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In the search for drugs to effectively treat cancer, the last 10 years have seen a resurgence of interest in targeting ribosome biogenesis. CX-5461 is a potential inhibitor of ribosomal RNA synthesis that is now showing promise in phase I trials as a chemotherapeutic agent for a range of malignancies. Here, we show that CX-5461 irreversibly inhibits ribosomal RNA transcription by arresting RNA polymerase I (RPI/Pol1/PolR1) in a transcription initiation complex. CX-5461 does not achieve this by preventing formation of the pre-initiation complex nor does it affect the promoter recruitment of the SL1 TBP complex or the HMGB-box upstream binding factor (UBF/UBTF). CX-5461 also does not prevent the subsequent recruitment of the initiation-competent RPI–Rrn3 complex. Rather, CX-5461 blocks promoter release of RPI–Rrn3, which remains irreversibly locked in the pre-initiation complex even after extensive drug removal. Unexpectedly, this results in an unproductive mode of RPI recruitment that correlates with the onset of nucleolar stress, inhibition of DNA replication, genome-wide DNA damage and cellular senescence. Our data demonstrate that the cytotoxicity of CX-5461 is at least in part the result of an irreversible inhibition of RPI transcription initiation and hence are of direct relevance to the design of improved strategies of chemotherapy.

Aim To evaluate the degree of enamel demineralization of teeth bonded with ceramic and metal brackets. Materials and methods In this cross-sectional experimental in vitro study, 60 extracted human premolar teeth were selected according to the experimental criteria. They were divided into three groups; 20 premolar teeth in each group. Teeth in group 1 were bonded with "ceramic brackets", and teeth in group 2 were bonded with "metal brackets", while teeth in group 3 served as the "control group" without any brackets. Teeth in all groups were then immersed in demineralization media, de-bonded, sectioned into three parts (proximal 1, middle, and proximal 2), and evaluated to determine the level of enamel demineralization under a Scanning Electron Microscope. Results On tooth level, the results show that the control group has significantly less enamel demineralization compared to the other two experimental groups, with mean values of 145.3 µm and 192.7 µm, respectively (P=0.000). The mean value of enamel demineralization in the metal group is 55.93 µm, compared to 72.55 µm in the ceramic group, which is significantly less (P≤0.05), while there is no difference between the control and metal group with regard to enamel demineralization. On section level, the control group has significantly less enamel demineralization in all three sections compared to the ceramic group, while a significant difference is found in one of the proximal sections when compared with the metal group. Moreover, the ceramic group has significantly higher enamel demineralization in the middle section compared to the metal group (73.54 µm, 46.5 µm, respectively) (P=0.000), while there is no statistical significant difference between the two experimental groups in proximal sections. Conclusion In vitro, non-bonded teeth show least demineralization compared to the bonded teeth. Teeth bonded with ceramic brackets show significantly higher enamel demineralization compared to teeth bonded with metal brackets.

El tratamiento quirurgico de las anomalias del conducto peritoneovaginal (CPV) infantiles es una de las intervenciones mas frecuentes en cirugia pediatrica. Sin embargo, este procedimiento no debe trivializarse, porque conlleva un riesgo para la gonada que no es nulo, debido a la diseccion del cordon espermatico en los varones. En este articulo, se describen sucesivamente las tres anomalias principales relacionadas con la persistencia de todo o de una parte del CPV. Se trata de las hernias inguinales, los hidroceles y los quistes del cordon espermatico. El tratamiento varia entre los distintos cuadros y es sustancialmente distinto al del adulto.