Investigation of the dependence of joint contact forces on musculotendon parameters using a codified workflow for image-based modelling

The generation of subject-specific musculoskeletal models of the lower limb has become a feasible taskthanks to improvements in medical imaging technology and musculoskeletal modelling software.Nevertheless, clinical use of these models in paediatric applications is still limited for what concernsthe estimation of muscle and joint contact forces. Aiming to improve the current state of the art, amethodology to generate highly personalized subject-specific musculoskeletal models of the lower limbbased on magnetic resonance imaging (MRI) scans was codified as a step-by-step procedure and appliedto data from eight juvenile individuals. The generated musculoskeletal models were used to simulate 107gait trials using stereophotogrammetric and force platform data as input. To ensure completeness of themodelling procedure, muscles’ architecture needs to be estimated. Four methods to estimate muscles’maximum isometric force and two methods to estimate musculotendon parameters (optimal fiber lengthand tendon slack length) were assessed and compared, in order to quantify their influence on the models’output. Reported results represent the first comprehensive subject-specific model-based characterizationof juvenile gait biomechanics, including profiles of joint kinematics and kinetics, muscle forces and jointcontact forces. Our findings suggest that, when musculotendon parameters were linearly scaled from areference model and the muscle force-length-velocity relationship was accounted for in the simulations,realistic knee contact forces could be estimated and these forces were not sensitive the method used tocompute muscle maximum isometric force

Automatic centerline extraction of coronary arteries in coronary computed tomographic angiography

Coronary computed tomographic angiography (CCTA) is a non-invasive imaging modality for the visualization of the heart and coronary arteries. To fully exploit the potential of the CCTA datasets and apply it in clinical practice, an automated coronary artery extraction approach is needed. The purpose of this paper is to present and validate a fully automatic centerline extraction algorithm for coronary arteries in CCTA images. The algorithm is based on an improved version of Frangi’s vesselness filter which removes unwanted step-edge responses at the boundaries of the cardiac chambers. Building upon this new vesselness filter, the coronary artery extraction pipeline extracts the centerlines of main branches as well as side-branches automatically. This algorithm was first evaluated with a standardized evaluation framework named Rotterdam Coronary Artery Algorithm Evaluation Framework used in the MICCAI Coronary Artery Tracking challenge 2008 (CAT08). It includes 128 reference centerlines which were manually delineated. The average overlap and accuracy measures of our method were 93.7% and 0.30 mm, respectively, which ranked at the 1st and 3rd place compared to five other automatic methods presented in the CAT08. Secondly, in 50 clinical datasets, a total of 100 reference centerlines were generated from lumen contours in the transversal planes which were manually corrected by an expert from the cardiology department. In this evaluation, the average overlap and accuracy were 96.1% and 0.33 mm, respectively. The entire processing time for one dataset is less than 2 min on a standard desktop computer. In conclusion, our newly developed automatic approach can extract coronary arteries in CCTA images with excellent performances in extraction ability and accuracy

Linking joint impairment and gait biomechanics in patients with Juvenile Idiopathic Arthritis

Juvenile Idiopathic Arthritis (JIA) is a paediatric musculoskeletal disease of unknown aetiology, leading to walking alterations when the lower-limb joints are involved. Diagnosis of JIA is mostly clinical. Imaging can quantify impairments associated to inflammation and joint damage. However, treatment planning could be better supported using dynamic information, such as joint contact forces (JCFs). To this purpose, we used a musculoskeletal model to predict JCFs and investigate how JCFs varied as a result of joint impairment in eighteen children with JIA. Gait analysis data and magnetic resonance images (MRI) were used to develop patient-specific lower-limb musculoskeletal models, which were evaluated for operator-dependent variability (< 3.6°, 0.05 N kg−1 and 0.5 BW for joint angles, moments, and JCFs, respectively). Gait alterations and JCF patterns showed high between-subjects variability reflecting the pathology heterogeneity in the cohort. Higher joint impairment, assessed with MRI-based evaluation, was weakly associated to overall joint overloading. A stronger correlation was observed between impairment of one limb and overload of the contralateral limb, suggesting risky compensatory strategies being adopted, especially at the knee level. This suggests that knee overloading during gait might be a good predictor of disease progression and gait biomechanics should be used to inform treatment planning

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC