Biology subjects

Dall'Ara, E.

Publications and source records attributed to Dall'Ara, E..

8 recordsLinked to original sources

bioRxiv2026

Personalised prediction of anomalous bone regeneration in multiple myeloma patients

Recent advances in immunotherapies have dramatically extended the lives of patients with multiple myeloma, resulting in a growing population of elderly patients suffering from damage to their vertebrae caused by this blood cancer. Clinicians typically intervene to fill in these lytic lesions in an attempt to reduce the risk of vertebral collapse and spinal cord injury, however observations of rapid bone regeneration post-cancer treatment suggest that surgery may not always be required. Here we develop a series of mechanistic computational models, optimised using cohorts of healthy volunteer and patient data, to show that vertebrae of recovering multiple myeloma patients rapidly strengthen in a manner not entirely explained by known bone remodelling mechanisms. Furthermore, using pathways informed by genomics data and patient-specific bone biomarkers, we demonstrate the potential for these models to provide personalised predictions of bone disease trajectory.

bioengineering↗

bioRxiv2026

Geroprotective interventions preserve trabecular bone during ageing in female mice

Geroprotectors extend lifespan and improve several aspects of healthspan, yet their effects on skeletal ageing remain poorly understood. They hold potential advantages over current bone-targeted osteoporosis therapies, as they may simultaneously improve bone, neuromuscular function, and vision, thereby reducing the risk of falls, the major cause of fractures. Here we examined, for the first time, the long-term effects of rapamycin, acarbose, and 17-estradiol, administered at lifespan-extending doses on trabecular and cortical bone architecture in male and female UM-HET3 mice measured with micro-computed tomography at 12 and 22 months of age. Bayesian modelling analysis reveals that all interventions produced responses in trabecular bone in females at 22 months. These effects were driven mainly by increases in trabecular number, with little evidence for changes in trabecular thickness. In contrast, treatment effects in males were generally negligible. Cortical responses were modest. Moderate increases in cortical area fraction were observed in females treated with rapamycin or 17-estradiol at 22 months, whereas cortical thickness remained largely unchanged, suggesting a geometrical rather than anabolic effect. Interestingly, geroprotectors strongest skeletal responses in females contrasts with the predominantly male-biased lifespan extension reported for acarbose and 17-estradiol, suggesting differential mechanisms mediating lifespan extension and bone structure preservation.

pharmacology and toxicology↗

bioRxiv2026

Prediction of compressive strength of vertebral body with metastatic lesions based on quantitative computed tomography-based subject-specific finite element models

Pathologic vertebral fractures are a major complication in metastatic spine disease. However, current clinical scores, such as Spinal Instability Neoplastic Score (SINS), show limited predictive capability, particularly within the indeterminate range where most clinical uncertainty lies. This study aimed to develop and evaluate quantitative computed tomography (qCT)-based subject-specific finite element (SSFE) models to predict vertebral strength in presence of different metastatic lesion types. Twelve ex vivo human spine segments, each containing one metastatic (n=12) and one adjacent control vertebra (n=12), were scanned using qCT and calibrated using a calibration phantom. Homogenised nonlinear finite element models were developed with spatially heterogeneous, isotropic, density-dependent material properties and loaded under uniaxial compression corresponding to 1.9% apparent strain. Ultimate failure load, stiffness, and strain distributions were compared between metastatic and control vertebrae. Predicted failure load ranged from 0.2 kN to 6.2 kN (mean. {+/-} standard deviation: 1.8 {+/-} 1.6 kN metastatic; 1.7 {+/-} 1.5 kN control), with no statistically significant difference between groups (p > 0.05). Normalised failure load varied widely, reflecting lesion-specific mechanical heterogeneity. Lytic lesions generally weakened vertebrae, whereas mixed and blastic lesions occasionally enhanced strength, likely due to localised sclerosis or reactive bone formation. High compressive axial strains (greater than 0.019) were frequently concentrated near the endplates, particularly in lytic vertebrae. qCT-derived bone mineral density strongly correlated with failure load (R{superscript 2} = 0.74-0.77). These findings highlight the complexity of metastatic vertebral mechanics and demonstrate that qCT-based SSFE modelling provides a quantitative framework for assessing fracture risk, complementing conventional imaging-based tools.

bioengineering↗

bioRxiv2026

Strong correlation between phantomless and inline phantom-based densitometric calibration of vertebral properties from CT scans of healthy volunteers

Phantom calibration is currently the gold standard for calibrating CT scans and for calculating material properties of dense tissues for computational models. However, in Oncology departments and low-resource settings, it is not routine to include a calibration phantom within the scanning protocol. Therefore, retrospective scan datasets are challenging to calibrate for biomechanical investigations, precluding detailed measurements of material and mechanical properties. In this study, we compared the results from a phantomless calibration technique, where the density within each scan was independently calibrated based on known tissue densities captured within each scan (e.g. air), with those from a traditional inline phantom calibration. To do so we used scans from a cohort of healthy volunteers from the control arm of a clinical trial dataset (ANTELOPE) in which inline calibration phantoms were included. We found that, when selecting air and the aorta as regions for calibration within individual CT scans, a strong individual-specific correlation existed between bone mineral density measured in the phantomless and phantom calibrations. This indicates that the phantomless calibration method can be a useful and reliable tool for quantifying the densitometric material properties of healthy human vertebrae, and provides the opportunity for further analysis of spinal CT scans in either retrospective datasets or in low-resource clinical settings.

