Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease

A prospective development study of software-guided radio-frequency ablation of primary and secondary liver tumors: Clinical intervention modelling, planning and proof for ablation cancer treatment (ClinicIMPPACT)

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A prospective development study of software-guided radio-frequency ablation of primary and secondary liver tumors: Clinical intervention modelling, planning and proof for ablation cancer treatment (ClinicIMPPACT)

Introduction: Radio-frequency ablation (RFA) is a promising minimal-invasive treatment option for early liver cancer, however monitoring or predicting the size of the resulting tissue necrosis during the RFA-procedure is a challenging task, potentially resulting in a significant rate of under- or over treatments. Currently there is no reliable lesion size prediction method commercially available. Objectives: ClinicIMPPACT is designed as multicenter-, prospective-, non-randomized clinical trial to evaluate the accuracy and efficiency of innovative planning and simulation software. 60 patients with early liver cancer will be included at four European clinical institutions and treated with the same RFA system. The preinterventional imaging datasets will be used for computational planning of the RFA treatment. All ablations will be simulated simultaneously to the actual RFA procedure, using the software environment developed in this project. The primary outcome measure is the comparison of the simulated ablation zones with the true lesions shown in follow-up imaging after one month, to assess accuracy of the lesion prediction. Discussion: This unique multicenter clinical trial aims at the clinical integration of a dedicated software solution to accurately predict lesion size and shape after radiofrequency ablation of liver tumors. Accelerated and optimized workflow integration, and real-time intraoperative image processing, as well as inclusion of patient specific information, e.g. organ perfusion and registration of the real RFA needle position might make the introduced software a powerful tool for interventional radiologists to optimize patient outcomes

Interactive Volumetry Of Liver Ablation Zones

Percutaneous radiofrequency ablation (RFA) is a minimally invasive technique that destroys cancer cells by heat. The heat results from focusing energy in the radiofrequency spectrum through a needle. Amongst others, this can enable the treatment of patients who are not eligible for an open surgery. However, the possibility of recurrent liver cancer due to incomplete ablation of the tumor makes post-interventional monitoring via regular follow-up scans mandatory. These scans have to be carefully inspected for any conspicuousness. Within this study, the RF ablation zones from twelve post-interventional CT acquisitions have been segmented semi-automatically to support the visual inspection. An interactive, graph-based contouring approach, which prefers spherically shaped regions, has been applied. For the quantitative and qualitative analysis of the algorithm’s results, manual slice-by-slice segmentations produced by clinical experts have been used as the gold standard (which have also been compared among each other). As evaluation metric for the statistical validation, the Dice Similarity Coefficient (DSC) has been calculated. The results show that the proposed tool provides lesion segmentation with sufficient accuracy much faster than manual segmentation. The visual feedback and interactivity make the proposed tool well suitable for the clinical workflow.Peer reviewe

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease