Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signalling

Dysfunctional regulation of signalling pathways downstream of the insulin receptor plays a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes. In this study we report both in vitro and in vivo experimental evidence for a role of Cullin-RING E3 ubiquitin ligase 7 (CRL7) in the regulation of insulin signalling and glucose homeostasis. We show that Cul7−/− mouse embryonic fibroblasts displayed enhanced AKT and Erk MAP kinase phosphorylation upon insulin stimulation. Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signalling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin-induced degradation of insulin receptor substrate 1 (IRS1). In vivo, heterozygosity of either Cul7 or Fbxw8, both key components of CRL7, resulted in elevated PI3 kinase / AKT activation in skeletal muscle tissue upon insulin stimulation when compared to wild-type controls. Finally, Cul7+/− or Fbxw8+/− mice exhibited enhanced insulin sensitivity and plasma glucose clearance. Collectively, our findings point to a yet unrecognized role of CRL7 in insulin-mediated control of glucose homeostasis by restraining PI3 kinase / AKT activities in skeletal muscle cells

Machine learning and augmented data for automated treatment planning in complex external beam radiation therapy

External beam radiation therapy is currently one of the most commonly used modalities for treating cancer. With the rise of new technologies and increasing computational power, machine learning, deep learning and artificial intelligence applications used for classification and regression problems have begun to find their way into the field of radiation oncology. One such application is the automated generation of radiotherapy treatment plans, which must be optimized for every single patient. The department of radiation physics in Lund, Sweden, has developed an autoplanning software, which in combination with a commercially available treatment planning system (TPS), can be used for automatic creation of clinical treatment plans. The parameters of a multivariable cost function are changed iteratively, making it possible to generate a great amount of different treatment plans for a single patient. The output leads to optimal, near-optimal, clinically acceptable or even non-acceptable treatment plans. In this thesis, the possibility of using machine and deep learning to minimize the amount of treatment plans generated by the autoplanning software as well as the possibility of finding cost function parameters that lead to clinically acceptable optimal or near-optimal plans is evaluated. Data augmentation is used to create matrices of optimal treatment plan parameters, which are stored in a training database.  Patient specific training features are extracted from the TPS, as well as from the bottleneck layer of a trained deep neural network autoencoder. The training features are then matched against the same features extracted for test patients, using a k-nearest neighbor algorithm. Finally, treatment plans for a new patient are generated using the output plan parameter matrices of its nearest neighbors. This allows for a reduction in computation time as well as for finding suitable cost function parameters for a new patient

Determining the impact of air-side cleaning for heat exchangers in ventilation systems

Cleaning coils can be an efficient way to reduce the need for reparations and maintain the functionality of a ventilation system. This study builds upon existing knowledge concerning the contamination of heat exchangers. Through field measurements on coils and heat-recovery units, a laboratory experiment on a coil, and a generic calculation example, this study determines the impact of sustained contamination on heat-recovery units with regards to energy use. Field measurements made before and after cleaning of heat exchangers show an average increase in the pressure drop by 12% and decrease in the thermal exchange efficiency by 8.1% due to mass deposited on the surface of the heat exchangers. Results from a laboratory test show a correlation between the mass deposited on a coil and (1) the increase in pressure drop over the coil, as well as (2) a diminishing heat exchange. Accumulating contamination on heat-recovery units in residential and commercial buildings (over time) is then linked to increasing pressure drop and diminishing thermal efficiency. With models based on these links, energy loss over time is calculated based on a generic calculation example in a realistic scenario. Practical application : The results from this study emphasize the need for maintenance of buildings with ventilation systems with coils, but more so those with heat-recovery units. The presented field measurements and laboratory study correlate energy loss with sustained accumulation of contaminants on coils and heat-recovery units. These results should serve as a recommendation to property owners considering maintenance of such units in their buildings

