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Agora exibindo 1 - 10 de 16
  • bookPart
    Tumores neuroendócrinos
    (2013) LOURENçO JR., Delmar Muniz; TOLEDO, Rodrigo Almeida; TOLEDO, Sergio Pereira de Almeida
  • article 2 Citação(ões) na Scopus
    Assessing the emerging oncogene protein kinase C epsilon as a candidate gene in families with Carney complex-2
    (2012) TOLEDO, Rodrigo A.; SEKIYA, Tomoko; HORVATH, Anelia; FAUCZ, Fabio; FRAGOSO, Maria C. B. V.; LONGUINI, Viviane C.; LOURENCO JR., Delmar M.; TOLEDO, Sergio P. A.; STRATAKIS, Constantine A.
  • article 2 Citação(ões) na Scopus
    RET haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family
    (2012) QUEDAS, Elisangela P. S.; LONGUINI, Viviane C.; SEKIYA, Tomoko; COUTINHO, Flavia L.; TOLEDO, Sergio P. A.; TANNURI, Uenis; TOLEDO, Rodrigo A.
    Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the co-occurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.
  • article 114 Citação(ões) na Scopus
    Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10
    (2011) FRANK-RAUE, Karin; RYBICKI, Lisa A.; ERLIC, Zoran; SCHWEIZER, Heiko; WINTER, Aurelia; MILOS, Ioana; TOLEDO, Sergio P. A.; TOLEDO, Rodrigo A.; TAVARES, Marcos R.; ALEVIZAKI, Maria; MIAN, Caterina; SIGGELKOW, Heide; HUEFNER, Michael; WOHLLK, Nelson; OPOCHER, Giuseppe; DVORAKOVA, Sarka; BENDLOVA, Bela; CZETWERTYNSKA, Malgorzata; SKASKO, Elzbieta; BARONTINI, Marta; SANSO, Gabriela; VORLAENDER, Christian; MAIA, Ana Luiza; PATOCS, Attila; LINKS, Thera P.; GROOT, Jan Willem de; KERSTENS, Michiel N.; VALK, Gerlof D.; MIEHLE, Konstanze; MUSHOLT, Thomas J.; BIARNES, Josefina; DAMJANOVIC, Svetozar; MURESAN, Mihaela; WUESTER, Christian; FASSNACHT, Martin; PECZKOWSKA, Mariola; FAUTH, Christine; GOLCHER, Henriette; WALTER, Martin A.; PICHL, Josef; RAUE, Friedhelm; ENG, Charis; NEUMANN, Hartmut P. H.
    Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609-620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected. Hum Mutat 32:51-58, 2011. (C) 2010 Wiley-Liss, Inc.
  • article 15 Citação(ões) na Scopus
    Growth hormone response to growth hormone-releasing peptide-2 in growth hormone-deficient Little mice
    (2012) PERONI, Cibele N.; HAYASHIDA, Cesar Y.; NASCIMENTO, Nancy; LONGUINI, Viviane C.; TOLEDO, Rodrigo A.; BARTOLINI, Paolo; BOWERS, Cyril Y.; TOLEDO, Sergio P. A.
    OBJECTIVE: To investigate a possible direct, growth hormone-releasing, hormone-independent action of a growth hormone secretagogue, GHRP-2, in pituitary somatotroph cells in the presence of inactive growth hormone-releasing hormone receptors. MATERIALS AND METHODS: The responses of serum growth hormone to acutely injected growth hormone-releasing P-2 in lit/litmice, which represent a model of GH deficiency arising frommutated growth hormone-releasing hormone-receptors, were compared to those observed in the heterozygous (lit/+) littermates and wild-type (+/+) C57BL/6J mice. RESULTS: After the administration of 10 mcg of growth hormone-releasing P-2 to lit/lit mice, a growth hormone release of 9.3 +/- 1.5 ng/ml was observed compared with 1.04 +/- 1.15 ng/ml in controls (p<0.001). In comparison, an intermediate growth hormone release of 34.5 +/- 9.7 ng/ml and a higher growth hormone release of 163 +/- 46 ng/ml were induced in the lit/+ mice and wild-type mice, respectively. Thus, GHRP-2 stimulated growth hormone in the lit/lit mice, and the release of growth hormone in vivo may be only partially dependent on growth hormone-releasing hormone. Additionally, the plasma leptin and ghrelin levels were evaluated in the lit/lit mice under basal and stimulated conditions. CONCLUSIONS: Here, we have demonstrated that lit/lit mice, which harbor a germline mutation in the Growth hormone-releasing hormone gene, maintain a limited but statistically significant growth hormone elevation after exogenous stimulation with GHRP-2. The present data probably reflect a direct, growth hormone-independent effect on Growth hormone S (ghrelin) stimulation in the remaining pituitary somatotrophs of little mice that is mediated by growth hormone S-R 1a.
