Systematisation of spatial uncertainties for comparison between a MR and a CT-based radiotherapy workflow for prostate treatments

<p>Abstract</p> <p>Background</p> <p>In the present work we compared the spatial uncertainties associated with a MR-based workflow for external radiotherapy of prostate cancer to a standard CT-based workflow. The MR-based workflow relies on target definition and patient positioning based on MR imaging. A solution for patient transport between the MR scanner and the treatment units has been developed. For the CT-based workflow, the target is defined on a MR series but then transferred to a CT study through image registration before treatment planning, and a patient positioning using portal imaging and fiducial markers.</p> <p>Methods</p> <p>An "open bore" 1.5T MRI scanner, Siemens Espree, has been installed in the radiotherapy department in near proximity to a treatment unit to enable patient transport between the two installations, and hence use the MRI for patient positioning. The spatial uncertainty caused by the transport was added to the uncertainty originating from the target definition process, estimated through a review of the scientific literature. The uncertainty in the CT-based workflow was estimated through a literature review.</p> <p>Results</p> <p>The systematic uncertainties, affecting all treatment fractions, are reduced from 3-4 mm (1Sd) with a CT based workflow to 2-3 mm with a MR based workflow. The main contributing factor to this improvement is the exclusion of registration between MR and CT in the planning phase of the treatment.</p> <p>Conclusion</p> <p>Treatment planning directly on MR images reduce the spatial uncertainty for prostate treatments.</p

UNC45A deficiency causes microvillus inclusion disease–like phenotype by impairing myosin VB–dependent apical trafficking

International audienceVariants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45A(KO) Caco-2 cells. In keeping with impaired myosin VB function, UNC45A(KO) Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45A(KO) 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease