2016

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1.-PREMIO Karger-Hormone Research, otorgado en el XXVI Congreso de la Sociedad Latinoamericana de Endocrinología Pediátricia (SLEP), Buenos Aires, 2016.

Cardiometabolic Health Is Associated with the Chances of High School Completion in a Chilean Birth Cohort. Correa, P(1); Rodriguez, Y(1); Blanco, E(2); Gahagan, S(2); Burrows, R(1) (1)Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile. Santiago, Chile (2)Division of Child Development and Community Health, University of California San Diego. San Diego, United States

ABSTRACT

Background: The Metabolic Syndrome (MetS), a clustering of risk factors for type-2 diabetes mellitus and cardiovascular disease, is known to affect cognition and raise the risk for dementia in adults. Positive cognitive changes have been seen with some interventions targeting individual MetS components. Very few studies have explored these relationships in younger age populations and even few have investigated the impact on educational outcomes.

Aim: We explored the association between a number of cardiometabolic markers and the rates of high school (HS) completion in adolescents from a Chilean birth cohort.

Methods: Of 678 16 years-old participants, 633 (93%; 52% males) entered HS and, thus, met criteria for the study. At 16 yearsold, waist circumference (WC), systolic and diastolic blood pressure (SBP&DBP), triglycerides (TG), HDL-cholesterol and glucose.

HOMA-IR was estimated. A continuous score (zMetS) representing a composite metabolic risk factor profile was computed with gender-specific z-scores of WC, SBP, Gli, TG and HDL; lower values denotes a healthier cardiometabolic profile. MetS was diagnosed with the NHBLI/AHA/IDF criteria. HS graduation data were collected from administrative records. Data were analyzed with multiple linear and logistic regressions, controlling for sociodemographic, lifestyle and educational confounders.

Results: In the sample, 90% completed the HS diploma. Seventy-nine percent had at least one CDV risk factor and 8.1% had MetS. The association of zMetS, WC, and TG at 16 y with the odds of completing HS was negative and significant, even after controlling other influences. Notably, for a one-unit increase in the zMetS, we found 43% reduction in the odds of getting the HS diploma (OR: 0.57, 95% CI: 0.41–0.79). Conversely, HDL levels were positive and significantly related with the odds of HS completion. Finally, the chances of HS completion in participants diagnosed with MetS were 10% (95% CI: 0.02–0.36) that of participants with no cardiometabolic risk factors.

Conclusions: In adolescents, cardiometabolic health appears to be associated with the chances of high school completion. Funding: NHLBI/NIH (grant R01HL088530)

 

2.-PREMIOS de la Sociedad Latinoamericana de Endocrinología Pediátricia (SLEP) otorgados en el XXVI Congreso de la Sociedad Latinoamericana de Endocrinología Pediátricia, Buenos Aires, 2016.

PRIMER PREMIO

Disruption in SF1-mediated AMH promoter regulation leading to Persistent Müllerian Duct Syndrome (PMDS). Valeri, C(1); di Clemente, N(2, 3); Marshall, I(4); Schteingart, H(1); Josso, N(2, 3); Rey, R(1, 5); Picard, J(2, 3)

Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez. C1425EFD Buenos Aires, Argentina (2) CNRS, UMR8251, Biologie Fonctionnelle et Adaptative, F-75013, Université Paris Diderot, Sorbonne Paris Cité. F-75013 Paris, France (3) INSERM U1133, Physiologie de l’Axe Gonadotrope, F-75013, Université Paris Diderot, Sorbonne Paris Cité. F-75013 Paris, France (4) Division of Pediatric Endocrinology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey. New Brunswick, N J08901, USA (5) Departamento de Histología, Biología Celular, Embriología y Genética, Facultad de Medicina, Universidad de Buenos Aires. C1121ABG Buenos Aires, Argentina

ABSTRACT

In early fetal life, AMH secreted by the testes provokes the regression of Müllerian ducts. AMH expression in fetal Sertoli cells is triggered by SOX9, and further up regulated by SF1, GATA4 and WT1, all binding to specific sites on the proximal AMH gene promoter.

The absence of AMH signalling in the XY fetus results in the Persistent Müllerian duct syndrome (PMDS).

We report the case of a non-dysmorphic newborn who presented with a normal sized penis and non-palpable gonads. Lab work-up showed normal serum testosterone (358 ng/dl), very low serum AMH (7.8 pmol/l) and a 46,XY karyotype. A sonogram and MRI showed a uterus measuring 5 x 1.4 x 1.9 cm; VCUG showed a normal male urethra without a urogenital sinus.

DNA sequencing detected no mutations in the AMH gene coding sequences, but a homozygous single-base deletion (c.-225delA) was identified at a putative SF1 response element of the AMH promoter. The AMH promoter activity of the c.-225delA variant, analysed in luciferase assays, was decreased by 58 ± 14%, to a similar extent (66 ± 5%) of what was observed when the SF1 site was completely disrupted by in vitro directed mutagenesis. The interaction between SF1 and its binding site was lost when the oligonucleotide carried c.-225delA or the fully disrupted SF1 site, when studied by EMSA.

In conclusion, the single base deletion c.-225delA within the SF1 site of the AMH gene promoter impaired SF1 binding to andtransactivation of the AMH promoter, resulting in extremely decreased AMH production, leading to PMDS in this patient. This is the first description of an AMH promoter mutation leading to PMDS.

 

SEGUNDO PREMIO

Vitamin D Receptor (VDR) is Underexpressed in Pediatric Adrenocortical Tumors and 1,25(OH)2D3/VDR Plays Antiproliferative Effects Via Suppression of Beta-Catenin and Cell Cycle Arrest in Adrenal Cells. Bueno, AC(1); Leal, LF(1); Gomes, DC(2); Montaldi, AP(3); Brandalise, SR(4); Masterallo, MJ(4); Cardinalli, IA(4); Yunes, JA(4); Martinelli Jr, CE(1); Tone, LG(1); Scrideli, CA(1); Moreira, AC(5); Molina, CA(6); Ramalho, F(7); Ramalho, LNZ(7); Tucci Jr, S(6); Castro, M(5); Antonini, SR(1)

(1)Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo. Ribeirao Preto, Brazil (2)Pediatrics, Federal University of Uberlandia. Uberlandia, Brazil (3)Genetics, Ribeirao Preto Medical School, University of Sao Paulo. Ribeirao Preto, Brazil (4)Boldrini Children’s Center. Campinas, Brazil (5)Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo. Ribeirao Preto, Brazil (6)Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo. Ribeirao Preto, Brazil (7)Pathology, Ribeirao Preto Medical School, University of Sao Paulo. Ribeirao Preto, Brazil

ABSTRACT

Vitamin D Receptor (VDR) Is Underexpressed inPediatric Adrenocortical Tumors and 1,25(OH)2D3/ VDR Plays Antiproliferative Effects via Suppression of Beta-Catenin and Cell Cycle Arrest in Adrenal Cells Bueno, A.C.1; Leal, L.F.1; Gomes, D.C.2; Montaldi, A.P.3; Brandalise, S.R.4; Masterallo, M.J.4; Cardinalli, I.A.4; Yunes, J.A.4; Martinelli Jr, C.E.1; Tone, L.G.1; Scrideli, C.A.1; Moreira, A.C.5; Molina, C.A.6; Ramalho, F.7; Ramalho, L.N.Z.7; Tucci Jr, S.6; Castro, M.5; Antonini, S.R.1

1Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; 2Pediatrics, Federal University of Uberlandia, Uberlandia, Brazil; 3Genetics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; 4Boldrini Children’s Center, Campinas, Brazil; 5Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; 6Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; 7Pathology, Ribeirao Preto Medical School, University of Sao  Paulo, RibeiraoPreto, Brazil

Wnt/Beta-catenin pathway is activated in pediatric adrenocortical tumors (pACTs). The vitamin D3 (calcitriol-1,25(OH)2D3) receptor (VDR) was shown to be underexpressed in adult adrenocortical carcinomas (ACCs). It is possible that 1,25(OH)2D3/VDR interacts with beta-catenin in adrenal cells.

Aim: To investigate the role of 1,25(OH)2D3/VDR in pACTs tumorigenesis and its interaction with beta-catenin and adrenocortical cell proliferation.

Methods: Clinicopathological features and VDR expression were evaluated in 72 pACTs, 33 fetal (FAs) and 12 pediatric adrenals (pNAs) by qPCR and immunohistochemistry. In vitro, we evaluated in NCI-H295 cells the effects of VDR activation by 1,25(OH)2D3 (10–7 M) or inhibition (siRNA knock-down) on vitamin D pathway (CYP27A1 and CYP24A1), beta-catenin, and cell cycle markers (CTNNB1, MYC, CCND1, CDK4, CCNE1, and CDK2) mRNA expression (qPCR); protein expression (western blot), cell localization (immunofluorescence-IF), cell cycle (flow cytometry) and cell viability (MTS).

Results: VDR expression was observed mainly in the nucleus of FAs subcapsular cells (20th week) and progressively increased, extended to the cytoplasm and spread throughout the cortex in late gestation and postnatal adrenals. In pACTs, VDR staining was absent in 4.3%, nuclear/cytoplasmatic in 28.3% and cytoplasmatic in 67.4%. Strong VDR staining inversely associated with Weiss score (p < 0.001). Compared to pNAs, VDR mRNA expression was de creased in pACTs (p = 0.01), especially in carcinomas (p < 0.05).

In vitro, the activation of VDR by 1,25(OH)2D3 (48 h) was confirmed by decreased CYP27A1 (p  < 0.0001) and increased CYP24A1 (p < 0.001), VDR expression (mRNA: p = 0.001; protein: 87%) and nuclear cell staining. 1,25(OH)2D3/VDR activation arrested cell cycle in GO/G1 (53 to 60%; p < 0.01), decreased G2 (25 to 19%; p  < 0.05), and reduced the mRNA expression of G1-S markers CCND1 (p < 0.0001), CDK4 (p = 0.001), CCNE1 (p <0.0001), CDK2 (p = 0.001). MYC (p < 0.001) and CTNNB1 (p <0.001) mRNA expression were also reduced and beta-catenin staining (IF) was impaired. Cell viability was reduced after 96 h of 1,25(OH)2D3 treatment (–8.7%; p  < 0.001). VDR knockdown (–77%; 48 h) increased beta-catenin expression (79.5%; p = 0.01).

When activated by 1,25(OH)2D3, remaining VDR (23%) reduced MYC (–23%; p = 0.01) and CCND1 (–28%; p = 0.01) expression.

Conclusions: VDR plays a role in adrenocortical differentiation and is underexpressed in pACTs, mainly in pACC. In vitro, 1,25(OH)2D3/VDR inhibits beta-catenin, reducing adrenal cell proliferation and may emerge as a new antitumor target.