Interrelationship between TP53 gene deletion, protein expression and chromosome 17 aneusomy in gastric adenocarcinoma

Background: This study evaluates the existence of numerical alterations of chromosome 17 and TP53 gene deletion in gastric adenocarcinoma. the p53 protein expression was also evaluated, as well as, possible associations with clinicopathological characteristics.Methods: Dual-color fluorescence in situ hybridization and immunostaining were performed in twenty gastric cancer samples of individuals from Northern Brazil.Results: Deletion of TP53 was found in all samples. TP53 was inactivated mainly by single allelic deletion, varying to 7-39% of cells/case. Aneusomy of chromosome 17 was observed in 85% of cases. Chromosome 17 monosomy and gain were both observed in about half of cases. Cells with gain of chromosome 17 frequently presented TP53 deletion. the frequency of cells with two chr17 and one TP53 signals observed was higher in diffuse than in intestinal-type GC. Immunoreactivity of p53 was found only in intestinal-type samples. the frequency of cells with two chr17 and two TP53 signals found was higher in samples with positive p53 expression than in negative cases in intestinal-type GC.Conclusion: We suggest that TP53 deletion and chromosome 17 aneusomy is a common event in GC and other TP53 alterations, as mutation, may be implicated in the distinct carcinogenesis process of diffuse and intestinal types.Financiadora de Estudos e Projetos (FINEP CT-INFRA/FADESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fed Univ Para, Inst Biol Sci, Humans Cytogenet Lab, BR-66075900 Belem, Para, BrazilUniv Fed Piaui, Dept Biol, Campus Minist Reis Velloso Parnaiba, Teresina, PI, BrazilUniversidade Federal de São Paulo, Dept Morphol, Div Genet, São Paulo, BrazilUniv Fed Ceara, Sch Med, Dept Pathol, Mol Genet Lab, Fortaleza, Ceara, BrazilFed Univ Para, Joao de Barros Barreto Univ Hosp, BR-66075900 Belem, Para, BrazilUniversidade Federal de São Paulo, Dept Morphol, Div Genet, São Paulo, BrazilFinanciadora de Estudos e Projetos (FINEP CT-INFRA/FADESP): 0927-03. RRBWeb of Scienc

Review of Flywheel based Internal Combustion Engine Hybrid Vehicles

Hybrid vehicles of different configurations and utilizing different energy storage systems have existed in development for many decades and more recently in limited production. They can be grouped as parallel, series or complex hybrids. Another classification is micro, mild and full hybrids which makes the distinction on the basis of functionality. The common energy storage systems in hybrid vehicles are batteries, supercapacitors and high speed flywheels. This paper aims to review a specific type of hybrid vehicle which involves the internal combustion engine (ICE) as the prime mover and the high speed flywheel as an energy storage device. Such hybrids are now attracting considerable interest given their potential for low cost. It is hence timely to produce a review of research and development in this subject. The flywheel is coupled to the drive line with a continuous variable transmission (CVT). The CVT can be of various types such as electrical, hydraulic or mechanical but usually in this case it is a non-electrical one. Different configurations are possible and the paper provides a timeline of the development of such powertrains with various examples. These types of hybrid vehicles have existed as prototypes for many decades and the authors believe that their development has reached levels where they can be considered serious contenders for production vehicles

Structural Basis of Enzymatic Activity for the Ferulic Acid Decarboxylase (FADase) from Enterobacter sp. Px6-4

Microbial ferulic acid decarboxylase (FADase) catalyzes the transformation of ferulic acid to 4-hydroxy-3-methoxystyrene (4-vinylguaiacol) via non-oxidative decarboxylation. Here we report the crystal structures of the Enterobacter sp. Px6-4 FADase and the enzyme in complex with substrate analogues. Our analyses revealed that FADase possessed a half-opened bottom β-barrel with the catalytic pocket located between the middle of the core β-barrel and the helical bottom. Its structure shared a high degree of similarity with members of the phenolic acid decarboxylase (PAD) superfamily. Structural analysis revealed that FADase catalyzed reactions by an “open-closed” mechanism involving a pocket of 8×8×15 Å dimension on the surface of the enzyme. The active pocket could directly contact the solvent and allow the substrate to enter when induced by substrate analogues. Site-directed mutagenesis showed that the E134A mutation decreased the enzyme activity by more than 60%, and Y21A and Y27A mutations abolished the enzyme activity completely. The combined structural and mutagenesis results suggest that during decarboxylation of ferulic acid by FADase, Trp25 and Tyr27 are required for the entering and proper orientation of the substrate while Glu134 and Asn23 participate in proton transfer

CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

The gene encoding the transcription factor C/EBP alpha is mutated in 10-15% of acute myeloid leukemia (AML) patients. N-terminal CEBPA mutations cause ablation of full-length C/EBP alpha without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is incompletely understood. Here, we demonstrate that the MLL1 histone-methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. Oncogenic C/EBP alpha p30 and MLL1 show global co-localization on chromatin and p30 exhibits robust physical interaction with the MLL1 complex. CRISPR/Cas9-mediated mutagenesis of MLL1 results in proliferation arrest and myeloid differentiation in C/EBP alpha p30-expressing cells. In line, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological targeting of the MLL1 complex. Inhibitor treatment impairs proliferation and restores myeloid differentiation potential in mouse and human AML cells with CEBPA mutations. Finally, we identify the transcription factor GATA2 as a direct critical target of the p30-MLL1 interaction. Altogether, we show that C/EBP alpha p30 requires the MLL1 complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the MLL1 complex. These findings identify the MLL1 complex as a potential therapeutic target in AML with CEBPA mutations