Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling.

Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss-of-function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia-based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co-receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.

Prolonged treatment planning can increase real rectal dose in 3D brachytherapy for cervical cancer.

PURPOSE: The purpose of this study was to evaluate the influence of 3D brachytherapy planning time on the real dose distribution. MATERIAL AND METHODS: 10 patients with cervical cancer were evaluated using 2 computed tomography (CT) scans brachytherapy. The first scan was performed after the insertion of UVAG applicators, and the second was done after creating the treatment plan, just before the irradiation of first and third fraction. Both plans were compared in terms of changes of volumes and differences in the dose for high-risk organs using GEC-ESTRO Working Group parameters. RESULTS: The median planning time was 54 minutes (36-64 minutes). The absolute median change of volume for bladder, rectum, and sigmoid was 32.1 cm3 (1.6-108.6 cm3), 5.6 cm3 (0.4-61.8 cm3), and 8.4 cm3 (0.2-74.1 cm3), respectively. This difference led to an increased dose for bladder and sigmoid for D0.1cc by 46.7 cGy and 25.7 cGy, for D1cc by 59.2 cGy and 11.8 cGy, and for D2cc by 44.7 cGy and 10 cGy, respectively, per each fraction. Measured volume change in case of rectum led to a decreased dose per each fraction for D0.1cc with 7.1 cGy, for D1cc with 3.5 cGy, and for D2cc with 4.8 cGy. We observed that statistically significant dependency between the planning time and the dose was proved for rectum. The longer time for planning, the higher dose for rectum. The correlation coefficient for D0.1cc was 0.6715 (p = 0.0061), for D1cc was 0.6404 (p = 0.011), and for D2cc was 0.5891 (p = 0.0197). CONCLUSIONS: Extended treatment planning time for brachytherapy due to the changes in topography of small pelvis can lead to different dose in high-risk organs than previously planned. It seems that the most significant changes are related to rectum.