PROP1 and CTNNB1 expression in adamantinomatous craniopharyngiomas with or without β-catenin mutations

INTRODUCTION: Activating mutations in exon 3 of the β-catenin gene are involved in the pathogenesis of adamantinomatous craniopharyngiomas. Recently, the interaction between β-catenin and PROP1 has been shown to be responsible for pituitary cell lineage determination. We hypothesized that dysregulated PROP1 expression could also be involved in the pathogenesis of craniopharyngiomas OBJECTIVES: To determine whether dysregulated gene expression was responsible for tumor pathogenesis in adamantinomatous craniopharyngiomas, the β-catenin gene was screened for mutations, and the expression of the β-catenin gene and PROP1 was evaluated. β-catenin gene was amplified and sequenced from 14 samples of adamantinomatous craniopharyngiomas. PROP1 and β-catenin gene expression was assessed by real-time RT-PCR from 12 samples, and β-catenin immunohistochemistry was performed on 11 samples. RESULTS: Mutations in the β-catenin gene were identified in 64% of the adamantinomatous craniopharyngiomas samples. Evidence of β-catenin gene overexpression was found in 71% of the tumors with β-catenin mutations and in 40% of the tumors without mutations, and β-catenin immunohistochemistry revealed a nuclear staining pattern for each of the analyzed samples. PROP1 expression was undetectable in all of the tumor samples. CONCLUSION: We found evidence of β-catenin gene overexpression in the majority of adamantinomatous craniopharyngiomas, and we also detected a nuclear β-catenin staining pattern regardless of the presence of a bcatenin gene mutation. These results suggest that WNT signaling activation plays an important role in the pathogenesis of adamantinomatous craniopharyngiomas. Additionally, this study was the first to evaluate PROP1 expression in adamantinomatous craniopharyngiomas, and the absence of PROP1 expression indicates that this gene is not involved in the pathogenesis of this tumor, at least in this cohort

The Interactive Effect of GHR-Exon 3 and -202 A/C IGFBP3 Polymorphisms on rhGH Responsiveness and Treatment Outcomes in Patients with Turner Syndrome

Context: There is great interindividual variability in the response to recombinant human (rh) GH therapy in patients with Turner syndrome (TS). Ascertaining genetic factors can improve the accuracy of growth response predictions. Objective: The objective of the study was to assess the individual and combined influence of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms on the short-and long-term outcomes of rhGH therapy in patients with TS. Design and Patients: GHR-exon 3 and -202 A/C IGFBP3 genotyping (rs2854744) was correlated with height data of 112 patients with TS who remained prepubertal during the first year of rhGH therapy and 65 patients who reached adult height after 5 +/- 2.5 yr of rhGH treatment. Main Outcome Measures: First-year growth velocity and adult height were measured. Results: Patients carrying at least one GHR-d3 or -202 A-IGFBP3 allele presented higher mean first-year growth velocity and achieved taller adult heights than those homozygous for GHR-fl or -202 C-IGFBP3 alleles, respectively. The combined analysis of GHR-exon 3 and -202 A/C IGFBP3 genotypes showed a clear nonadditive epistatic influence on adult height of patients with TS treated with rhGH (GHR-exon 3 alone, R-2 = 0.27; -202 A/C IGFBP3, R-2 = 0.24; the combined genotypes, R-2 = 0.37 at multiple linear regression). Together with clinical factors, these genotypes accounted for 61% of the variability in adult height of patients with TS after rhGH therapy. Conclusion: Homozygosity for the GHR-exon3 full-length allele and/or the -202C-IGFBP3 allele are associated with less favorable short-and long-term growth outcomes after rhGH treatment in patients with TS. (J Clin Endocrinol Metab 97: E671-E677, 2012)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [05/04726-0, 05/50144-2]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [301339/2008-9, 300938/06-3, 475870/2009-3, 301477/2009-4

Synthesis and preliminary ex vivo evaluation of the spasmolytic activity of 1,3-thiazolium- and 1,3,4-thiadiazolium-5-methylthio- and 5-tioacetate derivatives

Seven new compounds have been synthetized in satisfactory yields (51-78 %), through the treatment of mesoionic 1,3-thiazolium-5-thiolate (4a-d) and 1,3,4-thiadiazolium-5-thiolate (10a,b) with chloroacetic acid or methyl iodide: 1,3-thiazolium-5-methylthio- (5a-c), 5-thioacetate (6a,b) and 1,3,4-thiadiazolium-5-methylthio- (11) and 5-thioacetate (12). The structure of the title compounds was elucidated by elemental analysis, IR, 1H and 13C NMR spectroscopy. The newly synthesized compounds 5a, 6a, 11 and 12 were evaluated for their ex vivo spasmolytic potential on four isolated smooth muscles (rat aorta and uterus, guinea pig ileum and trachea) and compared with scopolamine. Some of the compounds exhibited potent spasmolytic activity equal to or stronger than scopolamine

Deforestation, degradation and violence in the “Gurupi Mosaic” – The most threatened region of Amazonia

O "Mosaico Gurupi" está localizado entre o oeste do Maranhão e o leste do Pará, na Área de Endemismo Belém, que embora seja a região mais desmatada do Bioma Amazônico no Brasil, preserva uma diversidade cultural e biológica superlativa. O mosaico engloba seis Terras Indígenas (Alto Turiaçu, Awá, Caru, Arariboia, Rio Pindaré e Alto Rio Guamá) e uma Unidade de Conservação (Reserva Biológica do Gurupi). Essas áreas protegidas conservam os principais remanescentes florestais da região e garantem a manutenção de serviços ecossistêmicos essenciais aos dois estados, principalmente de regulação hidrológica. No entanto, essa região vive sob ameaças constantes de desmatamento e de degradação pela extração ilegal de madeira, e por incêndios criminosos. Os povos indígenas e lideranças comunitárias da região são vitimados pela violência associada a tais crimes. Para promover a conservação e a restauração dessas áreas, uma rede formada por diversas instituições indígenas e não indígenas vem trabalhando em conjunto para o reconhecimento do "Mosaico Gurupi" pelo Ministério do Meio Ambiente. A proposta aqui apresentada inclui o mosaico em questão e o Corredor Ecológico da Amazônia Maranhense, que irá conectar os principais remanescentes florestais da região, por meio da restauração das matas ciliares ao longo dos rios Buriticupu, Pindaré e Zutiua. A conformação do mosaico visa integrar esforços para a proteção territorial, a restauração florestal e o fortalecimento da cultura e educação indígena; o que poderá converter a região mais ameaçada da Amazônia em um exemplo de conservação e sustentabilidade econômica e social por meio da promoção da restauração florestal.The "Gurupi Mosaic" is located between west Maranhão and east Pará states, in the Belém Endemism Area, which although being the most deforested region of the Amazonian biome in Brazil, preserves superlative biological and cultural diversity. The Mosaic includes six indigenous lands (Alto Turiaçu, Awá, Caru, Araribóia, Rio Pindaré, Alto Rio Guamá) and a conservation unit (Gurupi Biological Reserve). These protected areas conserve the region’s main forest remnants and guarantee the maintenance of essential ecosystem services. However, this region is under constant threats of deforestation and degradation by illegal logging and arson. Indigenous peoples living in the region are victims of the violence associated with such crimes. To promote the conservation and restoration of these areas, several indigenous and non-indigenous institutions have been working together to formalize the "Gurupi Mosaic" with the Ministry of the Environment. The proposal presented here includes the Mosaic and one ecological corridor in the state of Maranhão, which will connect the region’s last forest remnants through the restoration of the riparian forests along the main rivers. The conformation of the Mosaic aims to integrate efforts to protect territories, restore forests and strengthen indigenous culture and education. This could turn the most threatened region of Amazonia into an example of conservation and economic and social sustainability