Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer.

Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies

Evaluation Kidney Layer Segmentation on Whole Slide Imaging using Convolutional Neural Networks and Transformers

The segmentation of kidney layer structures, including cortex, outer stripe, inner stripe, and inner medulla within human kidney whole slide images (WSI) plays an essential role in automated image analysis in renal pathology. However, the current manual segmentation process proves labor-intensive and infeasible for handling the extensive digital pathology images encountered at a large scale. In response, the realm of digital renal pathology has seen the emergence of deep learning-based methodologies. However, very few, if any, deep learning based approaches have been applied to kidney layer structure segmentation. Addressing this gap, this paper assesses the feasibility of performing deep learning based approaches on kidney layer structure segmetnation. This study employs the representative convolutional neural network (CNN) and Transformer segmentation approaches, including Swin-Unet, Medical-Transformer, TransUNet, U-Net, PSPNet, and DeepLabv3+. We quantitatively evaluated six prevalent deep learning models on renal cortex layer segmentation using mice kidney WSIs. The empirical results stemming from our approach exhibit compelling advancements, as evidenced by a decent Mean Intersection over Union (mIoU) index. The results demonstrate that Transformer models generally outperform CNN-based models. By enabling a quantitative evaluation of renal cortical structures, deep learning approaches are promising to empower these medical professionals to make more informed kidney layer segmentation

Reconstructing the First Metatarsophalangeal Joint of Homo naledi

The aim of the present study was to develop a new method to reconstruct damaged metatarsophalangeal joint (MTPJ) of Homo naledi's fossil and to deepen the understanding of the first metatarsal head (FMH) morphological adaptation in different gait patterns. To this purpose three methods were introduced. The first served to compare the anthropometric linear and volumetric measurements of Homo naledi's MTPJ to that of 10 various athletes. The second was employed to measure curvature diameter in FMH's medial and lateral grooves for sesamoid bones. The third was used to determine the parallelism between medial and lateral FMH grooves. The anthropometric measurements of middle-distance runner to the greatest extent mimicked that of Homo naledi. Thus, it was used to successfully reconstruct the damaged Homo naledi's MTPJ. The highest curvature diameter of medial FMH groove was found in Homo naledi, while in lateral FMH groove it was the highest in volleyball player, suggesting their increased bear loading. The parallelism of medial and lateral FMH grooves was observed only in Homo naledi, while in investigated athletes it was dis-parallel. Athletes' dis-paralleled structures make first MTPJ simple flexion movement a complicated one: not rotating about one axis, but about many, which may result in bringing a negative effect on running. In conclusion, the presented method for the reconstruction of the damaged foot bone paves the way for morphological and structural analysis of modern population and fossil hominins' gait pattern

Eosinophils Instance Object Segmentation on Whole Slide Imaging Using Multi-label Circle Representation

Eosinophilic esophagitis (EoE) is a chronic and relapsing disease characterized by esophageal inflammation. Symptoms of EoE include difficulty swallowing, food impaction, and chest pain which significantly impact the quality of life, resulting in nutritional impairments, social limitations, and psychological distress. The diagnosis of EoE is typically performed with a threshold (15 to 20) of eosinophils (Eos) per high-power field (HPF). Since the current counting process of Eos is a resource-intensive process for human pathologists, automatic methods are desired. Circle representation has been shown as a more precise, yet less complicated, representation for automatic instance cell segmentation such as CircleSnake approach. However, the CircleSnake was designed as a single-label model, which is not able to deal with multi-label scenarios. In this paper, we propose the multi-label CircleSnake model for instance segmentation on Eos. It extends the original CircleSnake model from a single-label design to a multi-label model, allowing segmentation of multiple object types. Experimental results illustrate the CircleSnake model's superiority over the traditional Mask R-CNN model and DeepSnake model in terms of average precision (AP) in identifying and segmenting eosinophils, thereby enabling enhanced characterization of EoE. This automated approach holds promise for streamlining the assessment process and improving diagnostic accuracy in EoE analysis. The source code has been made publicly available at https://github.com/yilinliu610730/EoE

Deep Learning-Based Open Source Toolkit for Eosinophil Detection in Pediatric Eosinophilic Esophagitis