bioengineering↗

bioRxiv2024

PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner

P21 activated kinase 6 (PAK6) is a serine-threonine kinase with physiological expression enriched in the brain and overexpressed in a number of human tumors. While the role of PAK6 in cancer cells has been extensively investigated, the physiological function of the kinase in the context of brain cells is poorly understood. Our previous work uncovered a link between PAK6 and the Parkinsons disease (PD)-associated kinase LRRK2, with PAK6 controlling LRRK2 activity and subcellular localization via phosphorylation of 14-3-3 proteins. Here, to gain more insights into PAK6 physiological function, we performed protein-protein interaction arrays and identified a subgroup of PAK6 binders related to ciliogenesis. We confirmed that endogenous PAK6 localizes at both the centrosome and the cilium, and positively regulates ciliogenesis not only in tumor cells but also in neurons and astrocytes. Strikingly, PAK6 rescues ciliogenesis and centrosomal cohesion defects associated with the G2019S but not the R1441C LRRK2 PD mutation. Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity.

neuroscience↗

bioRxiv2022

Deformable image registration for automatic muscle segmentation and the generation of augmented imaging datasets

Muscle segmentation is a process relied upon to gather medical image-based muscle characterisation, useful in directly assessing muscle volume and geometry, that can be used as inputs to musculoskeletal modelling pipelines. Manual or semi-automatic techniques are typically employed to segment the muscles and quantify their properties, but they require significant manual labour and incur operator repeatability issues. In this study an automatic process is presented, aiming to segment all lower limb muscles from Magnetic Resonance (MR) imaging data simultaneously using three-dimensional (3D) deformable image registration. Twenty-three of the major lower limb skeletal muscles were segmented from five subjects, with an average Dice similarity coefficient of 0.72, and average absolute relative volume error of 12.7% (average relative volume error of -2.2%) considering the optimal subject combinations. Segmented MR imaging datasets of the lower limb are not widely available in the literature, limiting the potential of new, probabilistic methods such as deep learning to be used in the context of muscle segmentation. In this work, Non-linear deformable image registration is used to generate 69 manually checked, segmented, 3D, artificial datasets, allowing access for future studies to use these new methods, with a large amount of reliable reference data.

bioengineering↗

bioRxiv2020

The Digital Mouse: why computational modelling of mouse models of disease can improve translation

Computational models can be used to study the mechanistic phenomena of disease. Current mechanistic computer simulation models mainly focus on (patho)physiology in humans. However, often data and experimental findings from preclinical studies are used as input to develop such models. Biological processes underlying age-related chronic diseases are studied in animal models. The translation of these observations to clinical applications is not trivial. As part of a group of international scientists working in the COST Action network MouseAGE, we argue that in order to boost the translation of pre-clinical research we need to develop accurate in silico counterparts of the in vivo animal models. The Digital Mouse is proposed as framework to support the development of evidence-based medicine, for example to develop geroprotectors, which are drugs that target fundamental mechanisms of ageing. HighlightsO_LIComputational modelling of human (patho)physiology is advancing rapidly, often using and extrapolating experimental findings from preclinical disease models. C_LIO_LIThe lack of in silico models to support in vivo modelling in mice is a missing link in current approaches to study complex, chronic diseases. C_LIO_LIThe development of mechanistic computational models to simulate disease in mice can boost the discovery of novel therapeutic interventions. C_LIO_LIThe Digital Mouse is proposed as a framework to implement this ambition. The development of a Digital Mouse Frailty Index (DM:FI) to study aging and age-related diseases is provided as an example. C_LI

bioengineering↗

bioRxiv2018

Prenatal growth map of the mouse knee joint by mean of deformable registration technique

Joint morphogenesis is the process during which distinct and functional joint shapes emerge during pre- and post-natal joint development. In this study, a repeatable semi-automatic protocol capable of providing a 3D realistic developmental map of the prenatal mouse knee joint was designed by combining Optical Projection Tomography imaging (OPT) and a deformable registration algorithm (Sheffield Image Registration toolkit, ShIRT). Eleven left limbs of healthy murine embryos were scanned with OPT (voxel size: 14.63[1/4]m) at two different stages of development: Theiler stage (TS) 23 (approximately 14.5 embryonic days) and 24 (approximately 15.5 embryonic days). One TS23 limb was used to evaluate the precision of the displacement predictions for this specific case. The remaining limbs were then used to estimate Developmental Tibia and Femur Maps. Acceptable uncertainties of the displacement predictions were found for both epiphyses (between 0.7 and 1.4 m, along all directions and anatomical sites) for nodal spacing of 1 voxel. The protocol was found to be reproducible with maximum Modified Housdorff Distance differences equal to 1.9 m and 1.5 m for the tibial and femoral epiphyses respectively. The effect of the initial shape of the rudiment affected the developmental maps by 21.7 m and 21.9 m for the tibial and femoral epiphyses respectively, which correspond to 1.4 and 1.5 times the voxel size. To conclude, this study proposes a repeatable semi-automatic protocol capable of providing mean 3D realistic developmental map of a developing rudiment allowing researchers to study how growth and adaptation are directed by biological and mechanobiological factors.

bioengineering↗