Pub Date : 2025-02-13DOI: 10.1016/j.ajpath.2025.01.011
Michelle Kha, Ylva Magnusson, Iva Johansson, Gülay Altiparmak, Jaana Lundgren, Jenny Nyström, Kerstin Ebefors, Karl Swärd, Martin E Johansson
Recent studies have demonstrated that the transcription factor hepatocyte nuclear factor 4α (HNF4A) drives epithelial differentiation in the renal proximal tubules (PTs) and is critical for maintaining a mature PT phenotype. Furthermore, HNF4A down-regulation has been observed following kidney injury in mouse models. The aim of the present work was to investigate the role of HNF4A during acute and chronic human kidney disease and the loss of the mature PT phenotype in cultured PT cells. By immunohistochemistry, we discovered that loss of HNF4A expression and gain of vimentin expression are reciprocal and gradual during both acute and chronic kidney disease. Healthy human kidneys demonstrated partial or total loss of HNF4A expression in vimentin-positive scattered tubular cells. Primary cell isolation and subculture of PT cells recapitulated HNF4A-associated loss of the PT phenotype. Re-expression of HNF4A in cultured PT cells by adenoviral transduction increased transcripts related to brush border formation as well as absorptive and transport processes, as shown by RNA sequencing and gene set enrichment analyses. Thus, the reduction of HNF4A and increase of vimentin expression are connected to both acute and chronic kidney disease and represent a stereotypic injury response of the PT, resulting in dedifferentiation. HNF4A re-expression in cultured primary PT cells could provide a more reliable and predictive in vitro model to study PT function and injury.
{"title":"Injured Proximal Tubular Epithelial Cells Lose Hepatocyte Nuclear Factor 4α Expression Crucial for Brush Border Formation and Transport.","authors":"Michelle Kha, Ylva Magnusson, Iva Johansson, Gülay Altiparmak, Jaana Lundgren, Jenny Nyström, Kerstin Ebefors, Karl Swärd, Martin E Johansson","doi":"10.1016/j.ajpath.2025.01.011","DOIUrl":"10.1016/j.ajpath.2025.01.011","url":null,"abstract":"<p><p>Recent studies have demonstrated that the transcription factor hepatocyte nuclear factor 4α (HNF4A) drives epithelial differentiation in the renal proximal tubules (PTs) and is critical for maintaining a mature PT phenotype. Furthermore, HNF4A down-regulation has been observed following kidney injury in mouse models. The aim of the present work was to investigate the role of HNF4A during acute and chronic human kidney disease and the loss of the mature PT phenotype in cultured PT cells. By immunohistochemistry, we discovered that loss of HNF4A expression and gain of vimentin expression are reciprocal and gradual during both acute and chronic kidney disease. Healthy human kidneys demonstrated partial or total loss of HNF4A expression in vimentin-positive scattered tubular cells. Primary cell isolation and subculture of PT cells recapitulated HNF4A-associated loss of the PT phenotype. Re-expression of HNF4A in cultured PT cells by adenoviral transduction increased transcripts related to brush border formation as well as absorptive and transport processes, as shown by RNA sequencing and gene set enrichment analyses. Thus, the reduction of HNF4A and increase of vimentin expression are connected to both acute and chronic kidney disease and represent a stereotypic injury response of the PT, resulting in dedifferentiation. HNF4A re-expression in cultured primary PT cells could provide a more reliable and predictive in vitro model to study PT function and injury.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-13DOI: 10.1016/j.ajpath.2025.01.012
Alissa Keegan, Gayathri Malamal, Yichien Lee, Kyle Korolowicz, Blythe D Shepard, Carolyn M Ecelbarger, Mariana Moya Rubiano, Maria Laura Avantaggiati, Moshe Levi, Laurie Rich, Massimo Alfano, Avi Rosenberg, Stanley Fricke, Chris Albanese, Jithin Jose, Olga Rodriguez
Chronic diseases of the liver are major public health concerns worldwide. Steatosis and steatohepatitis associated with alcoholic liver disease, metabolic dysfunction-associated fatty liver disease/nonalcoholic fatty liver disease, and hepatitis B and C contribute to chronic diseases of the liver. Liver fibrosis occurs in all forms of advanced chronic diseases of the liver, the confirmation of which is typically performed by needle biopsy. Imaging approaches for liver diagnosis exist but do not provide sufficient diagnostic accuracy for defining the various stages of fibrosis or steatosis. Therefore, there is a need for improved imaging capabilities to enhance disease diagnosis. Ultrasonography-based photoacoustic imaging has recently emerged as a noninvasive, nonionizing modality, capable of capturing structural details and oxygen saturation changes during disease progression. However, its potential for detecting surrogate metabolic dysfunction-associated fatty liver disease markers, such as collagen and lipids, which are often poorly resolved by other conventional imaging techniques, has yet to be investigated in detail. The novelty of this study lies in the innovative use of spectral photoacoustic imaging for the direct detection and quantification of key biomarkers of liver disease, such as fibrosis, collagen, lipids, and oxygenated and deoxygenated hemoglobin, in a mouse model of steatotic fatty liver disease. We established that ultrasonography-based photoacoustic imaging, validated with magnetic resonance imaging, effectively identified increases in liver adiposity and fibrosis, enabling the noninvasive detection of changes in liver pathology associated with metabolic dysfunction.
