Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer.

The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.

Fast deep learning reconstruction techniques for preclinical magnetic resonance fingerprinting.

We propose a deep learning (DL) model and a hyperparameter optimization strategy to reconstruct T1 and T2 maps acquired with the magnetic resonance fingerprinting (MRF) methodology. We applied two different MRF sequence routines to acquire images of ex vivo rat brain phantoms using a 7-T preclinical scanner. Subsequently, the DL model was trained using experimental data, completely excluding the use of any theoretical MRI signal simulator. The best combination of the DL parameters was implemented by an automatic hyperparameter optimization strategy, whose key aspect is to include all the parameters to the fit, allowing the simultaneous optimization of the neural network architecture, the structure of the DL model, and the supervised learning algorithm. By comparing the reconstruction performances of the DL technique with those achieved from the traditional dictionary-based method on an independent dataset, the DL approach was shown to reduce the mean percentage relative error by a factor of 3 for T1 and by a factor of 2 for T2 , and to improve the computational time by at least a factor of 37. Furthermore, the proposed DL method enables maintaining comparable reconstruction performance, even with a lower number of MRF images and a reduced k-space sampling percentage, with respect to the dictionary-based method. Our results suggest that the proposed DL methodology may offer an improvement in reconstruction accuracy, as well as speeding up MRF for preclinical, and in prospective clinical, investigations.

Muscle diffusion tensor imaging in facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Muscle diffusion tensor imaging has not yet been explored in facioscapulohumeral muscular dystrophy (FSHD). We assessed diffusivity parameters in FSHD subjects compared with healthy controls (HCs), with regard to their ability to precede any fat replacement or edema. METHODS: Fat fraction (FF), water T2 (wT2), mean, radial, axial diffusivity (MD, RD, AD), and fractional anisotropy (FA) of thigh muscles were calculated in 10 FSHD subjects and 15 HCs. All parameters were compared between FSHD and controls, also exploring their gradient along the main axis of the muscle. Diffusivity parameters were tested in a subgroup analysis as predictors of disease involvement in muscle compartments with different degrees of FF and wT2 and were also correlated with clinical severity scores. RESULTS: We found that MD, RD, and AD were significantly lower in FSHD subjects than in controls, whereas we failed to find a difference for FA. In contrast, we found a significant positive correlation between FF and FA and a negative correlation between MD, RD, and AD and FF. No correlation was found with wT2. In our subgroup analysis we found that muscle compartments with no significant fat replacement or edema (FF < 10% and wT2 < 41 ms) showed a reduced AD and FA compared with controls. Less involved compartments showed different diffusivity parameters than more involved compartments. DISCUSSION: Our exploratory study was able to demonstrate diffusivity parameter abnormalities even in muscles with no significant fat replacement or edema. Larger cohorts are needed to confirm these preliminary findings.

Impact of the inversion time on regional brain perfusion estimation with clinical arterial spin labeling protocols.

OBJECTIVE: Evaluating the impact of the Inversion Time (TI) on regional perfusion estimation in a pediatric cohort using Arterial Spin Labeling (ASL). MATERIALS AND METHODS: Pulsed ASL (PASL) was acquired at 3 T both at TI 1500 ms and 2020 ms from twelve MRI-negative patients (age range 9-17 years). A volume of interest (VOIs) and a voxel-wise approach were employed to evaluate subject-specific TI-dependent Cerebral Blood Flow (CBF) differences, and grey matter CBF Z-score differences. A visual evaluation was also performed. RESULTS: CBF was higher for TI 1500 ms in the proximal territories of the arteries (PTAs) (e.g. insular cortex and basal ganglia ï»¿- P < 0.01 and P < 0.05 from the VOI analysis, respectively), and for TI 2020 ms in the distal territories of the arteries (DTAs), including the watershed areas (e.g. posterior parietal and occipital cortex - P < 0.001 and P < 0.01 from the VOI analysis, respectively). Similar differences were also evident when analyzing patient-specific CBF Z-scores and at a visual inspection. CONCLUSIONS: TI influences ASL perfusion estimates with a region-dependent effect. The presence of intraluminal arterial signal in PTAs and the longer arterial transit time in the DTAs (including watershed areas) may account for the TI-dependent differences. Watershed areas exhibiting a lower perfusion signal at short TIs (~ 1500 ms) should not be misinterpreted as focal hypoperfused areas.

Radiomics and machine learning applied to STIR sequence for prediction of quantitative parameters in facioscapulohumeral disease.

Purpose: Quantitative Muscle MRI (qMRI) is a valuable and non-invasive tool to assess disease involvement and progression in neuromuscular disorders being able to detect even subtle changes in muscle pathology. The aim of this study is to evaluate the feasibility of using a conventional short-tau inversion recovery (STIR) sequence to predict fat fraction (FF) and water T2 (wT2) in skeletal muscle introducing a radiomic workflow with standardized feature extraction combined with machine learning algorithms. Methods: Twenty-five patients with facioscapulohumeral muscular dystrophy (FSHD) were scanned at calf level using conventional STIR sequence and qMRI techniques. We applied and compared three different radiomics workflows (WF1, WF2, WF3), combined with seven Machine Learning regression algorithms (linear, ridge and lasso regression, tree, random forest, k-nearest neighbor and support vector machine), on conventional STIR images to predict FF and wT2 for six calf muscles. Results: The combination of WF3 and K-nearest neighbor resulted to be the best predictor model of qMRI parameters with a mean absolute error about ± 5 pp for FF and ± 1.8 ms for wT2. Conclusion: This pilot study demonstrated the possibility to predict qMRI parameters in a cohort of FSHD subjects starting from conventional STIR sequence.