Eosinophilic Esophagitis (EoE) is a chronic, immune/antigen-mediated esophageal disease, characterized by symptoms related to esophageal dysfunction and histological evidence of eosinophil-dominant inflammation. Owing to the intricate microscopic representation of EoE in imaging, current methodologies which depend on manual identification are not only labor-intensive but also prone to inaccuracies. In this study, we develop an open-source toolkit, named Open-EoE, to perform end-to-end whole slide image (WSI) level eosinophil (Eos) detection using one line of command via Docker. Specifically, the toolkit supports three state-of-the-art deep learning-based object detection models. Furthermore, Open-EoE further optimizes the performance by implementing an ensemble learning strategy, and enhancing the precision and reliability of our results. The experimental results demonstrated that the Open-EoE toolkit can efficiently detect Eos on a testing set with 289 WSIs. At the widely accepted threshold of >= 15 Eos per high power field (HPF) for diagnosing EoE, the Open-EoE achieved an accuracy of 91%, showing decent consistency with pathologist evaluations. This suggests a promising avenue for integrating machine learning methodologies into the diagnostic process for EoE. The docker and source code has been made publicly available at https://github.com/hrlblab/Open-EoE

Dressing as a Whole: Outfit Compatibility Learning Based on Node-wise Graph Neural Networks

With the rapid development of fashion market, the customers' demands of customers for fashion recommendation are rising. In this paper, we aim to investigate a practical problem of fashion recommendation by answering the question "which item should we select to match with the given fashion items and form a compatible outfit". The key to this problem is to estimate the outfit compatibility. Previous works which focus on the compatibility of two items or represent an outfit as a sequence fail to make full use of the complex relations among items in an outfit. To remedy this, we propose to represent an outfit as a graph. In particular, we construct a Fashion Graph, where each node represents a category and each edge represents interaction between two categories. Accordingly, each outfit can be represented as a subgraph by putting items into their corresponding category nodes. To infer the outfit compatibility from such a graph, we propose Node-wise Graph Neural Networks (NGNN) which can better model node interactions and learn better node representations. In NGNN, the node interaction on each edge is different, which is determined by parameters correlated to the two connected nodes. An attention mechanism is utilized to calculate the outfit compatibility score with learned node representations. NGNN can not only be used to model outfit compatibility from visual or textual modality but also from multiple modalities. We conduct experiments on two tasks: (1) Fill-in-the-blank: suggesting an item that matches with existing components of outfit; (2) Compatibility prediction: predicting the compatibility scores of given outfits. Experimental results demonstrate the great superiority of our proposed method over others.Comment: 11 pages, accepted by the 2019 World Wide Web Conference (WWW-2019

Spatial Pathomics Toolkit for Quantitative Analysis of Podocyte Nuclei with Histology and Spatial Transcriptomics Data in Renal Pathology

Podocytes, specialized epithelial cells that envelop the glomerular capillaries, play a pivotal role in maintaining renal health. The current description and quantification of features on pathology slides are limited, prompting the need for innovative solutions to comprehensively assess diverse phenotypic attributes within Whole Slide Images (WSIs). In particular, understanding the morphological characteristics of podocytes, terminally differentiated glomerular epithelial cells, is crucial for studying glomerular injury. This paper introduces the Spatial Pathomics Toolkit (SPT) and applies it to podocyte pathomics. The SPT consists of three main components: (1) instance object segmentation, enabling precise identification of podocyte nuclei; (2) pathomics feature generation, extracting a comprehensive array of quantitative features from the identified nuclei; and (3) robust statistical analyses, facilitating a comprehensive exploration of spatial relationships between morphological and spatial transcriptomics features.The SPT successfully extracted and analyzed morphological and textural features from podocyte nuclei, revealing a multitude of podocyte morphomic features through statistical analysis. Additionally, we demonstrated the SPT's ability to unravel spatial information inherent to podocyte distribution, shedding light on spatial patterns associated with glomerular injury. By disseminating the SPT, our goal is to provide the research community with a powerful and user-friendly resource that advances cellular spatial pathomics in renal pathology. The implementation and its complete source code of the toolkit are made openly accessible at https://github.com/hrlblab/spatial_pathomics

False Negative/Positive Control for SAM on Noisy Medical Images

The Segment Anything Model (SAM) is a recently developed all-range foundation model for image segmentation. It can use sparse manual prompts such as bounding boxes to generate pixel-level segmentation in natural images but struggles in medical images such as low-contrast, noisy ultrasound images. We propose a refined test-phase prompt augmentation technique designed to improve SAM's performance in medical image segmentation. The method couples multi-box prompt augmentation and an aleatoric uncertainty-based false-negative (FN) and false-positive (FP) correction (FNPC) strategy. We evaluate the method on two ultrasound datasets and show improvement in SAM's performance and robustness to inaccurate prompts, without the necessity for further training or tuning. Moreover, we present the Single-Slice-to-Volume (SS2V) method, enabling 3D pixel-level segmentation using only the bounding box annotation from a single 2D slice. Our results allow efficient use of SAM in even noisy, low-contrast medical images. The source code will be released soon