  • article 8 Citação(ões) na Scopus
    Surgical approach to medullary thyroid carcinoma associated with multiple endocrine neoplasia type 2
    (2012) TAVARES, Marcos R.; TOLEDO, Sergio P. A.; MONTENEGRO, Fabio L. M.; MOYSES, Raquel A.; TOLEDO, Rodrigo A.; SEKYIA, Tomoko; CERNEA, Claudio R.; BRANDAO, Lenine G.
    We briefly review the surgical approaches to medullary thyroid carcinoma associated with multiple endocrine neoplasia type 2 (medullary thyroid carcinoma/multiple endocrine neoplasia type 2). The recommended surgical approaches are usually based on the age of the affected carrier/patient, tumor staging and the specific rearranged during transfection codon mutation. We have focused mainly on young children with no apparent disease who are carrying a germline rearranged during transfection mutation. Successful management of medullary thyroid carcinoma in these cases depends on early diagnosis and treatment. Total thyroidectomy should be performed before 6 months of age in infants carrying the rearranged during transfection 918 codon mutation, by the age of 3 years in rearranged during transfection 634 mutation carriers, at 5 years of age in carriers with level 3 risk rearranged during transfection mutations, and by the age of 10 years in level 4 risk rearranged during transfection mutations. Patients with thyroid tumor >5 mm detected by ultrasound, and basal calcitonin levels >40 pg/ml, frequently have cervical and upper mediastinal lymph node metastasis. In the latter patients, total thyroidectomy should be complemented by extensive lymph node dissection. Also, we briefly review our data from a large familial medullary thyroid carcinoma genealogy harboring a germline rearranged during transfection Cys620Arg mutation. All 14 screened carriers of the rearranged during transfection Cys620Arg mutation who underwent total thyroidectomy before the age of 12 years presented persistently undetectable serum levels of calcitonin (<2 pg/ml) during the follow-up period of 2-6 years. Although it is recommended that preventive total thyroidectomy in rearranged during transfection codon 620 mutation carriers is performed before the age of 5 years, in this particular family the surgical intervention performed before the age of 12 years led to an apparent biochemical cure.
  • article 8 Citação(ões) na Scopus
    Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus
    (2011) COSTA, Marcia Helena Soares; DOMENICE, Sorahia; TOLEDO, Rodrigo Almeida; JUNIOR, Delmar Muniz L.; LATRONICO, Ana Claudia; PINTO, Emilia Modolo; TOLEDO, Sergio Pereira Almeida; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson Villares
    BACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the Delta Delta CT method, and beta-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions.
  • article 40 Citação(ões) na Scopus
    The uncertain consequences of transferring bacterial strains between laboratories - rpoS instability as an example
    (2011) SPIRA, Beny; TOLEDO, Rodrigo de Almeida; MAHARJAN, Ram P.; FERENCI, Thomas
    Background: Microbiological studies frequently involve exchanges of strains between laboratories and/or stock centers. The integrity of exchanged strains is vital for archival reasons and to ensure reproducible experimental results. For at least 50 years, one of the most common means of shipping bacteria was by inoculating bacterial samples in agar stabs. Long-term cultures in stabs exhibit genetic instabilities and one common instability is in rpoS. The sigma factor RpoS accumulates in response to several stresses and in the stationary phase. One consequence of RpoS accumulation is the competition with the vegetative sigma factor sigma(70). Under nutrient limiting conditions mutations in rpoS or in genes that regulate its expression tend to accumulate. Here, we investigate whether short-term storage and mailing of cultures in stabs results in genetic heterogeneity. Results: We found that samples of the E. coli K-12 strain MC4100TF exchanged on three separate occasions by mail between our laboratories became heterogeneous. Reconstruction studies indicated that LB-stabs exhibited mutations previously found in GASP studies in stationary phase LB broth. At least 40% of reconstructed stocks and an equivalent proportion of actually mailed stock contained these mutations. Mutants with low RpoS levels emerged within 7 days of incubation in the stabs. Sequence analysis of ten of these segregants revealed that they harboured each of three different rpoS mutations. These mutants displayed the classical phenotypes of bacteria lacking rpoS. The genetic stability of MC4100TF was also tested in filter disks embedded in glycerol. Under these conditions, GASP mutants emerge only after a 3-week period. We also confirm that the intrinsic high RpoS level in MC4100TF is mainly due to the presence of an IS1 insertion in rssB. Conclusions: Given that many E. coli strains contain high RpoS levels similar to MC4100TF, the integrity of such strains during transfers and storage is questionable. Variations in important collections may be due to storage-transfer related issues. These results raise important questions on the integrity of bacterial archives and transferred strains, explain variation like in the ECOR collection between laboratories and indicate a need for the development of better methods of strain transfer.
  • article 28 Citação(ões) na Scopus
    Biochemical, bone and renal patterns in hyperparathyroidism associated with multiple endocrine neoplasia type 1
    (2012) LOURENCO JR., Delmar M.; COUTINHO, Flavia L.; TOLEDO, Rodrigo A.; GONCALVES, Tatiana Denck; MONTENEGRO, Fabio L. M.; TOLEDO, Sergio P. A.
    Primary hyperparathyroidism associated with multiple endocrine neoplasia type I (hyperparathyroidism/ multiple endocrine neoplasia type 1) differs in many aspects from sporadic hyperparathyroidism, which is the most frequently occurring form of hyperparathyroidism. Bone mineral density has frequently been studied in sporadic hyperparathyroidism but it has very rarely been examined in cases of hyperparathyroidism/ multiple endocrine neoplasia type 1. Cortical bone mineral density in hyperparathyroidism/ multiple endocrine neoplasia type 1 cases has only recently been examined, and early, severe and frequent bone mineral losses have been documented at this site. Early bone mineral losses are highly prevalent in the trabecular bone of patients with hyperparathyroidism/multiple endocrine neoplasia type 1. In summary, bone mineral disease in multiple endocrine neoplasia type 1-related hyperparathyroidism is an early, frequent and severe disturbance, occurring in both the cortical and trabecular bones. In addition, renal complications secondary to sporadic hyperparathyroidism are often studied, but very little work has been done on this issue in hyperparathyroidism/ multiple endocrine neoplasia type 1. It has been recently verified that early, frequent, and severe renal lesions occur in patients with hyperparathyroidism/ multiple endocrine neoplasia type 1, which may lead to increased morbidity and mortality. In this article we review the few available studies on bone mineral and renal disturbances in the setting of hyperparathyroidism/ multiple endocrine neoplasia type 1. We performed a meta-analysis of the available data on bone mineral and renal disease in cases of multiple endocrine neoplasia type 1-related hyperparathyroidism.
  • article 8 Citação(ões) na Scopus
    Somatotroph pituitary adenoma with acromegaly and autosomal dominant polycystic kidney disease: SSTR5 polymorphism and PKD1 mutation
    (2012) SYRO, Luis V.; SUNDSBAK, Jamie L.; SCHEITHAUER, Bernd W.; TOLEDO, Rodrigo A.; CAMARGO, Mauricio; HEYER, Christina M.; SEKIYA, Tomoko; URIBE, Humberto; ESCOBAR, Jorge I.; VASQUEZ, Martin; ROTONDO, Fabio; TOLEDO, Sergio P. A.; KOVACS, Kalman; HORVATH, Eva; BABOVIC-VUKSANOVIC, Dusica; HARRIS, Peter C.
    A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0-5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48-255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Pathologic, cytogenetic, molecular and in silico analysis was undertaken. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.142C > A (p.L48M, rs4988483) in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subjected to extensive morphological, ultrastructural, cytogenetic and molecular studies. The physical proximity of the PKD1 and SSTR5 genes on chromosome 16 suggests a causal relationship between ADPKD and somatotroph adenoma.