass, plasma triglycerides, and insulin resistance index (all p < 0.05). CONCLUSIONS: Genes related to immune and metabolic processes were upregulated in retroperitoneal adipose tissue following catch-up growth in juvenile rats and were found to be associated with fat expansion and metabolic parameters. Our results provide evidence for several dysregulated genes in white adipose tissue that could help develop novel strategies to prevent the metabolic abnormalities associated with catch-up growth. IMPACT: Catch-up growth presents several dysregulated genes in white adipose tissue related to metabolic abnormalities. Ccl21, Npr3, Serpina3n, Pnpla3, Slc2a4, and Serpina12 were validated to be upregulated in catch-up pups and related to visceral fat expansion and metabolic parameters. Profiling and validation of these dysregulated genes in visceral adipose tissue could help develop novel strategies to prevent the metabolic abnormalities associated with catch-up growth.
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- 2022
4. Metabolic programming in the offspring after gestational overfeeding in the mother: toward neonatal rescuing with metformin in a swine model
- Author
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Xargay-Torrent S, Mas-Parés B, Carreras-Badosa G, Lizárraga-Mollinedo E, Tibau J, Reixach J, Platero-Gutierrez E, Prats A, de Zegher F, Ibañez-Toda L, Bassols-Casadevall J, and López-Bermejo A
- Abstract
OBJECTIVES: Maternal overfeeding during gestation may lead to adverse metabolic programming in the offspring mediated by epigenetic alterations. Potential reversal, in early life, of these alterations may help in the prevention of future cardio-metabolic conditions. In this context, our aims were: (1) to study the effects of maternal overfeeding on the metabolic and epigenetic programming of offspring's adipose tissue; and (2) to test the potential of postnatal metformin treatment to reverse these changes. METHODS: We used a swine animal model where commercial production sows were either overfed or kept under standard diet during gestation, and piglets at birth were randomly assigned to metformin (n = 16 per group) or vehicle treatment during lactation (n = 16 per group). RESULTS: Piglets born to overfed sows showed a worse metabolic profile (higher weight, weight gain from birth and abdominal circumference; all p < 0.05) together with altered serological markers (increased HOMA-IR, fructosamine, total cholesterol, C-Reactive Protein and lower HMW adiponectin; all p < 0.05). The visceral adipose tissue also showed altered morphology (increased adipocyte area, perimeter and diameter; all p < 0.05), as well as changes in gene expression (higher CCL2 and INSR, lower DLK1; all p < 0.05), and in DNA methylation (96 hypermethylated and 99 hypomethylated CpG sites; FDR < 0.05). Metformin treatment significantly ameliorated the abnormal metabolic profile, decreasing piglets' weight, weight gain from birth, abdominal circumference and fructosamine (all p < 0.05) and reduced adipocyte area, perimeter, and diameter in visceral adipose tissue (all p < 0.05). In addition, metformin treatment potentiated several associations between gene expression in visceral adipose tissue and the altered metabolic markers. CONCLUSIONS: Maternal overfeeding during gestation leads to metabolic abnormalities in the offspring, including adipose tissue alterations. Early metformin treatment mitigates these effects and could help rescue the offspring's metabolic health.
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- 2022
5. Estimated glomerular filtration rate and cardiometabolic risk factors in a longitudinal cohort of children
- Author
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Xargay-Torrent S, Puerto-Carranza E, Marcelo I, Mas-Parés B, Gómez-Vilarrubla A, Martínez-Calcerrada JM, de Zegher F, Ibañez-Toda L, López-Bermejo A, and Bassols J
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nutritional and metabolic diseases - Abstract
Associations between glomerular filtration rate (GFR) and cardiometabolic risk factors have been reported in adult and pediatric patients with renal disease. We aimed to assess the relationship between the estimated GFR (eGFR) and cardiometabolic risk factors in apparently healthy children. A longitudinal study in 401 asymptomatic Caucasian children (mean age 8 years) followed up after 4 years (mean age 12 years). GFR was estimated using the pediatric form of the FAS-equation. Children were classified at baseline according to their obesity status (normal weight and overweight) and according to eGFR levels (lower, average, and higher). The association of eGFR with anthropometric data [body mass index (BMI) and waist], blood pressure [systolic (SBP) and diastolic (DBP)], metabolic parameters [glucose, insulin resistance (HOMA-IR) and serum lipids], and renal ultrasonography measurements were assessed at baseline and follow-up. Baseline eGFR associated with several cardiometabolic risk factors at follow-up including higher waist, SBP, HOMA-IR, and kidney size (all p < 0.0001) in both normal weight and overweight children. In multivariate analysis, baseline eGFR was independently associated with follow-up HOMA-IR and SBP in both normal weight and overweight subjects (model R(2): 0.188-0.444), and with follow-up BMI and waist in overweight subjects (model R(2): 0.367-0.477). Moreover, children with higher filtration rates at baseline showed higher waist, SBP, DBP, HOMA-IR and renal size both at baseline and follow-up. eGFR is related to insulin resistance, blood pressure and adiposity measures in school-age children. eGFR may help to profile the cardiometabolic risk of children.
- Published
- 2021
6. Fatty acids in the placenta of appropiate- versus small-for-gestational-age infants at term birth
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Gómez-Vilarrubla A, Mas-Parés B, Díaz-Silva M, Xargay-Torrent S, Carreras-Badosa G, Jové M, Martin-Gari M, Bonmatí-Santané A, de Zegher F, Ibañez-Toda L, López-Bermejo A, and Bassols J
- Subjects
Placenta ,Fatty acids ,Desaturase and elongase ,SGA ,female genital diseases and pregnancy complications ,reproductive and urinary physiology - Abstract
INTRODUCTION: Fatty acids are essential nutrients for the fetus and are supplied by the mother through the placenta. Desaturase and elongase enzymes play an important role in modulating the fatty acid composition of body tissues. We aimed to compare the fatty acid profile and the estimated desaturase and elongase activities in the placenta of appropriate (AGA) versus small-for-gestational-age (SGA), and to determine their relationship with the offspring size at birth. METHODS: The placental fatty acid profile was analyzed by gas chromatography in 84 infants (45 AGA and 30 SGA) from a prenatal cohort study. The estimated desaturase and elongase activities were calculated from product-precursor fatty acid ratios. Results were associated with maternal (age, body mass index and weight gain during gestation) and neonatal (gestational age, sex, birth weight and birth length) parameters. RESULTS: Differences in placental fatty acid composition between AGA and SGA infants rather than correlations thereof with neonatal parameters were observed. Placentas from SGA infants contained lower levels of omega-3 (ALA, EPA, DPA, and DHA) and high omega-6/omega-3 ratios (AA/DHA and LA/ALA), as well as low elongase (Elovl5) and high desaturase (D9Dn7 and D5Dn6) activity as compared to AGA infants (all p
- Published
- 2021
7. Longitudinal association of the anti-inflammatory serum marker GDF-15 with serum IgA and IgG in apparently healthy children
- Author
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Carreras-Badosa G, Gómez-Vilarrubla A, Mas-Parés B, Xargay-Torrent S, Prats A, Puerto-Carranza E, de Zegher F, Ibañez-Toda L, Bassols-Casadevall J, and López-Bermejo A
- Subjects
embryonic structures - Abstract
Both the innate and adaptive immune responses are deregulated in individuals with obesity and are key drivers of its associated metabolic alterations. Although the anti-inflammatory growth differentiation factor 15 (GDF-15) is a candidate protein against obesity, its mechanisms regulating the immune responses are not fully cleared. We examined whether GDF-15 was related to serum immunoglobulins in a children's cohort assessed longitudinally during childhood. Results showed that circulating GDF-15 positively associated with IgA (p < 0.002) and IgG (p < 0.001) levels and the IgA*IgG product (p < 0.001) in apparently healthy children at both baseline (age 9) and follow-up (age 13). The associations were readily observed in heavier children (those with BMI-SDS above the median) as well as in children with higher renal fat accumulation (those with renal fat-to-height ratio above the median) and remained significant after correcting for possible confounding variables. Serum GDF-15 levels accounted for up to 16% of the variance of follow-up IgG levels and up to 14% of the variance of follow-up IgA*IgG product. The longitudinal associations of the anti-inflammatory GDF-15 with IgA, IgG and the IgA*IgG product in children with higher BMI or higher renal fat accumulation suggest a role of GDF-15 in human obesity through the regulation of the immune adaptive system.
- Published
- 2021
8. Sorafenib targets BCR kinases and blocks migratory and microenvironmental survival signals in CLL cells
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López-Guerra, M, Xargay-Torrent, S, Pérez-Galán, P, Saborit-Villarroya, I, Rosich, L, Villamor, N, Aymerich, M, Roué, G, Campo, E, Montserrat, E, and Colomer, D
- Published
- 2012
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9. Use of Static Cutoffs of Hypertension to Determine High cIMT in Children and Adolescents: An International Collaboration Study
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Yang, L, Whincup, PH, López-Bermejo, A, Caserta, CA, Muniz Medeiros, CC, Kollias, A, Pacifico, L, Reinehr, T, Litwin, M, Owen, CG, Bassols, J, Romeo, EL, Almeida Ramos, TD, Stergiou, GS, Zhao, M, Xargay-Torrent, S, Amante, A, Estrela, TM, Grammatikos, E, Wang, M, Prats-Puig, A, Franklin de Carvalho, D, Carreras-Badosa, G, de Oliveira Simões, M, Mas-Pares, B, Shui, W, Deanfield, JE, Magnussen, CG, Xi, B, and International Childhood Vascular Structure Evaluation Consortium
- Abstract
BACKGROUND: Pediatric hypertension is typically defined as blood pressure ≥ sex-, age-, and height-specific 95th percentile (high) cutoffs. Given the number of strata, there are hundreds of cutoffs for defining elevated and high blood pressure that make it cumbersome to use in clinical practice. This study aimed to evaluate the utility of the static cutoffs for pediatric hypertension (120/80 mm Hg for children and 130/80 mm Hg for adolescents) in determining high carotid intimamedia thickness (cIMT) in children and adolescents. METHODS: Data were from 6 population-based cross-sectional studies in Brazil, China, Greece, Italy, Spain, and the United Kingdom. A total of 4280 children and adolescents, aged 6 to 17 years, were included. High cIMT was defined as cIMT ≥ sex-, age- and cohort-specific 90th percentile cutoffs. RESULTS: Compared with normal blood pressure, hypertension defined using the percentile-based cutoffs from 2017 American Academy of Pediatrics guideline, and the static cutoffs were associated with similar higher odds for high cIMT (percentile-based cutoffs: odds ratio [OR], 1.46, 95% confidence interval [CI], 1.15-1.86; static cutoffs: OR, 1.65, 95% CI, 1.25-2.17), after adjustment for sex, age, race/ethnicity, body mass index, high-density lipoprotein-cholesterol, triglyceride, and fasting blood glucose. The similar utility of 2 definitions in determining high cIMT was further confirmed by area under the receiver operating characteristic curve and net reclassification improvement methods (P for difference > 0.05). CONCLUSION: Static cutoffs (120/80 mm Hg for children, 130/80 mm Hg for adolescents) performed similarly compared with percentile-based cutoffs in determining high cIMT, supporting the use of static cutoffs in identifying pediatric hypertension in clinical practice.
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- 2020
10. Metabolic syndrome, clustering of cardiovascular risk factors and high carotid intima-media thickness in children and adolescents
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Zhao, M. Caserta, C.A. Medeiros, C.C.M. López-Bermejo, A. Kollias, A. Zhang, Q. Pacifico, L. Reinehr, T. Litwin, M. Bassols, J. Romeo, E.L. Ramos, T.D.A. Stergiou, G.S. Yang, L. Xargay-Torrent, S. Amante, A. Estrela, T.M. Grammatikos, E. Zhang, Y. Prats-Puig, A. Franklin de Carvalho, D. Yang, L. Carreras-Badosa, G. de Oliveira Simões, M. Hou, Y. Lizarraga-Mollinedo, E. Shui, W. Guo, T. Wang, M. Zhang, Y. Bovet, P. Xi, B. International Childhood Vascular Structure Evaluation Consortium
- Abstract
OBJECTIVE: The clinical utility of screening for pediatric metabolic syndrome (MetS) in children and adolescents is still controversial. We examined the performance of pediatric MetS vs. clustering of cardiovascular risk factors (which are the components of MetS) for predicting high carotid intima-media thickness (cIMT) in children and adolescents. METHODS: Participants included 2427 children and adolescents aged 6-17 years from population-based studies in three countries (Brazil, China and Italy). Pediatric MetS was defined using either the modified National Cholesterol Education Program Adult Treatment Panel III criteria or the modified International Diabetes Federation criteria. Clustering of cardiovascular risk factors was calculated as the sum of five components of MetS (i.e. central obesity, elevated blood pressure, elevated triglycerides, reduced HDL-cholesterol and elevated fasting blood glucose). High cIMT was defined as cIMT at least 95th percentile values for sex and age developed from European children. RESULTS: Presence of one, two or at least three cardiovascular risk factors (using the National Cholesterol Education Program Adult Treatment Panel III criteria), as compared with none, was associated with gradually increasing odds of high cIMT [odds ratios (95% confidence intervals): 1.60 (1.29-1.99), 2.89 (2.21-3.78) and 4.24 (2.81-6.39), respectively]. High cIMT was also associated with presence (vs. absence) of MetS (odds ratio = 2.88, 95% confidence interval = 1.95-4.26). However, clustering of cardiovascular risk factors predicted high cIMT markedly better than MetS (area under the curve of 0.66 vs. 0.54, respectively). Findings were similar using the International Diabetes Federation criteria for pediatric MetS. CONCLUSION: In children and adolescents, a graded score based on five cardiovascular risk factors (used to define MetS) predicted high cIMT markedly better than MetS. These findings do not support the clinical utility of MetS for screening youth at increased cardiovascular risk, as expressed in this study by high cIMT.
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- 2020
11. Methylation of the C19MC microRNA locus in the placenta: association with maternal and chilhood body size
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Prats A, Xargay-Torrent S, Carreras-Badosa G, Mas-Parés B, Bassols J, Petry CJ, Girardot M, D E Zegher F, Ibañez-Toda L, Dunger DB, Feil R, and López-Bermejo A
- Abstract
OBJECTIVES: To study DNA methylation at the C19MC locus in the placenta and its association with (1) parental body size, (2) transmission of haplotypes for the C19MC rs55765443 SNP, and (3) offspring's body size and/or body composition at birth and in childhood. SUBJECTS AND METHODS: Seventy-two pregnant women-infant pairs and 63 fathers were included in the study. Weight and height of mothers, fathers and newborns were registered during pregnancy or at birth (n = 72). Placental DNA methylation at the C19MC imprinting control region (ICR) was quantified by bisulfite pyrosequencing. Genotyping of the SNP was performed using restriction fragment length polymorphisms. The children's body size and composition were reassessed at age 6 years (n = 32). RESULTS: Lower levels of placental C19MC methylation were associated with increased body size of mother, specifically with higher pregestational and predelivery weights and height of the mother (ß from -0.294 to -0.371; R(2) from 0.04 to 0.10 and all p < 0.019), and with higher weight, height, waist and hip circumferences, and fat mass of the child (ß from -0.428 to -0.552; R(2) from 0.33 to 0.56 and all p < 0.009). Parental transmission of the SNP did not correlate with an altered placental methylation status at the C19MC ICR. CONCLUSIONS: Increased maternal size is associated with reduced placental C19MC methylation, which, in turn, relate to larger body size of the child.