{"title":"Multimodal Diagnostic Imaging of Metabolic Dysfunction-Associated Steatotic Liver Disease: Noninvasive Analyses by Photoacoustic Ultrasound and Magnetic Resonance Imaging.","authors":"Alissa Keegan, Gayathri Malamal, Yichien Lee, Kyle Korolowicz, Blythe D Shepard, Carolyn M Ecelbarger, Mariana Moya Rubiano, Maria Laura Avantaggiati, Moshe Levi, Laurie Rich, Massimo Alfano, Avi Rosenberg, Stanley Fricke, Chris Albanese, Jithin Jose, Olga Rodriguez","doi":"10.1016/j.ajpath.2025.01.012","DOIUrl":"10.1016/j.ajpath.2025.01.012","url":null,"abstract":"<p><p>Chronic diseases of the liver are major public health concerns worldwide. Steatosis and steatohepatitis associated with alcoholic liver disease, metabolic dysfunction-associated fatty liver disease/nonalcoholic fatty liver disease, and hepatitis B and C contribute to chronic diseases of the liver. Liver fibrosis occurs in all forms of advanced chronic diseases of the liver, the confirmation of which is typically performed by needle biopsy. Imaging approaches for liver diagnosis exist but do not provide sufficient diagnostic accuracy for defining the various stages of fibrosis or steatosis. Therefore, there is a need for improved imaging capabilities to enhance disease diagnosis. Ultrasonography-based photoacoustic imaging has recently emerged as a noninvasive, nonionizing modality, capable of capturing structural details and oxygen saturation changes during disease progression. However, its potential for detecting surrogate metabolic dysfunction-associated fatty liver disease markers, such as collagen and lipids, which are often poorly resolved by other conventional imaging techniques, has yet to be investigated in detail. The novelty of this study lies in the innovative use of spectral photoacoustic imaging for the direct detection and quantification of key biomarkers of liver disease, such as fibrosis, collagen, lipids, and oxygenated and deoxygenated hemoglobin, in a mouse model of steatotic fatty liver disease. We established that ultrasonography-based photoacoustic imaging, validated with magnetic resonance imaging, effectively identified increases in liver adiposity and fibrosis, enabling the noninvasive detection of changes in liver pathology associated with metabolic dysfunction.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-11DOI: 10.1016/j.ajpath.2025.02.001
{"title":"This Month in AJP.","authors":"","doi":"10.1016/j.ajpath.2025.02.001","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.02.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ajpath.2024.09.011
Lili Huang , Jingbo Yang , Jinjin Zhu , Huaishan Wang , Liyun Dong , Yeye Guo , Yeqing Chen , Feng Zhang , David J. Xu , Lingling Ou , Jaiden R. Xu , Lei Guan , Quoc D. Doan , Andrew Y. Fan , Wenqun Zhong , Jina Ko , Chengyu Liang , Meenhard Herlyn , Wei Guo , Xiaowei Xu , Shujing Liu
Tumor-associated macrophages (TAMs) play dual roles (both pro- and antitumor) in tumor progression. TAMs induce programmed death ligand-1 (PD-L1) expression in cancer cells. However, the regulatory effects of PD-L1 in melanoma cells on TAM phenotypical switching remain underexplored. Herein, CD163 and MRC1 levels were significantly elevated in metastatic melanomas compared with those in primary melanomas, correlating with CD274 expression and predicted patient clinical outcomes. To study the mechanisms regulating M2-like polarization, PD-L1 was knocked out in both YUMM1.7 and B16-F10 melanoma cells. Knocking out PD-L1 (PD-L1KO) in melanoma resulted in a decelerated in vivo growth rate, accompanied by a significantly increased M1/M2 ratio, more dendritic cells, and enhanced activation of CD8+ T cells compared with wild-type (WT) melanoma cells. These alterations were associated with decreased expression of M2-associated chemokines (CCL2, CCL3, and CXCL2) and cytokines (IL6, IL10, and TGFB1). Mice harboring PD-L1KO melanomas exhibited elevated levels of CD8+ T cells in both the tumor-draining lymph nodes and the bloodstream compared with mice with PD-L1WT melanomas. Treatment with extracellular vesicles (EVs) derived from PD-L1KO melanoma resulted in a reduced tumor growth rate and fewer M2-like macrophages in the tumors compared with EVs from PD-L1WT melanomas. Therefore, these data suggest that PD-L1 in melanoma and melanoma-derived EVs induces M2-like polarization, contributing to local and regional immune suppression.
