RESUMO
Maternal mortality in the United States is a public health crisis of preventable deaths among young women. The role of echocardiography in the evaluation of pregnant women with cardiovascular symptoms or risk factors without known heart disease is unclear. We retrospectively examined the clinical characteristics of consecutive pregnant patients without established heart disease who underwent echocardiography and evaluated associations between abnormal exam findings and obstetric outcomes. Among low-risk women undergoing echocardiography during pregnancy, older age, higher parity and a history of chronic hypertension are associated with a higher likelihood of echocardiographic abnormalities, which in turn are associated with a higher likelihood of adverse obstetric outcomes including caesarean section and preterm delivery.
RESUMO
Hematopoietic stem cells (HSCs) can remain quiescent or they can enter the cell cycle, and either self-renew or differentiate. Although cyclin C and cyclin dependent kinase (cdk3) are essential for the transition from the G(0) to the G(1) phase of the cell cycle in human fibroblasts, the role of cyclin C in hematopoietic stem/progenitor cells (HSPCs) is not clear. We have identified an important role of cyclin C (CCNC) in regulating human HSPC quiescence, as knocking down CCNC expression in human cord blood CD34(+) cells resulted in a significant increase in quiescent cells that maintain CD34 expression. CCNC knockdown also promotes in vitro HSPC expansion and enhances their engraftment potential in sublethally irradiated immunodeficient mice. Our studies establish cyclin C as a critical regulator of the G(0)/G(1) transition of human HSPCs and suggest that modulating cyclin C levels may be useful for HSC expansion and more efficient engraftment.
Assuntos
Ciclina C/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Animais , Antígenos CD34/metabolismo , Western Blotting , Ciclo Celular/genética , Ciclo Celular/fisiologia , Divisão Celular/genética , Divisão Celular/fisiologia , Células Cultivadas , Ciclina C/genética , Ciclina C/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Reação em Cadeia da Polimerase , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/fisiologiaRESUMO
Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have generated conditional Fbw7 knockout animals and inactivated the gene in hematopoietic stem cells (HSCs), progenitors, and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects hematopoiesis in a cell-autonomous manner. Fbw7(-/-) HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7(-/-) progenitors are unable to colonize the thymus, leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow (BM) stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E is visibly stabilized in the BM of Fbw7-deficient mice. Gene expression studies of Fbw7(-/-) HSCs and hematopoietic progenitors indicate that Fbw7 regulates, through the regulation of HSC cycle entry, the transcriptional "signature" that is associated with the quiescent, self-renewing HSC phenotype.
