Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Health care reform in the USA: Recommendations from USA and non-USA radiologists

AIM: To compare the opinions and recommendations of imaging specialists from United States (USA) and non-USA developed nations for USA health care reform

A framework based on subject-specific musculoskeletal models and Monte Carlo simulations to personalize muscle coordination retraining

Abstract Excessive loads at lower limb joints can lead to pain and degenerative diseases. Altering joint loads with muscle coordination retraining might help to treat or prevent clinical symptoms in a non-invasive way. Knowing how much muscle coordination retraining can reduce joint loads and which muscles have the biggest impact on joint loads is crucial for personalized gait retraining. We introduced a simulation framework to quantify the potential of muscle coordination retraining to reduce joint loads for an individuum. Furthermore, the proposed framework enables to pinpoint muscles, which alterations have the highest likelihood to reduce joint loads. Simulations were performed based on three-dimensional motion capture data of five healthy adolescents (femoral torsion 10°–29°, tibial torsion 19°–38°) and five patients with idiopathic torsional deformities at the femur and/or tibia (femoral torsion 18°–52°, tibial torsion 3°–50°). For each participant, a musculoskeletal model was modified to match the femoral and tibial geometry obtained from magnetic resonance images. Each participant’s model and the corresponding motion capture data were used as input for a Monte Carlo analysis to investigate how different muscle coordination strategies influence joint loads. OpenSim was used to run 10,000 simulations for each participant. Root-mean-square of muscle forces and peak joint contact forces were compared between simulations. Depending on the participant, altering muscle coordination led to a maximum reduction in hip, knee, patellofemoral and ankle joint loads between 5 and 18%, 4% and 45%, 16% and 36%, and 2% and 6%, respectively. In some but not all participants reducing joint loads at one joint increased joint loads at other joints. The required alteration in muscle forces to achieve a reduction in joint loads showed a large variability between participants. The potential of muscle coordination retraining to reduce joint loads depends on the person’s musculoskeletal geometry and gait pattern and therefore showed a large variability between participants, which highlights the usefulness and importance of the proposed framework to personalize gait retraining