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- 2020
12. Use of Static Cutoffs of Hypertension to Determine High cIMT in Children and Adolescents: An International Collaboration Study
- Author
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Yang, L. Whincup, P.H. López-Bermejo, A. Caserta, C.A. Muniz Medeiros, C.C. Kollias, A. Pacifico, L. Reinehr, T. Litwin, M. Owen, C.G. Bassols, J. Romeo, E.L. Almeida Ramos, T.D. Stergiou, G.S. Zhao, M. Yang, L. Xargay-Torrent, S. Amante, A. Gusmão, T.M.E. Grammatikos, E. Wang, M. Prats-Puig, A. Franklin de Carvalho, D. Carreras-Badosa, G. de Oliveira Simões, M. Mas-Pares, B. Shui, W. Deanfield, J.E. Magnussen, C.G. Xi, B. International Childhood Vascular Structure Evaluation Consortium
- Abstract
Background: Pediatric hypertension is typically defined as blood pressure ≥ sex-, age-, and height-specific 95th percentile (high) cutoffs. Given the number of strata, there are hundreds of cutoffs for defining elevated and high blood pressure that make it cumbersome to use in clinical practice. This study aimed to evaluate the utility of the static cutoffs for pediatric hypertension (120/80 mm Hg for children and 130/80 mm Hg for adolescents) in determining high carotid intimamedia thickness (cIMT) in children and adolescents. Methods: Data were from 6 population-based cross-sectional studies in Brazil, China, Greece, Italy, Spain, and the United Kingdom. A total of 4280 children and adolescents, aged 6 to 17 years, were included. High cIMT was defined as cIMT ≥ sex-, age- and cohort-specific 90th percentile cutoffs. Results: Compared with normal blood pressure, hypertension defined using the percentile-based cutoffs from 2017 American Academy of Pediatrics guideline, and the static cutoffs were associated with similar higher odds for high cIMT (percentile-based cutoffs: odds ratio [OR], 1.46, 95% confidence interval [CI], 1.15-1.86; static cutoffs: OR, 1.65, 95% CI, 1.25-2.17), after adjustment for sex, age, race/ethnicity, body mass index, high-density lipoprotein-cholesterol, triglyceride, and fasting blood glucose. The similar utility of 2 definitions in determining high cIMT was further confirmed by area under the receiver operating characteristic curve and net reclassification improvement methods (P for difference > 0.05). Conclusion: Static cutoffs (120/80 mm Hg for children, 130/80 mm Hg for adolescents) performed similarly compared with percentile-based cutoffs in determining high cIMT, supporting the use of static cutoffs in identifying pediatric hypertension in clinical practice. © 2020 Canadian Cardiovascular Society
- Published
- 2020
13. Circulating IGF-1 Independently Predicts Blood Pressure in Children With Higher Calcium-Phosphorus Product Levels
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Xargay-Torrent S, Dorado-Ceballos E, Benavides-Boixader A, Lizárraga-Mollinedo E, Mas-Parés B, Montesinos-Costa M, De Zegher F, Ibañez-Toda L, Bassols J, and López-Bermejo A
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IGFBP-3 ,IGF-1 ,calcium-phosphorus product ,hypertension - Abstract
OBJECTIVE: To study the association between insulin-like growth factor 1 (IGF-1) and blood pressure in children, in particular, the potential interaction with the serum calcium-phosphorus product (Ca*P). METHODS: A longitudinal study included 521 children (age 8.8 ± 0.1) from northeastern Spain, of whom 158 were followed-up after 5 years. IGF-1, insulin-like growth factor-binding protein 3 (IGFBP-3), and serum calcium and phosphorus were measured at baseline. Anthropometric (body-mass index [BMI] and waist) and cardiometabolic variables (systolic [SBP] and diastolic blood pressure), pulse pressure, insulin, homeostatic model assessment of insulin resistance [HOMA-IR], high-density lipoprotein [HDL]-cholesterol, and triglycerides) were assessed at baseline and at the end of follow-up. Statistical analysis included Pearson correlations followed by multivariable linear regression analyses. RESULTS: Baseline IGF-1 and IGF-1/IGFBP-3 molar ratio positively correlated with baseline and follow-up BMI, waist, SBP, pulse pressure, insulin, HOMA-IR and triglycerides (r 0.138-0.603; all P < 0.05). The associations with SBP were stronger with increasing Ca*P (r 0.261-0.625 for IGF-1; and r 0.174-0.583 for IGF-1/IGFBP-3). After adjusting for confounding variables, baseline IGF-1 and IGF-1/IGFBP-3 remained independently associated with both baseline and follow-up SBP in children in the highest Ca*P tertile (ß = 0.245-0.381; P < 0.01; model R2 = 0.246-0.566). CONCLUSIONS: Our results suggest that IGF-1 in childhood is an independent predictor of SBP in apparently healthy children, especially in those with high Ca*P levels.
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- 2020
14. DNA methylation signatures in placenta and umbilical cord: association with maternal obesity
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Mas-Pares, B, Xargay-Torrent, S, Gomez-Vilarrubla, A, Lizarraga-Mollinedo E, Martinez-Calcerrada, JM, Bonmati-Santane, A, de Zegher F, Ibañez-Toda L, López-Bermejo A, and Bassols-Casadevall J
- Published
- 2019
15. Dlk1 expression relates to visceral fat expansion and insulin resistance in male and female rats with postnatal catch-up growth
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Carreras-Badosa G, Remesar X, Prats A, Xargay-Torrent S, Lizarraga-Mollinedo E, de Zegher F, Ibañez-Toda L, Bassols J, and López-Bermejo A
- Abstract
BACKGROUND: Although prenatal and postnatal programming of metabolic diseases in adulthood is well established, the mechanisms underpinning metabolic programming are not. Dlk1, a key regulator of fetal development, inhibits adipocyte differentiation and restricts fetal growth. METHODS: Assess DLk1 expression in a Wistar rat model of catch-up growth following intrauterine restriction. Dams fed ad libitum delivered control pups (C) and dams on a 50% calorie-restricted diet delivered pups with low birth weight (R). Restricted offspring fed a standard rat chow showed catch-up growth (R/C) but those kept on a calorie-restricted diet did not (R/R). RESULTS: Decreased Dlk1 expression was observed in adipose tissue and skeletal muscle of R/C pups along with excessive visceral fat accumulation, decreased circulating adiponectin, increased triglycerides and HOMA-IR (from p < 0.05 to p < 0.0001). Moreover, in R/C pups the reduced Dlk1 expression in adipose tissue and skeletal muscle correlated with visceral fat (r = -0.820, p < 00001) and HOMA-IR (r = -0.745, p = 0.002). CONCLUSIONS: Decreased Dlk1 expression relates to visceral fat expansion and insulin resistance in a rat model of catch-up growth following prenatal growth restriction. Modulation of Dlk1 expression could be among the targets for the early prevention of fetal programming of adult metabolic disorders.
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- 2019
16. Effects of metformin administration on endocrine-metabolic parameters, visceral adiposity and cardiovascular risk factors in children with obesity and risk markers for metabolic syndrome: A pilot study
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Bassols-Casadevall J, Martínez-Calcerrada JM, Osiniri I, Díaz-Roldán F, Xargay-Torrent S, Mas-Parés B, Dorado-Ceballos E, Prats A, Carreras-Badosa G, de Zegher F, Ibañez-Toda L, and López-Bermejo A
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nutritional and metabolic diseases - Abstract
BACKGROUND: Metformin treatment (1000-2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity. METHODS: A pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months. RESULTS: The 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin-to-high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected. CONCLUSION: In this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits.
- Published
- 2019
17. Umbilical Cord miRNAs in Small-for-Gestational-Age Children and Association With Catch-Up Growth: A Pilot Study
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Mas-Parés B, Xargay-Torrent S, Bonmatí A, Lizarraga-Mollinedo E, Martínez-Calcerrada JM, Carreras-Badosa G, Prats A, de Zegher F, Ibañez-Toda L, López-Bermejo A, and Bassols J
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reproductive and urinary physiology - Abstract
CONTEXT: Catch-up growth in infants who are small for gestational age (SGA) is a risk factor for the development of cardiometabolic diseases in adulthood. The basis and mechanisms underpinning catch-up growth in newborns who are SGA are unknown. OBJECTIVE: To identify umbilical cord miRNAs associated with catch-up growth in infants who are SGA and study their relationship with offspring's cardiometabolic parameters. DESIGN: miRNA PCR panels were used to study the miRNA profile in umbilical cord tissue of five infants who were SGA with catch-up (SGA-CU), five without catch-up (SGA-nonCU), and five control infants [appropriate for gestational age (AGA)]. The miRNAs with the smallest nominal P values were validated in 64 infants (22 AGA, 18 SGA-nonCU, and 24 SGA-CU) and correlated with anthropometric parameters at 1 (n = 64) and 6 years of age (n = 30). RESULTS: miR-501-3p, miR-576-5p, miR-770-5p, and miR-876-3p had nominally significant associations with increased weight, height, weight catch-up, and height catch-up at 1 year, and miR-374b-3p, miR-548c-5p, and miR-576-5p had nominally significant associations with increased weight, height, waist, hip, and renal fat at 6 years. Multivariate analysis suggested miR-576-5p as a predictor of weight catch-up and height catch-up at 1 year, as well as weight, waist, and renal fat at 6 years. In silico studies suggested that miR-576-5p participates in the regulation of inflammatory, growth, and proliferation signaling pathways. CONCLUSIONS: Umbilical cord miRNAs could be novel biomarkers for the early identification of catch-up growth in infants who are SGA. miR-576-5p may contribute to the regulation of postnatal growth and influence the risk for cardiometabolic diseases associated with a mismatch between prenatal and postnatal weight gain.
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- 2019
18. Circulating Insulin-like Growth Factor-I independently predicts blood pressure in apparently healthy children
- Author
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Xargay-Torrent, S, Dorado-Ceballos, E, Benavides-Boixader, A, Lizarraga-Mollinedo E, Mas-Pares, B, Montesinos-Costa, M, de Zegher F, Ibañez-Toda L, Bassols-Casadevall J, and López-Bermejo A
- Published
- 2019
19. Carotid intima-media thickness relates rather to epicardial and perirenal fat than total body adiposity in apparently healthy children
- Author
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Prats-Puig, A, Xargay-Torrent, S, Camos-Carreras, M, Carreras-Badosa, G, Martinez-Calcerrada, JM, Riera, E, de Zegher F, Ibañez-Toda L, Bassols-Casadevall J, and López-Bermejo A
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- 2019
20. Renal size and cardiovascular risk in prepubertal children
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Lizarraga-Mollinedo E, Martínez-Calcerrada JM, Padrós-Fornieles C, Mas-Pares B, Xargay-Torrent S, Riera-Pérez E, Prats A, Carreras-Badosa G, de Zegher F, Ibañez-Toda L, Bassols J, and López-Bermejo A
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cardiovascular diseases - Abstract
Renal size is an important parameter for the evaluation and diagnosis of kidney disease and has been associated with several cardiovascular risk factors in patients with kidney failure. These results are however discordant and studies in healthy children are lacking. We aimed to study the association between renal size (length and volume) and cardiovascular risk parameters in healthy children. Clinical, analytical and ultrasound parameters [renal length, renal volume, perirenal fat and carotid intima-media thickness (cIMT)] were determined in 515 healthy prepubertal children (176 lean, 208 overweight and 131 obese). Renal length and volume associated significantly and positively with several anthropometric and cardiovascular risk parameters including cIMT and systolic blood pressure (SBP) (all p < 0.001). Renal length and volume associated with cIMT and SBP in all study subgroups, but these associations were predominant in obese children, in whom these associations were independent after adjusting for age, gender and BSA (all p < 0.05). In multivariate analyses in the study subjects as a whole, renal length was an independent predictor of cIMT (ß = 0.310, p < 0.0001) and SBP (ß = 0.116, p = 0.03). Renal size associates with cIMT and SBP, independent of other well-established cardiovascular risk factors, and may represent helpful parameters for the early assessment of cardiovascular risk in children.
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- 2019
21. Dysregulated gene expression profile in visceral adipose tissue of juvenile Wistar rats with catch-up growth: association with fat expansion and metabolic parameters
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Lizarraga-Mollinedo E, Carreras-Badosa, G, Remesar, X, Xargay-Torrent, S, Mas-Pares, B, Prats-Puig, A, de Zegher F, Ibañez-Toda L, López-Bermejo A, and Bassols-Casadevall J
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- 2019
22. The bilirubin/triglycerides ratio predicts changes over time in glycated hemoglobin in prepubertal healthy children
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Puerto-Carranza, E, Casals, SN, Portella, BR, Xargay-Torrent, S, Lizarraga-Mollinedo E, Mas-Pares, B, deZegher, F, Ibañez-Toda L, Bassols-Casadevall J, and López-Bermejo A
- Published
- 2019
23. Serum alkaline phosphatase relates to cardiovascular risk markers in children with high calcium-phosphorus product
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Xargay-Torrent S, Espuña-Capote N, Montesinos-Costa M, Prats A, Carreras-Badosa G, Díaz-Roldán F, De Zegher F, Ibañez-Toda L, Bassols J, and López-Bermejo A
- Abstract
Although alkaline phosphatase (ALP) correlates with cardiovascular risk in adults, there are no studies in children. We evaluated the association between serum ALP levels, calcium-phosphorus product (Ca*P) and cardiovascular risk markers in healthy children. Children aged 7.9 ± 1.4 (n = 379) were recruited in this cross-sectional study. The main outcome measures were systolic and diastolic blood pressure (SBP and DBP) and carotid intima-media thickness (cIMT). Additional assessments were body-mass index (BMI), waist circumference, homeostatic model assessment of insulin resistance (HOMA-IR) and fasting lipids, ALP, serum calcium, phosphorus and Ca*P. ALP was directly correlated with BMI (p < 0.0001), waist circumference (p < 0.0001), SBP (p < 0.0001), cIMT (p = 0.005), HOMA-IR (p < 0.0001), and fasting triglycerides (p = 0.0001). Among them, in children with Ca*P values above the median the associations were BMI (r = 0.231; p = 0.001), waist (r = 0.252; p < 0.0001), SBP (r = 0.324; p < 0.0001), cIMT (r = 0.248; p = 0.001) and HOMA-IR (r = 0.291; p < 0.0001)]. ALP independently associated with SBP (ß = 0.290, p < 0.001) and cIMT (ß = 0.179, p = 0.013) in children with higher Ca*P, after adjusting for confounding variables. Circulating ALP is associated with a more adverse cardiovascular profile in children with higher Ca*P. We suggest that serum ALP and Ca*P levels could contribute to the assessment of risk for cardiovascular disease in children.
