Relationships between blood chromium exposure and liver injury: Exploring the mediating role of systemic inflammation in a chromate-exposed population.

Hexavalent chromium and its compounds are prevalent pollutants, especially in the work environment, pose a significant risk for multisystem toxicity and cancers. While it is known that chromium accumulation in the liver can cause damage, the dose-response relationship between blood chromium (Cr) and liver injury, as well as the possible potential toxic mechanisms involved, remains poorly understood. To address this, we conducted a follow-up study of 590 visits from 305 participants to investigate the associations of blood Cr with biomarkers for liver injury, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL), and to evaluate the mediating effects of systemic inflammation. Platelet (PLT) and the platelet-to-lymphocyte ratio (PLR) were utilized as biomarkers of systemic inflammation. In the linear mixed-effects analyses, each 1-unit increase in blood Cr level was associated with estimated effect percentage increases of 0.82% (0.11%, 1.53%) in TBIL, 1.67% (0.06%, 3.28%) in DBIL, 0.73% (0.04%, 1.43%) in ALT and 2.08% (0.29%, 3.87%) in AST, respectively. Furthermore, PLT mediated 10.04%, 11.35%, and 10.77% increases in TBIL, DBIL, and ALT levels induced by chromate, respectively. In addition, PLR mediated 8.26% and 15.58% of the association between blood Cr and TBIL or ALT. These findings shed light on the mechanisms underlying blood Cr-induced liver injury, which is partly due to worsening systemic inflammation.

Immune Regulation Patterns in Response to Environmental Pollutant Chromate Exposure-Related Genetic Damage: A Cross-Sectional Study Applying Machine Learning Methods.

Exposure to hexavalent chromium damages genetic materials like DNA and chromosomes, further elevating cancer risk, yet research rarely focuses on related immunological mechanisms, which play an important role in the occurrence and development of cancer. We investigated the association between blood chromium (Cr) levels and genetic damage biomarkers as well as the immune regulatory mechanism involved, such as costimulatory molecules, in 120 workers exposed to chromates. Higher blood Cr levels were linearly correlated with higher genetic damage, reflected by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and blood micronucleus frequency (MNF). Exploratory factor analysis revealed that both positive and negative immune regulation patterns were positively associated with blood Cr. Specifically, higher levels of programmed cell death protein 1 (PD-1; mediated proportion: 4.12%), programmed cell death ligand 1 (PD-L1; 5.22%), lymphocyte activation gene 3 (LAG-3; 2.11%), and their constitutive positive immune regulation pattern (5.86%) indirectly positively influenced the relationship between blood Cr and urinary 8-OHdG. NOD-like receptor family pyrin domain containing 3 (NLRP3) positively affected the association between blood Cr levels and inflammatory immunity. This study, using machine learning, investigated immune regulation and its potential role in chromate-induced genetic damage, providing insights into complex relationships and emphasizing the need for further research.

ImageCAS: A large-scale dataset and benchmark for coronary artery segmentation based on computed tomography angiography images.

Cardiovascular disease (CVD) accounts for about half of non-communicable diseases. Vessel stenosis in the coronary artery is considered to be the major risk of CVD. Computed tomography angiography (CTA) is one of the widely used noninvasive imaging modalities in coronary artery diagnosis due to its superior image resolution. Clinically, segmentation of coronary arteries is essential for the diagnosis and quantification of coronary artery disease. Recently, a variety of works have been proposed to address this problem. However, on one hand, most works rely on in-house datasets, and only a few works published their datasets to the public which only contain tens of images. On the other hand, their source code have not been published, and most follow-up works have not made comparison with existing works, which makes it difficult to judge the effectiveness of the methods and hinders the further exploration of this challenging yet critical problem in the community. In this paper, we propose a large-scale dataset for coronary artery segmentation on CTA images. In addition, we have implemented a benchmark in which we have tried our best to implement several typical existing methods. Furthermore, we propose a strong baseline method which combines multi-scale patch fusion and two-stage processing to extract the details of vessels. Comprehensive experiments show that the proposed method achieves better performance than existing works on the proposed large-scale dataset. The benchmark and the dataset are published at https://github.com/XiaoweiXu/ImageCAS-A-Large-Scale-Dataset-and-Benchmark-for-Coronary-Artery-Segmentation-based-on-CT.