The FLASH effect depends on oxygen concentration

OBJECTIVE: Recent in vivo results have shown prominent tissue sparing effect of radiotherapy with ultra-high dose rates (FLASH) compared to conventional dose rates (CONV). Oxygen depletion has been proposed as the underlying mechanism, but in vitro data to support this have been lacking. The aim of the current study was to compare FLASH to CONV irradiation under different oxygen concentrations in vitro. METHODS: Prostate cancer cells were irradiated at different oxygen concentrations (relative partial pressure ranging between 1.6 and 20%) with a 10 MeV electron beam at a dose rate of either 600 Gy/s (FLASH) or 14 Gy/min (CONV), using a modified clinical linear accelerator. We evaluated the surviving fraction of cells using clonogenic assays after irradiation with doses ranging from 0 to 25 Gy. RESULTS: Under normoxic conditions, no differences between FLASH and CONV irradiation were found. For hypoxic cells (1.6%), the radiation response was similar up to a dose of about 5-10 Gy, above which increased survival was shown for FLASH compared to CONV irradiation. The increased survival was shown to be significant at 18 Gy, and the effect was shown to depend on oxygen concentration. CONCLUSION: The in vitro FLASH effect depends on oxygen concentration. Further studies to characterize and optimize the use of FLASH in order to widen the therapeutic window are indicated. ADVANCES IN KNOWLEDGE: This paper shows in vitro evidence for the role of oxygen concentration underlying the difference between FLASH and CONV irradiation

Deep learning-based classification of organs at risk and delineation guideline in pelvic cancer radiation therapy

Deep learning (DL) models for radiation therapy (RT) image segmentation require accurately annotated training data. Multiple organ delineation guidelines exist; however, information on the used guideline is not provided with the delineation. Extraction of training data with coherent guidelines can therefore be challenging. We present a supervised classification method for pelvis structure delineations where bowel cavity, femoral heads, bladder, and rectum data, with two guidelines, were classified. The impact on DL-based segmentation quality using mixed guideline training data was also demonstrated. Bowel cavity was manually delineated on CT images for anal cancer patients (n = 170) according to guidelines Devisetty and RTOG. The DL segmentation quality from using training data with coherent or mixed guidelines was investigated. A supervised 3D squeeze-and-excite SENet-154 model was trained to classify two bowel cavity delineation guidelines. In addition, a pelvis CT dataset with manual delineations from prostate cancer patients (n = 1854) was used where data with an alternative guideline for femoral heads, rectum, and bladder were generated using commercial software. The model was evaluated on internal (n = 200) and external test data (n = 99). By using mixed, compared to coherent, delineation guideline training data mean DICE score decreased 3% units, mean Hausdorff distance (95%) increased 5 mm and mean surface distance (MSD) increased 1 mm. The classification of bowel cavity test data achieved 99.8% unweighted classification accuracy, 99.9% macro average precision, 97.2% macro average recall, and 98.5% macro average F1. Corresponding metrics for the pelvis internal test data were all 99% or above and for the external pelvis test data they were 96.3%, 96.6%, 93.3%, and 94.6%. Impaired segmentation performance was observed for training data with mixed guidelines. The DL delineation classification models achieved excellent results on internal and external test data. This can facilitate automated guideline-specific data extraction while avoiding the need for consistent and correct structure labels

Development of a novel radiotherapy motion phantom using a stepper motor driver circuit and evaluation using optical surface scanning

Abstract: Recent developments in radiotherapy have focused on the management of patient motion during treatment. Studies have shown that significant gains in treatment quality can be made by ‘gating’ certain treatments, simultaneously keeping target coverage, and increasing separation to nearby organs at risk (OAR). Motion phantoms can be used to simulate patient breathing motion and provide the means to perform quality control (QC) and quality assurance (QA) of gating functionality as well as to assess the dosimetric impact of motion on individual patient treatments. The aim of this study was to design and build a motion phantom that accurately reproduces the breathing motion of patients to enable end-to-end gating system quality control of various gating systems as well as patient specific quality assurance. A motion phantom based on a stepper motor driver circuit was designed. The phantom can be programmed with both real patient data from an external gating system and with custom signals. The phantom was programmed and evaluated with patient data and with a square wave signal to be tracked with a Sentinel™ (C-Rad, Uppsala, Sweden) motion monitoring system. Results were compared to the original curves with respect to amplitude and phase. The comparison of patient curve data showed a mean error value of −0.09 mm with a standard deviation of 0.24 mm and a mean absolute error of 0.29 mm. The square wave signals could be reproduced with a mean error value of −0.03 mm, a standard deviation of 0.04 mm and a mean absolute error of 0.13 mm. Breathing curve data acquired from an optical scanning system can be reproduced accurately with the help of the in-house built motion phantom. The phantom can also be programmed to follow user designed curve data. This offers the potential for QC of gating systems and various dosimetric quality control applications. Graphical Abstract: [Figure not available: see fulltext.

Correction for Ion Recombination in a Built-in Monitor Chamber of a Clinical Linear Accelerator at Ultra-High Dose Rates

In the novel and promising radiotherapy technique known as FLASH, ultra-high dose-rate electron beams are used. As a step towards clinical trials, dosimetric advances will be required for accurate dose delivery of FLASH. The purpose of this study was to determine whether a built-in transmission chamber of a clinical linear accelerator can be used as a real-Time dosimeter to monitor the delivery of ultra-high-dose-rate electron beams. This was done by modeling the drop-in ion-collection efficiency of the chamber with increasing dose-per-pulse values, so that the ion recombination effect could be considered. The raw transmission chamber signal was extracted from the linear accelerator and its response was measured using radiochromic film at different dose rates/dose-per-pulse values, at a source-To-surface distance of 100 cm. An increase of the polarizing voltage, applied over the transmission chamber, by a factor of 2 and 3, improved the ion-collection efficiency, with corresponding increased efficiency at the highest dose-per-pulse values by a factor 1.4 and 2.2, respectively. The drop-in ion-collection efficiency with increasing dose-per-pulse was accurately modeled using a logistic function fitted to the transmission chamber data. The performance of the model was compared to that of the general theoretical Boag models of ion recombination in ionization chambers. The logistic model was subsequently used to correct for ion recombination at dose rates ranging from conventional to ultra-high, making the transmission chamber useful as a real-Time monitor for the dose delivery of FLASH electron beams in a clinical setup

Modifying a clinical linear accelerator for delivery of ultra-high dose rate irradiation

Objectives: The purpose of this study was to modify a clinical linear accelerator, making it capable of electron beam ultra-high dose rate (FLASH) irradiation. Modifications had to be quick, reversible, and without interfering with clinical treatments. Methods: Performed modifications: (1) reduced distance with three setup positions, (2) adjusted/optimized gun current, modulator charge rate and beam steering values for a high dose rate, (3) delivery was controlled with a microcontroller on an electron pulse level, and (4) moving the primary and/or secondary scattering foils from the beam path. Results: The variation in dose for a five-pulse delivery was measured to be 1% (using a diode, 4% using film) during 10 minutes after a warm-up procedure, later increasing to 7% (11% using film). A FLASH irradiation dose rate was reached at the cross-hair foil, MLC, and wedge position, with ≥30, ≥80, and ≥300 Gy/s, respectively. Moving the scattering foils resulted in an increased output of ≥120, ≥250, and ≥1000 Gy/s, at the three positions. The beam flatness was 5% at the cross-hair position for a 20 × 20 and a 10 × 10 cm2 area, with and without both scattering foils in the beam. The beam flatness was 10% at the wedge position for a 6 and 2.5 cm diametric area, with and without the scattering foils in the beam path. Conclusions: A clinical accelerator was modified to produce ultra-high dose rates, high enough for FLASH irradiation. Future work aims to fine-tune the dose delivery, using the on-board transmission chamber signal and adjusting the dose-per-pulse