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- 2018
24. Circulating sex hormone binding globulin: An integrating biomarker for an adverse cardio-metabolic profile in obese pregnant women
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Xargay-Torrent S, Carreras-Badosa G, Borrat-Padrosa S, Prats A, Soriano P, Álvarez-Castaño E, Ferri MJ, De Zegher F, Ibañez-Toda L, López-Bermejo A, and Bassols J
- Subjects
reproductive and urinary physiology ,hormones, hormone substitutes, and hormone antagonists - Abstract
Sex hormone-binding globulin (SHBG) negatively associates with pre-gestational body mass index (BMI) and gestational weight gain. The link with other cardio-metabolic risk factors in pregnant women is poorly understood. Our aim was to study the association of SHBG levels with common cardio-metabolic risk parameters in pregnant woman. Serum SHBG was quantified in 291 Caucasian pregnant women (142 with normal weight, 42 with pregestational obesity, 50 with gestational obesity and 57 with pregestational plus gestational obesity) with uncomplicated pregnancies and parturition. Cardio-metabolic [C-reactive protein (CRP), blood pressure (BP), glycosylated hemoglobin (HbAc1), glucose, C-peptide, insulin, triglycerides and high molecular weight (HMW) adiponectin], and endocrine [testosterone and estradiol] parameters were also assessed. SHBG was negatively correlated with BMI, but also with CRP, BP, HbAc1, pre and post-load glucose, C-peptide, HOMA-IR, triglycerides; and positively with HMW adiponectin (all p
- Published
- 2018
25. Expression of MIR-576-5p in Umbilical Cord as a Novel Biomarker for the Identification of Catch-Up Growth in Small-For-Gestational-Age Infants
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Bassols-Casadevall J, Mas-Pares, B, Bonmati, A, Xargay-Torrent, S, Carreras-Badosa, G, Lizarraga-Mollinedo E, Martinez-Calcerrada, JM, de Zegher F, Ibañez-Toda L, and López-Bermejo A
- Published
- 2018
26. MIRNAS IN UMBILICAL CORD OF SMALL-FOR-GESTATIONALAGE INFANTS AT BIRTH: ASSOCIATION WITH POSTNATAL CATCH-UP GROWTH
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Bassols-Casadevall J, Xargay-Torrent, S, Bonmati, A, Prats-Puig, A, Carreras-Badosa, G, Lizarraga-Mollinedo E, Badosa, E, de Zegher F, Ibañez-Toda L, and López-Bermejo A
- Published
- 2017
27. METABOLIC AND EPIGENETIC ABNORMALITIES OF ADIPOSE TISSUE IN PIGLETS BORN TO SOWS OVERFED DURING GESTATION: PARTIAL NORMALIZATION BY POSTNATAL METFORMIN TREATMENT
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Xargay-Torrent, S, Carreras-Badosa G, Tibau, J, Pallissera, J, Prats-Puig, A, Lizarraga-Mollinedo E, Petry, CJ, Dunger, DB, de Zegher F, Ibañez-Toda L, Bassols-Casadevall J, and López-Bermejo A
- Published
- 2017
28. Perirenal fat is related to carotid intima-media thickness in children
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Bassols, J, primary, Martínez-Calcerrada, J-M, additional, Prats-Puig, A, additional, Carreras-Badosa, G, additional, Xargay-Torrent, S, additional, Lizarraga-Mollinedo, E, additional, Feliu-Alsina, M, additional, Riera-Pérez, E, additional, Osiniri, I, additional, de Zegher, F, additional, Ibáñez, L, additional, and López-Bermejo, A, additional
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- 2017
- Full Text
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29. Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications
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Vegliante, M.C. (Maria Carmela), Royo, C. (Cristina), Palomero, J. (Jara), Salaverria, I. (Itziar), Balint, B. (Balazs), Martin-Guerrero, I. (Idoia), Agirre, X. (Xabier), Lujambio, A. (Amaya), Richter, J. (Julia), Xargay-Torrent, S. (Silvia), Bea, S. (Silvia), Hernandez, L. (Luis), Enjuanes, A. (Anna), Calasanz-Abinzano, M.J. (Maria Jose), Rosenwald, A. (Andreas), Ott, G. (German), Roman-Gomez, J. (José), Prosper, F. (Felipe), Esteller, M. (Manel), Jares, P. (Pedro), Siebert, R. (Reiner), Campo, E. (Elías), Martin-Subero, J.I. (Jose Ignacio), Amador, V. (Virginia), Vegliante, M.C. (Maria Carmela), Royo, C. (Cristina), Palomero, J. (Jara), Salaverria, I. (Itziar), Balint, B. (Balazs), Martin-Guerrero, I. (Idoia), Agirre, X. (Xabier), Lujambio, A. (Amaya), Richter, J. (Julia), Xargay-Torrent, S. (Silvia), Bea, S. (Silvia), Hernandez, L. (Luis), Enjuanes, A. (Anna), Calasanz-Abinzano, M.J. (Maria Jose), Rosenwald, A. (Andreas), Ott, G. (German), Roman-Gomez, J. (José), Prosper, F. (Felipe), Esteller, M. (Manel), Jares, P. (Pedro), Siebert, R. (Reiner), Campo, E. (Elías), Martin-Subero, J.I. (Jose Ignacio), and Amador, V. (Virginia)
- Abstract
Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications
- Published
- 2014
30. The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells
- Author
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López-Guerra, M, primary, Xargay-Torrent, S, additional, Rosich, L, additional, Montraveta, A, additional, Roldán, J, additional, Matas-Céspedes, A, additional, Villamor, N, additional, Aymerich, M, additional, López-Otín, C, additional, Pérez-Galán, P, additional, Roué, G, additional, Campo, E, additional, and Colomer, D, additional
- Published
- 2014
- Full Text
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31. Perirenal fat is related to carotid intima-media thickness in children
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Bassols, J, Martínez-Calcerrada, J-M, Prats-Puig, A, Carreras-Badosa, G, Xargay-Torrent, S, Lizarraga-Mollinedo, E, Feliu-Alsina, M, Riera-Pérez, E, Osiniri, I, de Zegher, F, Ibáñez, L, and López-Bermejo, A
- Abstract
Background/Objectives:It is well known that increased abdominal fat is associated with cardiovascular (CV) risk. Perirenal fat has been recently associated with CV risk in adults. However, studies with children are lacking. We investigated the relationship of perirenal fat and other abdominal fat depots (including preperitoneal, intra-abdominal and subcutaneous fat) with carotid intima-media thickness (cIMT—a surrogate marker of CV risk) in prepubertal children, so as to identify novel markers that can be easily assessed and used in the early prevention of cardiovascular disease.Subjects/Methods:Subjects were 702 asymptomatic prepubertal Caucasian children (418 lean, 142 overweight and 142 obese) who were recruited in a primary care setting. Ultrasound measurements (perirenal, preperitoneal, intra-abdominal and subcutaneous fat and cIMT), clinical (body mass index (BMI) and systolic blood pressure) and metabolic parameters (insulin resistance (HOMA-IR), high molecular weight (HMW) adiponectin and serum lipids) were assessed.Results:Perirenal fat was associated with diverse metabolic and CV risk factors in all the studied subjects. However, in overweight and obese children, perirenal fat was mostly associated with cIMT (P<0.001) and was the only fat depot that showed independent associations with cIMT in multivariate analyses (overweight chidren: β=0.250, P=0.003, r2=12.8%; obese children: β=0.254, P=0.002, r2=15.5%) after adjusting for BMI, gender, age and metabolic parameters. Perirenal fat was also the only fat depot that showed independent associations with HMW-adiponectin in obese children (β=−0.263, P=0.006, r2=22.8%).Conclusions:Perirenal fat is the main abdominal fat depot associated with cIMT, especially in overweight and obese children, and may thus represent a helpful parameter for assessing CV risk in the pediatric population.
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- 2018
- Full Text
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32. The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells
- Author
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Rosich, L., primary, Saborit-Villarroya, I., additional, Lopez-Guerra, M., additional, Xargay-Torrent, S., additional, Montraveta, A., additional, Aymerich, M., additional, Villamor, N., additional, Campo, E., additional, Perez-Galan, P., additional, Roue, G., additional, and Colomer, D., additional
- Published
- 2013
- Full Text
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33. 850 Autophagy Inhibition Sensitizes Mantle Cell Lymphoma Cells to Everolimus
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Rosich, L., primary, Xargay-Torrent, S., additional, Lopez-Guerra, M., additional, Campo, E., additional, Colomer, D., additional, and Roue, G., additional
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- 2012
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34. 1046 Sorafenib Inhibits Cell Migration and Stroma-mediated Bortezomib Resistance by Interfering BCR Signaling and Protein Translation in Mantle Cell Lymphoma
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Xargay-Torrent, S., primary, Lopez-Guerra, M., additional, Saborit-Villarroya, I., additional, Rosich, L., additional, Navarro, A., additional, Perez-Galan, P., additional, Roue, G., additional, Campo, E., additional, and Colomer, D., additional
- Published
- 2012
- Full Text
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35. Sorafenib targets BCR kinases and blocks migratory and microenvironmental survival signals in CLL cells
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López-Guerra, M, primary, Xargay-Torrent, S, additional, Pérez-Galán, P, additional, Saborit-Villarroya, I, additional, Rosich, L, additional, Villamor, N, additional, Aymerich, M, additional, Roué, G, additional, Campo, E, additional, Montserrat, E, additional, and Colomer, D, additional
- Published
- 2011
- Full Text
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36. 166 BAY 43-9006/Sorafenib overcomes the protective effect of stroma and synergizes with the BH3-mimetic GX15–070/Obatoclax in chronic lymphocytic leukemia cells
- Author
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Lopez-Guerra, M., primary, Xargay-Torrent, S., additional, Saborit-Villarroya, I., additional, Rosich, L., additional, Roue, G., additional, and Colomer, D., additional
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- 2010
- Full Text
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37. 117 Vorinostat induces acetylation of BH3-only gene promoters triggering their expression and leading to apoptosis in mantle cell lymphoma
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Xargay-Torrent, S., primary, Roué, G., additional, López-Guerra, M., additional, Saborit-Villarroya, I., additional, Campo, E., additional, and Colomer, D., additional
- Published
- 2010
- Full Text
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38. Cell Death Targeting Therapies in B Lymphoid Malignancies
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Saborit-Villarroya, I., primary, Roue, G., additional, Lopez-Guerra, M., additional, Alonso, R., additional, Xargay-Torrent, S., additional, Rosich, L., additional, and Colomer, D., additional
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- 2010
- Full Text
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39. Gestational Caloric Restriction Alters Adipose Tissue Methylome and Offspring's Metabolic Profile in a Swine Model.
- Author
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Mas-Parés B, Xargay-Torrent S, Carreras-Badosa G, Gómez-Vilarrubla A, Niubó-Pallàs M, Tibau J, Reixach J, Prats-Puig A, de Zegher F, Ibañez L, Bassols J, and López-Bermejo A
- Subjects
- Pregnancy, Animals, Female, Swine, Epigenome, Caloric Restriction, Adipose Tissue, Metabolome, Malnutrition, Metformin pharmacology
- Abstract
Limited nutrient supply to the fetus results in physiologic and metabolic adaptations that have unfavorable consequences in the offspring. In a swine animal model, we aimed to study the effects of gestational caloric restriction and early postnatal metformin administration on offspring's adipose tissue epigenetics and their association with morphometric and metabolic variables. Sows were either underfed (30% restriction of total food) or kept under standard diet during gestation, and piglets were randomly assigned at birth to receive metformin (n = 16 per group) or vehicle treatment (n = 16 per group) throughout lactation. DNA methylation and gene expression were assessed in the retroperitoneal adipose tissue of piglets at weaning. Results showed that gestational caloric restriction had a negative effect on the metabolic profile of the piglets, increased the expression of inflammatory markers in the adipose tissue, and changed the methylation of several genes related to metabolism. Metformin treatment resulted in positive changes in the adipocyte morphology and regulated the methylation of several genes related to atherosclerosis, insulin, and fatty acids signaling pathways. The methylation and gene expression of the differentially methylated FASN , SLC5A10 , COL5A1 , and PRKCZ genes in adipose tissue associated with the metabolic profile in the piglets born to underfed sows. In conclusion, our swine model showed that caloric restriction during pregnancy was associated with impaired inflammatory and DNA methylation markers in the offspring's adipose tissue that could predispose the offspring to later metabolic abnormalities. Early metformin administration could modulate the size of adipocytes and the DNA methylation changes.
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- 2024
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40. Correction: Dlk1 expression relates to visceral fat expansion and insulin resistance in male and female rats with postnatal catch-up growth.
- Author
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Carreras-Badosa G, Remesar X, Prats-Puig A, Xargay-Torrent S, Lizarraga-Mollinedo E, de Zegher F, Ibáñez L, Bassols J, and López-Bermejo A
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- 2024
- Full Text
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41. Gestational Weight Gain Relates to DNA Methylation in Umbilical Cord, Which, In Turn, Associates with Offspring Obesity-Related Parameters.
- Author
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Mas-Parés B, Xargay-Torrent S, Gómez-Vilarrubla A, Carreras-Badosa G, Prats-Puig A, De Zegher F, Ibáñez L, Bassols J, and López-Bermejo A
- Subjects
- Humans, DNA Methylation, Weight Gain genetics, Umbilical Cord, Body Mass Index, Gestational Weight Gain, Pediatric Obesity genetics
- Abstract
Excessive gestational weight gain (GWG) has a negative impact on offspring's health. Epigenetic modifications mediate these associations by causing changes in gene expression. We studied the association between GWG and DNA methylation in umbilical cord tissue; and determined whether the DNA methylation and the expression of corresponding annotated genes were associated with obesity-related parameters in offspring at 6 years of age. The methylated CpG sites (CpGs) associated with GWG were identified in umbilical cord tissue by genome-wide DNA methylation ( n = 24). Twelve top CpGs were validated in a wider sample by pyrosequencing ( n = 87), and the expression of their 5 annotated genes ( SETD8 , TMEM214 , SLIT3 , RPTOR , and HOXC8 ) was assessed by RT-PCR. Pyrosequencing results validated the association of SETD8, SLIT3, and RPTOR methylation with GWG and showed that higher levels of SETD8 and RPTOR methylation and lower levels of SLIT3 methylation relate to a higher risk of obesity in the offspring. The association of SETD8 and SLIT3 gene expression with offspring outcomes paralleled the association of methylation levels in opposite directions. Epigenetic changes in the umbilical cord tissue could explain, in part, the relationship between GWG and offspring obesity risk and be early biomarkers for the prevention of overweight and obesity in childhood.
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- 2023
- Full Text
- View/download PDF
42. Placental epigenetic marks related to gestational weight gain reveal potential genes associated with offspring obesity parameters.
- Author
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Gómez-Vilarrubla A, Mas-Parés B, Carreras-Badosa G, Xargay-Torrent S, Prats-Puig A, Bonmatí-Santané A, de Zegher F, Ibañez L, López-Bermejo A, and Bassols J
- Subjects
- Humans, Female, Pregnancy, Placenta, Obesity genetics, Epigenesis, Genetic, Body Mass Index, Proto-Oncogene Proteins, Adaptor Proteins, Signal Transducing, Weight Gain genetics, Gestational Weight Gain genetics
- Abstract
Objective: Offspring exposed to gestational obesity have an increased risk for chronic diseases. Increasing evidence suggests that epigenetics may play a mechanistic role in metabolic programming. This study aimed to identify placental DNA methylation marks associated with gestational weight gain (GWG) and to study their association with offspring obesity parameters at school age., Methods: A global methylation array was performed in 24 placentas from mothers with different degrees of GWG (screening sample). The methylation percentage of four cytosine-guanine (CpG) sites and the relative expression of the respective annotated genes were studied in 90 additional placentas (validation sample). Associations of these epigenetic marks with clinical parameters in the offspring at 6 years of age were examined., Results: The screening analysis identified 104 CpG sites (97 genes) associated with GWG. The validation analysis of four selected CpG sites (annotating for FRAT1, SNX5, and KCNK3 genes) showed that the upregulation of SNX5 methylation, the downregulation of FRAT1 methylation, and KCNK3 underexpression associated with an adverse metabolic phenotype in children of women with increased GWG., Conclusions: These results suggest that placental regulation of FRAT1, SNX5, and KCNK3 relates to obesity parameters in offspring exposed to excessive GWG and thereby could condition the risk for future metabolic disorders., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)
- Published
- 2023
- Full Text
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43. Use of Static Cutoffs of Hypertension to Determine High cIMT in Children and Adolescents: An International Collaboration Study.
- Author
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Yang L, Whincup PH, López-Bermejo A, Caserta CA, Muniz Medeiros CC, Kollias A, Pacifico L, Reinehr T, Litwin M, Owen CG, Bassols J, Romeo EL, Almeida Ramos TD, Stergiou GS, Zhao M, Yang L, Xargay-Torrent S, Amante A, Gusmão TME, Grammatikos E, Wang M, Prats-Puig A, Franklin de Carvalho D, Carreras-Badosa G, de Oliveira Simões M, Mas-Pares B, Shui W, Deanfield JE, Magnussen CG, and Xi B
- Subjects
- Adolescent, Child, Cross-Sectional Studies, Female, Global Health, Humans, Hypertension etiology, Hypertension physiopathology, Male, Morbidity trends, Pediatric Obesity epidemiology, Risk Factors, Blood Pressure physiology, Body Mass Index, Carotid Intima-Media Thickness, Hypertension diagnosis, Pediatric Obesity complications
- Abstract
Background: Pediatric hypertension is typically defined as blood pressure ≥ sex-, age-, and height-specific 95th percentile (high) cutoffs. Given the number of strata, there are hundreds of cutoffs for defining elevated and high blood pressure that make it cumbersome to use in clinical practice. This study aimed to evaluate the utility of the static cutoffs for pediatric hypertension (120/80 mm Hg for children and 130/80 mm Hg for adolescents) in determining high carotid intimamedia thickness (cIMT) in children and adolescents., Methods: Data were from 6 population-based cross-sectional studies in Brazil, China, Greece, Italy, Spain, and the United Kingdom. A total of 4280 children and adolescents, aged 6 to 17 years, were included. High cIMT was defined as cIMT ≥ sex-, age- and cohort-specific 90th percentile cutoffs., Results: Compared with normal blood pressure, hypertension defined using the percentile-based cutoffs from 2017 American Academy of Pediatrics guideline, and the static cutoffs were associated with similar higher odds for high cIMT (percentile-based cutoffs: odds ratio [OR], 1.46, 95% confidence interval [CI], 1.15-1.86; static cutoffs: OR, 1.65, 95% CI, 1.25-2.17), after adjustment for sex, age, race/ethnicity, body mass index, high-density lipoprotein-cholesterol, triglyceride, and fasting blood glucose. The similar utility of 2 definitions in determining high cIMT was further confirmed by area under the receiver operating characteristic curve and net reclassification improvement methods (P for difference > 0.05)., Conclusion: Static cutoffs (120/80 mm Hg for children, 130/80 mm Hg for adolescents) performed similarly compared with percentile-based cutoffs in determining high cIMT, supporting the use of static cutoffs in identifying pediatric hypertension in clinical practice., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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44. DNA Methylation Reorganization of Skeletal Muscle-Specific Genes in Response to Gestational Obesity.
