FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner.

INTRODUCTION: Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option is readily available. FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor with little information in liver fibrosis. OBJECTIVE: This study was designed to examine the role for FUNDC1 in carbon tetrachloride (CCl4)-induced liver injury. METHODS: GEO database analysis and subsequent validation of biological processes including western blot, immunofluorescence, and co-immunoprecipitation were applied to clarify the regulatory role of FUNDC1 on mitophagy and ferroptosis. RESULTS: Our data revealed elevated FUNDC1 levels in liver tissues of patients with liver fibrotic injury and CCl4-challenged mice. FUNDC1 deletion protected against CCl4-induced hepatic anomalies in mice. Moreover, FUNDC1 deletion ameliorated CCl4-induced ferroptosis in vivo and in vitro. Mechanically, FUNDC1 interacted with glutathione peroxidase (GPx4), a selenoenzyme to neutralize lipid hydroperoxides and ferroptosis, via its 96-133 amino acid domain to facilitate GPx4 recruitment into mitochondria from cytoplasm. GPx4 entered mitochondria through mitochondrial protein import system-the translocase of outer membrane/translocase of inner membrane (TOM/TIM) complex, prior to degradation of GPx4 mainly through mitophagy along with ROS-induced damaged mitochondria, resulting in hepatocyte ferroptosis. CONCLUSION: Taken together, our data favored that FUNDC1 promoted hepatocyte injury through GPx4 binding to facilitate its mitochondrial translocation through TOM/TIM complex, where GPx4 was degraded by mitophagy to trigger ferroptosis. Targeting FUNDC1 may be a promising therapeutic approach for liver fibrosis.

OpenKBP-Opt: an international and reproducible evaluation of 76 knowledge-based planning pipelines.

Objective.To establish an open framework for developing plan optimization models for knowledge-based planning (KBP).Approach.Our framework includes radiotherapy treatment data (i.e. reference plans) for 100 patients with head-and-neck cancer who were treated with intensity-modulated radiotherapy. That data also includes high-quality dose predictions from 19 KBP models that were developed by different research groups using out-of-sample data during the OpenKBP Grand Challenge. The dose predictions were input to four fluence-based dose mimicking models to form 76 unique KBP pipelines that generated 7600 plans (76 pipelines × 100 patients). The predictions and KBP-generated plans were compared to the reference plans via: the dose score, which is the average mean absolute voxel-by-voxel difference in dose; the deviation in dose-volume histogram (DVH) points; and the frequency of clinical planning criteria satisfaction. We also performed a theoretical investigation to justify our dose mimicking models.Main results.The range in rank order correlation of the dose score between predictions and their KBP pipelines was 0.50-0.62, which indicates that the quality of the predictions was generally positively correlated with the quality of the plans. Additionally, compared to the input predictions, the KBP-generated plans performed significantly better (P< 0.05; one-sided Wilcoxon test) on 18 of 23 DVH points. Similarly, each optimization model generated plans that satisfied a higher percentage of criteria than the reference plans, which satisfied 3.5% more criteria than the set of all dose predictions. Lastly, our theoretical investigation demonstrated that the dose mimicking models generated plans that are also optimal for an inverse planning model.Significance.This was the largest international effort to date for evaluating the combination of KBP prediction and optimization models. We found that the best performing models significantly outperformed the reference dose and dose predictions. In the interest of reproducibility, our data and code is freely available.

MoNuSAC2020: A Multi-Organ Nuclei Segmentation and Classification Challenge.

Detecting various types of cells in and around the tumor matrix holds a special significance in characterizing the tumor micro-environment for cancer prognostication and research. Automating the tasks of detecting, segmenting, and classifying nuclei can free up the pathologists' time for higher value tasks and reduce errors due to fatigue and subjectivity. To encourage the computer vision research community to develop and test algorithms for these tasks, we prepared a large and diverse dataset of nucleus boundary annotations and class labels. The dataset has over 46,000 nuclei from 37 hospitals, 71 patients, four organs, and four nucleus types. We also organized a challenge around this dataset as a satellite event at the International Symposium on Biomedical Imaging (ISBI) in April 2020. The challenge saw a wide participation from across the world, and the top methods were able to match inter-human concordance for the challenge metric. In this paper, we summarize the dataset and the key findings of the challenge, including the commonalities and differences between the methods developed by various participants. We have released the MoNuSAC2020 dataset to the public.

Technical Note: A cascade 3D U-Net for dose prediction in radiotherapy.

PURPOSE: Although large datasets are available, to learn a robust dose prediction model from a limited dataset still remains challenging. This work employed cascaded deep learning models and advanced training strategies with a limited dataset to precisely predict three-dimensional (3D) dose distribution. METHODS: A Cascade 3D (C3D) model is developed based on the cascade mechanism and 3D U-Net network units. During model training, data augmentations are used to improve the generalization ability of the prediction model. A knowledge distillation technique is employed to further improve the capability of model learning. The C3D network was evaluated using the OpenKBP challenge dataset and competed with those models proposed by more than 40 teams globally. Additionally, it was compared with five existing cutting-edge dose prediction models. The performance of these prediction models was evaluated by voxel-based mean absolute error (MAE) and clinical-related dosimetric metrics. The code and models are publicly available online (https://github.com/LSL000UD/RTDosePrediction). RESULTS: The MAE of a single C3D model without test-time augmentation is 2.50 Gy (3.57% related to prescription dose) for nonzero dose area, which outperforms the other five dose prediction models by about 0.1 Gy-1.7 Gy. The C3D model won both dose and DVH streams of AAPM 2020 OpenKBP challenge with dose score of 2.31 and DVH score of 1.55. CONCLUSIONS: The Cascading U-Nets is an ideal solution for 3D dose prediction from a limited dataset. The proper data preprocessing, data augmentation, and optimization procedure are more important than architectural modifications of deep learning network.

Predicting voxel-level dose distributions for esophageal radiotherapy using densely connected network with dilated convolutions.

This work aims to develop a voxel-level dose prediction framework by integrating distance information between PTV and OARs, as well as image information, into a densely-connected network (DCNN). Firstly, a four-channel feature map, consisting of a PTV image, an OAR image, a CT image, and a distance image, is constructed. A densely connected neural network is then built and trained for voxel-level dose prediction. Considering that the shape and size of OARs are highly inconsistent, a dilated convolution is employed to capture features from multiple scales. Finally, the proposed network is evaluated with five-fold cross-validation, based on ninety-eight clinically approved treatment plans. The voxel-level mean absolute error(MAE V ) of DCNN was 2.1% for PTV, 4.6% for left lung, 4.0% for right lung, 5.1% for heart, 6.0% for spinal cord, and 3.4% for body, which outperforms conventional U-Net, Resnet-antiResnet, U-Resnet-D by 0.1-0.8%. This result shows that with the introduction of a distance image and DCNN model, the accuracy of predicted dose distribution could be significantly improved. This approach offers a new dose prediction tool to support quality assurance and the automation of treatment planning in esophageal radiotherapy.