Binomial Mitotic Segregation of MYCN-Carrying Double Minutes in Neuroblastoma Illustrates the Role of Randomness in Oncogene Amplification

BACKGROUND: Amplification of the oncogene MYCN in double minutes (DMs) is a common finding in neuroblastoma (NB). Because DMs lack centromeric sequences it has been unclear how NB cells retain and amplify extrachromosomal MYCN copies during tumour development. PRINCIPAL FINDINGS: We show that MYCN-carrying DMs in NB cells translocate from the nuclear interior to the periphery of the condensing chromatin at transition from interphase to prophase and are preferentially located adjacent to the telomere repeat sequences of the chromosomes throughout cell division. However, DM segregation was not affected by disruption of the telosome nucleoprotein complex and DMs readily migrated from human to murine chromatin in human/mouse cell hybrids, indicating that they do not bind to specific positional elements in human chromosomes. Scoring DM copy-numbers in ana/telophase cells revealed that DM segregation could be closely approximated by a binomial random distribution. Colony-forming assay demonstrated a strong growth-advantage for NB cells with high DM (MYCN) copy-numbers, compared to NB cells with lower copy-numbers. In fact, the overall distribution of DMs in growing NB cell populations could be readily reproduced by a mathematical model assuming binomial segregation at cell division combined with a proliferative advantage for cells with high DM copy-numbers. CONCLUSION: Binomial segregation at cell division explains the high degree of MYCN copy-number variability in NB. Our findings also provide a proof-of-principle for oncogene amplification through creation of genetic diversity by random events followed by Darwinian selection

Genetic and Pharmacological Inhibition of MicroRNA-92a Maintains Podocyte Cell Cycle Quiescence and Limits Crescentic Glomerulonephritis

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury

The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression

International audienc

Prolactinomas: Aspectos neurocirúrgicos Prolactinomas: neurosurgical aspects

Relatamos nossa experiência com 38 casos de prolactinomas. Os adenomas foram divididos em três grupos. Os adenomas mono-hormonais tendem a ser microadenomas e manifestam-se com as alterações típicas deste tipo de tumor. Os bi- hormonais, em que a prolactina se associa principalmente ao GH ou sub unidade alfa tendem a apresentar sintomas visuais, assim como os pluri-hormonais. O tratamento dos prolactinomas é inicialmente clínico e a indicação cirúrgica está relacionada com intolerância a medicação ou a alterações visuais. O resultado cirúrgico com ressecção total do tumor foi possível em 50% dos casos.<br>We report our experience with 38 cases of prolactin secreting pituitary adenomas. The adenomas were divided in three different groups. The adenomas producing only prolactin tend to be microadenoma and they show the typical alterations of this type of tumor. The GH-PRL, GH-alpha subunit, the other combinations, and the pluri hormonal adenomas tend to present with visual symptoms. The treatment of the prolactinomas is initially clinical and the surgical indication for this type of adenomas is related to intolerance to the medication or to visual alterations. Surgical result with total resection of the tumor was possible in 50% of the cases