- Author
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Prats-Puig A, García-Retortillo S, Puig-Parnau M, Vasileva F, Font-Lladó R, Xargay-Torrent S, Carreras-Badosa G, Mas-Parés B, Bassols J, and López-Bermejo A
- Abstract
The goals were to investigate in umbilical cord tissue if gestational obesity: (1) was associated with changes in DNA methylation of skeletal muscle-specific genes; (2) could modulate the co-methylation interactions among these genes. Additionally, we assessed the associations between DNA methylation levels and infant's variables at birth and at age 6. DNA methylation was measured in sixteen pregnant women [8-gestational obesity group; 8-control group] in umbilical cord using the Infinium Methylation EPIC Bead Chip microarray. Differentially methylated CpGs were identified with Beta Regression Models [false discovery rate (FDR) < 0.05 and an Odds Ratio > 1.5 or < 0.67]. DNA methylation interactions between CpGs of skeletal muscle-specific genes were studied using data from Pearson correlation matrices. In order to quantify the interactions within each network, the number of links was computed. This identification analysis reported 38 differential methylated CpGs within skeletal muscle-specific genes (comprising 4 categories: contractibility, structure, myokines, and myogenesis). Compared to control group, gestational obesity (1) promotes hypermethylation in highly methylated genes and hypomethylation in low methylated genes; (2) CpGs in regions close to transcription sites and with high CpG density are hypomethylated while regions distant to transcriptions sites and with low CpG density are hypermethylated; (3) diminishes the number of total interactions in the co-methylation network. Interestingly, the associations between infant's fasting glucose at age 6 and MYL6, MYH11, TNNT3, TPM2, CXCL2, and NCAM1 were still relevant after correcting for multiple testing. In conclusion, our study showed a complex interaction between gestational obesity and the epigenetic status of muscle-specific genes in umbilical cord tissue. Additionally, gestational obesity may alter the functional co-methylation connectivity of CpG within skeletal muscle-specific genes interactions, our results revealing an extensive reorganization of methylation in response to maternal overweight. Finally, changes in methylation levels of skeletal muscle specific genes may have persistent effects on the offspring of mothers with gestational obesity., (Copyright © 2020 Prats-Puig, García-Retortillo, Puig-Parnau, Vasileva, Font-Lladó, Xargay-Torrent, Carreras-Badosa, Mas-Parés, Bassols and López-Bermejo.)
- Published
- 2020
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45. Metabolic syndrome, clustering of cardiovascular risk factors and high carotid intima-media thickness in children and adolescents.
- Author
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Zhao M, Caserta CA, Medeiros CCM, López-Bermejo A, Kollias A, Zhang Q, Pacifico L, Reinehr T, Litwin M, Bassols J, Romeo EL, Ramos TDA, Stergiou GS, Yang L, Xargay-Torrent S, Amante A, Estrela TM, Grammatikos E, Zhang Y, Prats-Puig A, Franklin de Carvalho D, Yang L, Carreras-Badosa G, de Oliveira Simões M, Hou Y, Lizarraga-Mollinedo E, Shui W, Guo T, Wang M, Zhang Y, Bovet P, and Xi B
- Subjects
- Adolescent, Blood Glucose metabolism, Brazil, Cardiovascular Diseases blood, Child, China, Cholesterol blood, Cluster Analysis, Female, Heart Disease Risk Factors, Humans, Hypertension complications, Italy, Male, Metabolic Syndrome blood, Metabolic Syndrome physiopathology, Pediatric Obesity physiopathology, Triglycerides blood, Cardiovascular Diseases etiology, Carotid Intima-Media Thickness, Metabolic Syndrome complications, Pediatric Obesity complications
- Abstract
Objective: The clinical utility of screening for pediatric metabolic syndrome (MetS) in children and adolescents is still controversial. We examined the performance of pediatric MetS vs. clustering of cardiovascular risk factors (which are the components of MetS) for predicting high carotid intima-media thickness (cIMT) in children and adolescents., Methods: Participants included 2427 children and adolescents aged 6-17 years from population-based studies in three countries (Brazil, China and Italy). Pediatric MetS was defined using either the modified National Cholesterol Education Program Adult Treatment Panel III criteria or the modified International Diabetes Federation criteria. Clustering of cardiovascular risk factors was calculated as the sum of five components of MetS (i.e. central obesity, elevated blood pressure, elevated triglycerides, reduced HDL-cholesterol and elevated fasting blood glucose). High cIMT was defined as cIMT at least 95th percentile values for sex and age developed from European children., Results: Presence of one, two or at least three cardiovascular risk factors (using the National Cholesterol Education Program Adult Treatment Panel III criteria), as compared with none, was associated with gradually increasing odds of high cIMT [odds ratios (95% confidence intervals): 1.60 (1.29-1.99), 2.89 (2.21-3.78) and 4.24 (2.81-6.39), respectively]. High cIMT was also associated with presence (vs. absence) of MetS (odds ratio = 2.88, 95% confidence interval = 1.95-4.26). However, clustering of cardiovascular risk factors predicted high cIMT markedly better than MetS (area under the curve of 0.66 vs. 0.54, respectively). Findings were similar using the International Diabetes Federation criteria for pediatric MetS., Conclusion: In children and adolescents, a graded score based on five cardiovascular risk factors (used to define MetS) predicted high cIMT markedly better than MetS. These findings do not support the clinical utility of MetS for screening youth at increased cardiovascular risk, as expressed in this study by high cIMT.
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- 2020
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46. Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells.
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López-Guerra M, Xargay-Torrent S, Fuentes P, Roldán J, González-Farré B, Rosich L, Silkenstedt E, García-León MJ, Lee-Vergés E, Giménez N, Giró A, Aymerich M, Villamor N, Delgado J, López-Guillermo A, Puente XS, Campo E, Toribio ML, and Colomer D
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Calcium-Binding Proteins genetics, Cell Movement, Cell Proliferation, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Nucleophosmin, Receptor, Notch1 immunology, Tumor Cells, Cultured, Adaptor Proteins, Signal Transducing metabolism, Antibodies, Monoclonal pharmacology, Calcium-Binding Proteins metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Mutation, Neovascularization, Pathologic drug therapy, Receptor, Notch1 antagonists & inhibitors, Receptor, Notch1 genetics
- Abstract
Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.
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- 2020
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47. Methylation of the C19MC microRNA locus in the placenta: association with maternal and chilhood body size.
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Prats-Puig A, Xargay-Torrent S, Carreras-Badosa G, Mas-Parés B, Bassols J, Petry CJ, Girardot M, D E Zegher F, Ibáñez L, Dunger DB, Feil R, and López-Bermejo A
- Subjects
- Adult, Child, Chromosomes, Human, Pair 19 metabolism, Fathers, Female, Follow-Up Studies, Humans, Infant, Newborn, Male, MicroRNAs metabolism, Mothers, Polymorphism, Single Nucleotide genetics, Pregnancy, Young Adult, Body Size genetics, Chromosomes, Human, Pair 19 genetics, DNA Methylation genetics, MicroRNAs genetics, Placenta metabolism
- Abstract
Objectives: To study DNA methylation at the C19MC locus in the placenta and its association with (1) parental body size, (2) transmission of haplotypes for the C19MC rs55765443 SNP, and (3) offspring's body size and/or body composition at birth and in childhood., Subjects and Methods: Seventy-two pregnant women-infant pairs and 63 fathers were included in the study. Weight and height of mothers, fathers and newborns were registered during pregnancy or at birth (n = 72). Placental DNA methylation at the C19MC imprinting control region (ICR) was quantified by bisulfite pyrosequencing. Genotyping of the SNP was performed using restriction fragment length polymorphisms. The children's body size and composition were reassessed at age 6 years (n = 32)., Results: Lower levels of placental C19MC methylation were associated with increased body size of mother, specifically with higher pregestational and predelivery weights and height of the mother (β from -0.294 to -0.371; R
2 from 0.04 to 0.10 and all p < 0.019), and with higher weight, height, waist and hip circumferences, and fat mass of the child (β from -0.428 to -0.552; R2 from 0.33 to 0.56 and all p < 0.009). Parental transmission of the SNP did not correlate with an altered placental methylation status at the C19MC ICR., Conclusions: Increased maternal size is associated with reduced placental C19MC methylation, which, in turn, relate to larger body size of the child.- Published
- 2020
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48. Effects of metformin administration on endocrine-metabolic parameters, visceral adiposity and cardiovascular risk factors in children with obesity and risk markers for metabolic syndrome: A pilot study.
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Bassols J, Martínez-Calcerrada JM, Osiniri I, Díaz-Roldán F, Xargay-Torrent S, Mas-Parés B, Dorado-Ceballos E, Prats-Puig A, Carreras-Badosa G, de Zegher F, Ibáñez L, and López-Bermejo A
- Subjects
- Adolescent, Body Mass Index, Body Weight, C-Reactive Protein analysis, Carotid Intima-Media Thickness, Child, Double-Blind Method, Female, Humans, Hyperinsulinism drug therapy, Insulin blood, Leptin blood, Male, Metformin therapeutic use, Obesity drug therapy, Pilot Projects, Spain, White People, Hyperinsulinism blood, Metabolic Syndrome blood, Metformin pharmacology, Obesity blood
- Abstract
Background: Metformin treatment (1000-2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity., Methods: A pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months., Results: The 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin-to-high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected., Conclusion: In this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits., Competing Interests: The authors have declared that no competing interests exist.
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- 2019
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49. Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy.
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Silkenstedt E, Arenas F, Colom-Sanmartí B, Xargay-Torrent S, Higashi M, Giró A, Rodriguez V, Fuentes P, Aulitzky WE, van der Kuip H, Beà S, Toribio ML, Campo E, López-Guerra M, and Colomer D
- Subjects
- Animals, Antineoplastic Agents, Immunological pharmacology, Cell Line, Tumor, Cell Movement drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Gene Regulatory Networks drug effects, Humans, Lymph Nodes metabolism, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell metabolism, Mice, Neoplasm Transplantation, Receptor, Notch1 antagonists & inhibitors, Signal Transduction drug effects, Adaptor Proteins, Signal Transducing metabolism, Antineoplastic Agents, Immunological administration & dosage, Calcium-Binding Proteins metabolism, Lymphoma, Mantle-Cell genetics, Mutation, Receptor, Notch1 genetics
- Abstract
Background: NOTCH1 gene mutations in mantle cell lymphoma (MCL) have been described in about 5-10% of cases and are associated with significantly shorter survival rates. The present study aimed to investigate the biological impact of this mutation in MCL and its potential as a therapeutic target., Methods: Activation of Notch1 signaling upon ligand-stimulation and inhibitory effects of the monoclonal anti-Notch1 antibody OMP-52M51 in NOTCH1-mutated and -unmutated MCL cells were assessed by Western Blot and gene expression profiling. Effects of OMP-52M51 treatment on tumor cell migration and tumor angiogenesis were evaluated with chemotaxis and HUVEC tube formation assays. The expression of Delta-like ligand 4 (DLL4) in MCL lymph nodes was analyzed by immunofluorescence staining and confocal microscopy. A MCL mouse model was used to assess the activity of OMP-52M51 in vivo., Results: Notch1 expression can be effectively stimulated in NOTCH1-mutated Mino cells by DLL4, whereas in the NOTCH1-unmutated cell line JeKo-1, less effect was observed upon any ligand-stimulation. DLL4 was expressed by histiocytes in both, NOTCH1-mutated and -unmutated MCL lymph nodes. Treatment of NOTCH1-mutated MCL cells with the monoclonal anti-Notch1 antibody OMP-52M51 effectively prevented DLL4-dependent activation of Notch1 and suppressed the induction of numerous direct Notch target genes involved in lymphoid biology, lymphomagenesis and disease progression. Importantly, in lymph nodes from primary MCL cases with NOTCH1/2 mutations, we detected an upregulation of the same gene sets as observed in DLL4-stimulated Mino cells. Furthermore, DLL4 stimulation of NOTCH1-mutated Mino cells enhanced tumor cell migration and angiogenesis, which could be abolished by treatment with OMP-52M51. Importantly, the effects observed were specific for NOTCH1-mutated cells as they did not occur in the NOTCH1-wt cell line JeKo-1. Finally, we confirmed the potential activity of OMP-52M51 to inhibit DLL4-induced Notch1-Signaling in vivo in a xenograft mouse model of MCL., Conclusion: DLL4 effectively stimulates Notch1 signaling in NOTCH1-mutated MCL and is expressed by the microenvironment in MCL lymph nodes. Our results indicate that specific inhibition of the Notch1-ligand-receptor interaction might provide a therapeutic alternative for a subset of MCL patients.
- Published
- 2019
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50. Metabolically Healthy Obesity and High Carotid Intima-Media Thickness in Children and Adolescents: International Childhood Vascular Structure Evaluation Consortium.
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Zhao M, López-Bermejo A, Caserta CA, Medeiros CCM, Kollias A, Bassols J, Romeo EL, Ramos TDA, Stergiou GS, Yang L, Xargay-Torrent S, Amante A, Gusmão TME, Grammatikos E, Zhang Y, Prats-Puig A, de Carvalho DF, Yang L, Carreras-Badosa G, Simões MO, Hou Y, Mas-Pares B, Shui W, Guo T, Wang M, Chen H, Lou X, Zhang Q, Zhang Y, Bovet P, Magnussen CG, and Xi B
- Subjects
- Adolescent, Blood Pressure, Brazil, Child, China, Cross-Sectional Studies, Female, Follow-Up Studies, Greece, Health Status, Humans, Italy, Logistic Models, Male, Obesity, Metabolically Benign blood, Overweight blood, Pediatric Obesity blood, Prevalence, Risk Factors, Spain, Carotid Intima-Media Thickness, Obesity, Metabolically Benign epidemiology, Overweight epidemiology, Pediatric Obesity epidemiology
- Abstract
Objective: It has been argued that metabolically healthy obesity (MHO) does not increase cardiovascular disease (CVD) risk. This study examines the association of MHO with carotid intima-media thickness (cIMT), a proxy of CVD risk, in children and adolescents., Research Design and Methods: Data were available for 3,497 children and adolescents aged 6-17 years from five population-based cross-sectional studies in Brazil, China, Greece, Italy, and Spain. Weight status categories (normal, overweight, and obese) were defined using BMI cutoffs from the International Obesity Task Force. Metabolic status (defined as "healthy" [no risk factors] or "unhealthy" [one or more risk factors]) was based on four CVD risk factors: elevated blood pressure, elevated triglyceride levels, reduced HDL cholesterol, and elevated fasting glucose. High cIMT was defined as cIMT ≥90th percentile for sex, age, and study population. Logistic regression model was used to examine the association of weight and metabolic status with high cIMT, with adjustment for sex, age, race/ethnicity, and study center., Results: In comparison with metabolically healthy normal weight, odds ratios (ORs) for high cIMT were 2.29 (95% CI 1.58-3.32) for metabolically healthy overweight and 3.91 (2.46-6.21) for MHO. ORs for high cIMT were 1.44 (1.03-2.02) for unhealthy normal weight, 3.49 (2.51-4.85) for unhealthy overweight, and 6.96 (5.05-9.61) for unhealthy obesity., Conclusions: Among children and adolescents, cIMT was higher for both MHO and metabolically healthy overweight compared with metabolically healthy normal weight. Our findings reinforce the need for weight control in children and adolescents irrespective of their metabolic status., (© 2018 by the American Diabetes Association.)
- Published
- 2019
- Full Text
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