Evaluation of a Developed MRI-Guided Focused Ultrasound System in 7 T Small Animal MRI and Proof-of-Concept in a Prostate Cancer Xenograft Model to Improve Radiation Therapy.

Focused ultrasound (FUS) can be used to physiologically change or destroy tissue in a non-invasive way. A few commercial systems have clinical approval for the thermal ablation of solid tumors for the treatment of neurological diseases and palliative pain management of bone metastases. However, the thermal effects of FUS are known to lead to various biological effects, such as inhibition of repair of DNA damage, reduction in tumor hypoxia, and induction of apoptosis. Here, we studied radiosensitization as a combination therapy of FUS and RT in a xenograft mouse model using newly developed MRI-compatible FUS equipment. Xenograft tumor-bearing mice were produced by subcutaneous injection of the human prostate cancer cell line PC-3. Animals were treated with FUS in 7 T MRI at 4.8 W/cm2 to reach ~45 °C and held for 30 min. The temperature was controlled via fiber optics and proton resonance frequency shift (PRF) MR thermometry in parallel. In the combination group, animals were treated with FUS followed by X-ray at a single dose of 10 Gy. The effects of FUS and RT were assessed via hematoxylin-eosin (H&E) staining. Tumor proliferation was detected by the immunohistochemistry of Ki67 and apoptosis was measured by a TUNEL assay. At 40 days follow-up, the impact of RT on cancer cells was significantly improved by FUS as demonstrated by a reduction in cell nucleoli from 189 to 237 compared to RT alone. Inhibition of tumor growth by 4.6 times was observed in vivo in the FUS + RT group (85.3%) in contrast to the tumor volume of 393% in the untreated control. Our results demonstrated the feasibility of combined MRI-guided FUS and RT for the treatment of prostate cancer in a xenograft mouse model and may provide a chance for less invasive cancer therapy through radiosensitization.

A Novel Matrix-Array-Based MR-Conditional Ultrasound System for Local Hyperthermia of Small Animals.

OBJECTIVE: The goal of this work was to develop a novel modular focused ultrasound hyperthermia (FUS-HT) system for preclinical applications with the following characteristics: MR-compatible, compact probe for integration into a PET/MR small animal scanner, 3D-beam steering capabilities, high resolution focusing for generation of spatially confined FUS-HT effects. METHODS: For 3D-beam steering capabilities, a matrix array approach with 11 × 11 elements was chosen. For reaching the required level of integration, the array was mounted with a conductive backing directly on the interconnection PCB. The array is driven by a modified version of our 128 channel ultrasound research platform DiPhAS. The system was characterized using sound field measurements and validated using tissue-mimicking phantoms. Preliminary MR-compatibility tests were performed using a 7T Bruker MRI scanner. RESULTS: Four 11 × 11 arrays between 0.5 and 2 MHz were developed and characterized with respect to sound field properties and HT generation. Focus sizes between 1 and 4 mm were reached depending on depth and frequency. We showed heating by 4 °C within 60 s in phantoms. The integration concept allows a probe thickness of less than 12 mm. CONCLUSION: We demonstrated FUS-HT capabilities of our modular system based on matrix arrays and a 128 channel electronics system within a 3D-steering range of up to ±30°. The suitability for integration into a small animal MR could be demonstrated in basic MR-compatibility tests. SIGNIFICANCE: The developed system presents a new generation of FUS-HT for preclinical and translational work providing safe, reversible, localized, and controlled HT.

Portable Ultrasound Research System for Use in Automated Bladder Monitoring with Machine-Learning-Based Segmentation.

We developed a new mobile ultrasound device for long-term and automated bladder monitoring without user interaction consisting of 32 transmit and receive electronics as well as a 32-element phased array 3 MHz transducer. The device architecture is based on data digitization and rapid transfer to a consumer electronics device (e.g., a tablet) for signal reconstruction (e.g., by means of plane wave compounding algorithms) and further image processing. All reconstruction algorithms are implemented in the GPU, allowing real-time reconstruction and imaging. The system and the beamforming algorithms were evaluated with respect to the imaging performance on standard sonographical phantoms (CIRS multipurpose ultrasound phantom) by analyzing the resolution, the SNR and the CNR. Furthermore, ML-based segmentation algorithms were developed and assessed with respect to their ability to reliably segment human bladders with different filling levels. A corresponding CNN was trained with 253 B-mode data sets and 20 B-mode images were evaluated. The quantitative and qualitative results of the bladder segmentation are presented and compared to the ground truth obtained by manual segmentation.