Identification of hub genes and potential ceRNA networks of diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), a common complication of diabetes, is defined as ventricular dysfunction in the absence of underlying heart disease. Noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), play a crucial role in the development of DCM. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify key modules in DCM-related pathways. DCM-related miRNA-mRNA network and DCM-related ceRNA network were constructed by miRNA-seq to identify hub genes in these modules. We identified five hub genes that are associated with the onset of DCM, including Troponin C1 (Tnnc1), Phospholamban (Pln), Fatty acid binding proteins 3 (Fabp3), Popeye domain containing 2 (Popdc2), and Tripartite Motif-containing Protein 63 (Trim63). miRNAs that target the hub genes were mainly involved in TGF-ß and Wnt signaling pathways. GO BP enrichment analysis found these miRNAs were involved in the signaling of TGF-ß and glucose homeostasis. Q-PCR results found the gene expressions of Pln, Fabp3, Trim63, Tnnc1, and Popdc2 were significantly increased in DCM. Our study identified five hub genes (Tnnc1, Pln, Fabp3, Popdc2, Trim63) whose associated ceRNA networks are responsible for the onset of DCM.

Target area distillation and section attention segmentation network for accurate 3D medical image segmentation.

3D medical image segmentation has an essential role in medical image analysis, while attention mechanism has improved the performance by a large margin. However, existing methods obtained the attention coefficient in a small receptive field, resulting in possible performance limitations. Radiologists usually scan all the slices first to have an overall idea of the target, and then analyze regions of interest in multiple 2D views in clinic practice. We simulate radiologists' recognition process and propose to exploit the 3D context information in a deeper manner for accurate 3D medical images segmentation. Due to the similarity of human body structure, medical images of different populations have highly similar shape and location information, so we use target region distillation to extract the common segmented region information. Particularly, we proposed two optimizations including Target Area Distillation and Section Attention. Target Area Distillation adds positions information to the original input to let the network has an initial attention of the target, while section attention performs attention extraction in three 2D sections thus with large range of receptive field. We compare our method against several popular networks in two public datasets including ImageCHD and COVID-19. Experimental results show that our proposed method improves the segmentation Dice score by 2-4% over the state-of-the-art methods. Our code has been released to the public (Anonymous link).

Pyramid-Net: Intra-layer Pyramid-Scale Feature Aggregation Network for Retinal Vessel Segmentation.

Retinal vessel segmentation plays an important role in the diagnosis of eye-related diseases and biomarkers discovery. Existing works perform multi-scale feature aggregation in an inter-layer manner, namely inter-layer feature aggregation. However, such an approach only fuses features at either a lower scale or a higher scale, which may result in a limited segmentation performance, especially on thin vessels. This discovery motivates us to fuse multi-scale features in each layer, intra-layer feature aggregation, to mitigate the problem. Therefore, in this paper, we propose Pyramid-Net for accurate retinal vessel segmentation, which features intra-layer pyramid-scale aggregation blocks (IPABs). At each layer, IPABs generate two associated branches at a higher scale and a lower scale, respectively, and the two with the main branch at the current scale operate in a pyramid-scale manner. Three further enhancements including pyramid inputs enhancement, deep pyramid supervision, and pyramid skip connections are proposed to boost the performance. We have evaluated Pyramid-Net on three public retinal fundus photography datasets (DRIVE, STARE, and CHASE-DB1). The experimental results show that Pyramid-Net can effectively improve the segmentation performance especially on thin vessels, and outperforms the current state-of-the-art methods on all the adopted three datasets. In addition, our method is more efficient than existing methods with a large reduction in computational cost. We have released the source code at https://github.com/JerRuy/Pyramid-Net.

ImageTBAD: A 3D Computed Tomography Angiography Image Dataset for Automatic Segmentation of Type-B Aortic Dissection.

Type-B Aortic Dissection (TBAD) is one of the most serious cardiovascular events characterized by a growing yearly incidence, and the severity of disease prognosis. Currently, computed tomography angiography (CTA) has been widely adopted for the diagnosis and prognosis of TBAD. Accurate segmentation of true lumen (TL), false lumen (FL), and false lumen thrombus (FLT) in CTA are crucial for the precise quantification of anatomical features. However, existing works only focus on only TL and FL without considering FLT. In this paper, we propose ImageTBAD, the first 3D computed tomography angiography (CTA) image dataset of TBAD with annotation of TL, FL, and FLT. The proposed dataset contains 100 TBAD CTA images, which is of decent size compared with existing medical imaging datasets. As FLT can appear almost anywhere along the aorta with irregular shapes, segmentation of FLT presents a wide class of segmentation problems where targets exist in a variety of positions with irregular shapes. We further propose a baseline method for automatic segmentation of TBAD. Results show that the baseline method can achieve comparable results with existing works on aorta and TL segmentation. However, the segmentation accuracy of FLT is only 52%, which leaves large room for improvement and also shows the challenge of our dataset. To facilitate further research on this challenging problem, our dataset and codes are released to the public (Dataset, 2020).

Effect of conglomeration gradation on loess shear strength with different water content.

Particle gradation and water content are important factors affecting shear strength of soil. However, due to chemical cementation and molecular attraction, loess particles commonly stick together forming conglomerations. Till date, the superposition effect of water content and conglomeration gradation on loess shear strength has rarely been studied and undeniably requires further systematic explorations and development. In this study, loess samples were prepared with three conglomeration gradations and five water contents, and the direct shear tests were systematically performed. The shear strength of sample 1 (continuous conglomeration gradation) was found to be the best, followed by sample 2 (large size conglomerations), and sample 3 (small size conglomerations). The difference of samples' shear strength decreased with increasing water content, and almost closed to zero when water content was 20%. The cohesion of samples first increased and then decreased with increasing water content, the maximum cohesion occurred at 10% water content. The internal friction angles decreased with increasing water content, and reached similar minimum values when the water content was 15%. The increased percentage values of cohesion and internal friction angle caused by conglomeration gradation are in the range of 33.2%-42.1% and 9.8%-32.5%, respectively. Finally, the empirical formulas for water content-cohesion and water content-internal friction angle of different conglomeration gradations samples were established, and the calculated values are in good agreement with test data. The effect of loess conglomeration gradation on shear strength decreased with increasing water content. When the water content was less than 15%, using a good conglomeration graduation could effectively improve loss shear strength.

Toehold-mediated ligation-free rolling circle amplification enables sensitive and rapid imaging of messenger RNAs in situ in cells.

In situ analysis of tumor-related messenger RNAs (mRNAs) is significant in identifying cancer cells at the genetic level in the early stage. Rolling circle amplification (RCA)-based methods are primary tools for in situ mRNA assay, however, the necessary ligation reaction not only shows low ligation efficiency, but also greatly prolongs the assay time that increases the risk of cells losing and mRNAs leakage. In this work, we propose a novel toehold-mediated ligation-free RCA (TMLFRCA) on a designed structure-switchable dumbbell-shaped probe (SDP). Target mRNA can specifically activate SDP from its circular form by toehold strand displacement, thereby initiates in situ RCA for mRNA imaging with the help of a short DNA primer. For the proof-of-concept demonstration, the TK1 mRNA was sensitively detected by TMLFRCA in less than 3.5 h with a limit of detection (LOD) of 0.39 fM (corresponds to 2.39×108copiesL-1), and significantly improved specificity capable for distinguishing single base difference. The sensitivity of the TMLFRCA for TK1 mRNA in situ assay is ∼29-fold and ∼7-fold higher than that of FISH and ligase-assisted RCA method, respectively, which enables the TMLFRCA method capability of highly sensitive and specific distinction mRNA expression levels between cancer cells and normal cells. We believe this TMLFRCA strategy would be of great value in both basic research and clinical diagnosis.

Aurora A Inhibition Eliminates Myeloid Cell-Mediated Immunosuppression and Enhances the Efficacy of Anti-PD-L1 Therapy in Breast Cancer.

The Aurora A inhibitor alisertib shows encouraging activities in clinical trials against advanced breast cancer. However, it remains unclear whether and how the inflammatory microenvironment is involved in its efficacy. Here, we demonstrated that inhibition of Aurora A directly reshaped the immune microenvironment through removal of tumor-promoting myeloid cells and enrichment of anticancer T lymphocytes, which established a tumor-suppressive microenvironment and significantly contributed to the regression of murine mammary tumors. Mechanistically, alisertib treatment triggered apoptosis in myeloid-derived suppressor cells (MDSC) and macrophages, resulting in their elimination from tumors. Furthermore, alisertib treatment disrupted the immunosuppressive functions of MDSC by inhibiting Stat3-mediated ROS production. These alterations led to significant increases of active CD8+ and CD4+ T lymphocytes, which efficiently inhibited the proliferation of tumor cells. Intriguingly, alisertib combined with PD-L1 blockade showed synergistic efficacy in the treatment of mammary tumors. These results detail the effects of Aurora A inhibition on the immune microenvironment and provide a novel chemo-immunotherapy strategy for advanced breast cancers. SIGNIFICANCE: These findings show that inhibition of Aurora A facilitates an anticancer immune microenvironment, which can suppress tumor progression and enhance anti-PD-L1 therapy in breast cancer.See related commentary by Rivoltini et al., p. 3169.

Mechanical Stress Regulates Osteogenesis and Adipogenesis of Rat Mesenchymal Stem Cells through PI3K/Akt/GSK-3ß/ß-Catenin Signaling Pathway.

Osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs) are regarded as being of great importance in the regulation of bone remodeling. In this study, rat BMSCs were exposed to different levels of cyclic mechanical stress generated by liquid drops and cultured in general medium or adipogenic medium. Markers of osteogenic (Runx2 and Collagen I) and adipogenic (C/EBPα, PPARγ, and lipid droplets) differentiation were detected using Western blot and histological staining. The protein levels of members of the phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase 3ß (GSK-3ß)/ß-catenin signaling pathway were also examined. Results showed that small-magnitude stress significantly upregulated Runx2 and Collagen I and downregulated PPARγ and C/EBPα expression in BMSCs cultured in adipogenic medium, while large-magnitude stress reversed the effect when compared with unloading groups. The PI3K/Akt signaling pathway could be strongly activated by mechanical stimulation; however, large-magnitude stress led to decreased activation of the signaling pathway when compared with small-magnitude stress. Activation of ß-catenin with LiCl led to increased expression of Runx2 and Collagen I and reduction of C/EBPα and PPARγ expression in BMSCs. Inhibition of PI3K/Akt signaling partially blocked the expression of ß-catenin. Taken together, our results indicate that mechanical stress-regulated osteogenesis and adipogenesis of rat BMSCs are mediated, at least in part, by the PI3K/Akt/GSK-3ß/ß-catenin signaling pathway.

Mechanical Loading Improves Tendon-Bone Healing in a Rabbit Anterior Cruciate Ligament Reconstruction Model by Promoting Proliferation and Matrix Formation of Mesenchymal Stem Cells and Tendon Cells.

BACKGROUND/AIMS: This study investigated the effect of mechanical stress on tendon-bone healing in a rabbit anterior cruciate ligament (ACL) reconstruction model as well as cell proliferation and matrix formation in co-culture of bone-marrow mesenchymal stem cells (BMSCs) and tendon cells (TCs). METHODS: The effect of continuous passive motion (CPM) therapy on tendon-bone healing in a rabbit ACL reconstruction model was evaluated by histological analysis, biomechanical testing and gene expressions at the tendon-bone interface. Furthermore, the effect of mechanical stretch on cell proliferation and matrix synthesis in BMSC/TC co-culture was also examined. RESULTS: Postoperative CPM therapy significantly enhanced tendon-bone healing, as evidenced by increased amount of fibrocartilage, elevated ultimate load to failure levels, and up-regulated gene expressions of Collagen I, alkaline phosphatase, osteopontin, Tenascin C and tenomodulin at the tendon-bone junction. In addition, BMSC/TC co-culture treated with mechanical stretch showed a higher rate of cell proliferation and enhanced expressions of Collagen I, Collagen III, alkaline phosphatase, osteopontin, Tenascin C and tenomodulin than that of controls. CONCLUSION: These results demonstrated that proliferation and differentiation of local precursor cells could be enhanced by mechanical stimulation, which results in enhanced regenerative potential of BMSCs and TCs in tendon-bone healing.

Cyclic Compressive Stress Regulates Apoptosis in Rat Osteoblasts: Involvement of PI3K/Akt and JNK MAPK Signaling Pathways.

It is widely accepted that physiological mechanical stimulation suppresses apoptosis and induces synthesis of extracellular matrix by osteoblasts; however, the effect of stress overloading on osteoblasts has not been fully illustrated. In the present study, we investigated the effect of cyclic compressive stress on rat osteoblasts apoptosis, using a novel liquid drop method to generate mechanical stress on osteoblast monolayers. After treatment with different levels of mechanical stress, apoptosis of osteoblasts and activations of mitogen-activated protein kinases (MAPKs) and PI3-kinase (PI3K)/Akt signaling pathways were investigated. Osteoblasts apoptosis was observed after treated with specific inhibitors prior to mechanical stimulation. Protein levels of Bax/Bcl-2/caspase-3 signaling were determined using western blot with or without inhibitors of PI3K/Akt and phosphorylation of c-jun N-terminal kinase (JNK) MAPK. Results showed that mechanical stimulation led to osteoblasts apoptosis in a dose-dependent manner and a remarkable activation of MAPKs and PI3K/Akt signaling pathways. Activation of PI3K/Akt protected against apoptosis, whereas JNK MAPK increased apoptosis via regulation of Bax/Bcl-2/caspase-3 activation. In summary, the PI3K/Akt and JNK MAPK signaling pathways played opposing roles in osteoblasts apoptosis, resulting in inhibition of apoptosis upon small-magnitude stress and increased apoptosis upon large-magnitude stress.

Organic selenium supplementation increases mercury excretion and decreases oxidative damage in long-term mercury-exposed residents from Wanshan, China.

Due to a long history of extensive mercury mining and smelting activities, local residents in Wanshan, China, are suffering from elevated mercury exposure. The objective of the present study was to study the effects of oral supplementation with selenium-enriched yeast in these long-term mercury-exposed populations. One hundred and three volunteers from Wanshan area were recruited and 53 of them were supplemented with 100 µg of organic selenium daily as selenium-enriched yeast while 50 of them were supplemented with the nonselenium-enriched yeast for 3 months. The effects of selenium supplementation on urinary mercury, selenium, and oxidative stress-related biomarkers including malondialdehyde and 8-hydroxy-2-deoxyguanosine were assessed. This 3-month selenium supplementation trial indicated that organic selenium supplementation could increase mercury excretion and decrease urinary malondialdehyde and 8-hydroxy-2-deoxyguanosine levels in local residents.