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Abstract 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.

Background: The relationship between the mean absorbed dose delivered to the tumour and the outcome in liver metastases from colorectal cancer patients treated with radioembolization has already been presented in several studies. The optimization of the personalized therapeutic activity to be administered is still an open challenge. In this context, how well the 99mTc-MAA SPECT/CT predicts the absorbed dose delivered by radioembolization is essential. This work aimed to analyse the differences between predictive 99mTc-MAA-SPECT/CT and post-treatment 90Y-microsphere PET/CT dosimetry at different levels. Dose heterogeneity was compared voxel-to-voxel using the quality-volume histograms, subsequently used to demonstrate how it could be used to identify potential clinical parameters that are responsible for quantitative discrepancies between predictive and post-treatment dosimetry. Results: We analysed 130 lesions delineated in twenty-six patients. Dose-volume histograms were computed from predictive and post-treatment dosimetry for all volumes: individual lesion, whole tumoural liver (TL) and non-tumoural liver (NTL). For all dose-volume histograms, the following indices were extracted: D90, D70, D50, Dmean and D20. The results showed mostly no statistical differences between predictive and post-treatment dosimetries across all volumes and for all indices. Notably, the analysis showed no difference in terms of Dmean, confirming the results from previous studies. Quality factors representing the spread of the quality-volume histogram (QVH) curve around 0 (ideal QF = 0) were determined for lesions, TL and NTL. QVHs were classified into good (QF < 0.18), acceptable (0.18 ≤ QF < 0.3) and poor (QF ≥ 0.3) correspondence. For lesions and TL, dose- and quality-volume histograms are mostly concordant: 69% of lesions had a QF within good/acceptable categories (40% good) and 65% of TL had a QF within good/acceptable categories (23% good). For NTL, the results showed mixed results with 48% QF within the poor concordance category. Finally, it was demonstrated how QVH analysis could be used to define the parameters that predict the significant differences between predictive and post-treatment dose distributions. Conclusion: It was shown that the use of the QVH is feasible in assessing the predictive value of 99mTc-MAA SPECT/CT dosimetry and in estimating the absorbed dose delivered to liver metastases from colorectal cancer via 90Y-microspheres. QVH analyses could be used in combination with DVH to enhance the predictive value of 99mTc-MAA SPECT/CT dosimetry and to assist personalized activity prescription. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]