Spatially Resolved MR-Compatible Doppler Ultrasound: Proof of Concept for Triggering of Diagnostic Quality Cardiovascular MRI for Function and Flow Quantification at 3T.

OBJECTIVE: We demonstrate the use of a magnetic-resonance (MR)-compatible ultrasound (US) imaging probe using spatially resolved Doppler for diagnostic quality cardiovascular MR imaging (MRI) as an initial step toward hybrid US/MR fetal imaging. METHODS: A newly developed technology for a dedicated MR-compatible phased array ultrasound-imaging probe acquired pulsed color Doppler carotid images, which were converted in near-real time to a trigger signal for cardiac cine and flow quantification MRI. Ultrasound and MR data acquired simultaneously were interference free. Conventional electrocardiogram (ECG) and the proposed spatially resolved Doppler triggering were compared in 10 healthy volunteers. A synthetic "false-triggered" image was retrospectively processed using metric optimized gating (MOG). Images were scored by expert readers, and sharpness, cardiac function and aortic flow were quantified. Four-dimensional (4-D) flow (two volunteers) showed feasibility of Doppler triggering over a long acquisition time. RESULTS: Imaging modalities were compatible. US probe positioning was stable and comfortable. Image quality scores and quantified sharpness were statistically equal for Doppler- and ECG-triggering (p ). ECG-, Doppler-triggered, and MOG ejection fractions were equivalent (p ), with false-triggered values significantly lower (p < 0.0005). Aortic flow showed no difference between ECG- and Doppler-triggered and MOG (p > 0.05). 4-D flow quantification gave consistent results between ECG and Doppler triggering. CONCLUSION: We report interference-free pulsed color Doppler ultrasound during MR data acquisition. Cardiovascular MRI of diagnostic quality was successfully obtained with pulsed color Doppler triggering. SIGNIFICANCE: The hardware platform could further enable advanced free-breathing cardiac imaging. Doppler ultrasound triggering is applicable where ECG is compromised due to pathology or interference at higher magnetic fields, and where direct ECG is impossible, i.e., fetal imaging.

SwitchFinder - a novel method and query facility for discovering dynamic gene expression patterns.

BACKGROUND: Biological systems and processes are highly dynamic. To gain insights into their functioning time-resolved measurements are necessary. Time-resolved gene expression data captures temporal behaviour of the genes genome-wide under various biological conditions: in response to stimuli, during cell cycle, differentiation or developmental programs. Dissecting dynamic gene expression patterns from this data may shed light on the functioning of the gene regulatory system. The present approach facilitates this discovery. The fundamental idea behind it is the following: there are change-points (switches) in the gene behaviour separating intervals of increasing and decreasing activity, whereas the intervals may have different durations. Elucidating the switch-points is important for the identification of biologically meanigfull features and patterns of the gene dynamics. RESULTS: We developed a statistical method, called SwitchFinder, for the analysis of time-series data, in particular gene expression data, based on a change-point model. Fitting the model to the gene expression time-courses indicates switch-points between increasing and decreasing activities of each gene. Two types of the model - based on linear and on generalized logistic function - were used to capture the data between the switch-points. Model inference was facilitated with the Bayesian methodology using Markov chain Monte Carlo (MCMC) technique Gibbs sampling. Further on, we introduced features of the switch-points: growth, decay, spike and cleft, which reflect important dynamic aspects. With this, the gene expression profiles are represented in a qualitative manner - as sets of the dynamic features at their onset-times. We developed a Web application of the approach, enabling to put queries to the gene expression time-courses and to deduce groups of genes with common dynamic patterns. SwitchFinder was applied to our original data - the gene expression time-series measured in neuroblastoma cell line upon treatment with all-trans retinoic acid (ATRA). The analysis revealed eight patterns of the gene expression responses to ATRA, indicating the induction of the BMP, WNT, Notch, FGF and NTRK-receptor signaling pathways involved in cell differentiation, as well as the repression of the cell-cycle related genes. CONCLUSIONS: SwitchFinder is a novel approach to the analysis of biological time-series data, supporting inference and interactive exploration of its inherent dynamic patterns, hence facilitating biological discovery process. SwitchFinder is freely available at https://newbioinformatics.eu/switchfinder.