{"title":"Programmed Death Ligand-1 in Melanoma and Extracellular Vesicles Promotes Local and Regional Immune Suppression through M2-like Macrophage Polarization","authors":"Lili Huang , Jingbo Yang , Jinjin Zhu , Huaishan Wang , Liyun Dong , Yeye Guo , Yeqing Chen , Feng Zhang , David J. Xu , Lingling Ou , Jaiden R. Xu , Lei Guan , Quoc D. Doan , Andrew Y. Fan , Wenqun Zhong , Jina Ko , Chengyu Liang , Meenhard Herlyn , Wei Guo , Xiaowei Xu , Shujing Liu","doi":"10.1016/j.ajpath.2024.09.011","DOIUrl":"10.1016/j.ajpath.2024.09.011","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs) play dual roles (both pro- and antitumor) in tumor progression. TAMs induce programmed death ligand-1 (PD-L1) expression in cancer cells. However, the regulatory effects of PD-L1 in melanoma cells on TAM phenotypical switching remain underexplored. Herein, <em>CD163</em> and <em>MRC1</em> levels were significantly elevated in metastatic melanomas compared with those in primary melanomas, correlating with <em>CD274</em> expression and predicted patient clinical outcomes. To study the mechanisms regulating M2-like polarization, PD-L1 was knocked out in both YUMM1.7 and B16-F10 melanoma cells. Knocking out PD-L1 (<em>PD-L1</em><sup><em>KO</em></sup>) in melanoma resulted in a decelerated <em>in vivo</em> growth rate, accompanied by a significantly increased M1/M2 ratio, more dendritic cells, and enhanced activation of CD8<sup>+</sup> T cells compared with wild-type (WT) melanoma cells. These alterations were associated with decreased expression of M2-associated chemokines (<em>CCL2</em>, <em>CCL3</em>, and <em>CXCL2</em>) and cytokines (<em>IL6</em>, <em>IL10</em>, and <em>TGF</em><em>B</em><em>1</em>). Mice harboring <em>PD-L1</em><sup><em>KO</em></sup> melanomas exhibited elevated levels of CD8<sup>+</sup> T cells in both the tumor-draining lymph nodes and the bloodstream compared with mice with <em>PD-L1</em><sup><em>WT</em></sup> melanomas. Treatment with extracellular vesicles (EVs) derived from <em>PD-L1</em><sup><em>KO</em></sup> melanoma resulted in a reduced tumor growth rate and fewer M2-like macrophages in the tumors compared with EVs from <em>PD-L1</em><sup><em>WT</em></sup> melanomas. Therefore, these data suggest that PD-L1 in melanoma and melanoma-derived EVs induces M2-like polarization, contributing to local and regional immune suppression.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 306-320"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ajpath.2024.09.009
Thaís Moré Milan, Gabriel Silva, Lucas Oliveira Sousa, Andréia Machado Leopoldino
Alterations in miRNAs, p53, and sphingolipid metabolism are associated with head and neck squamous cell carcinoma (HNSCC). However, the role of sphingosine kinase (SK)-2, an enzyme crucial for sphingolipid metabolism, is poorly understood in HNSCC. The aim of this study was to investigate how SK2 and p53 interact to regulate miRNAs miR-205 and miR-296. Analysis of small-RNA sequencing data from nontumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to controls (NOK-Ø) revealed differential expression of >100 miRNAs being half-regulated by p53. The expression of miR-205 was down-regulated, and miR-296 was up-regulated, in NOK-SK2 cells; however, cells with SK2 knockdown and p53 overexpression showed an opposite profile. Proteins involved in miRNA biogenesis were increased in NOK-SK2 cells, while levels were decreased in NOK-SK2 cells with p53 overexpression. Transfection with miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and the number of cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 regulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor-formation capacity, and NOK-SK2 cells abrogated tumor growth in mice. The results indicate crosstalk between SK2 and p53 in regulating miRNAs 205 and 296, which could be potential therapeutic targets in the treatment of HNSCC.
{"title":"Sphingosine Kinase 2 Controls the Aggressive Phenotype of Oral Squamous Cell Carcinoma by Regulating miR-205 and miR-296 through p53","authors":"Thaís Moré Milan, Gabriel Silva, Lucas Oliveira Sousa, Andréia Machado Leopoldino","doi":"10.1016/j.ajpath.2024.09.009","DOIUrl":"10.1016/j.ajpath.2024.09.009","url":null,"abstract":"<div><div>Alterations in miRNAs, p53, and sphingolipid metabolism are associated with head and neck squamous cell carcinoma (HNSCC). However, the role of sphingosine kinase (SK)-2, an enzyme crucial for sphingolipid metabolism, is poorly understood in HNSCC. The aim of this study was to investigate how SK2 and p53 interact to regulate miRNAs miR-205 and miR-296. Analysis of small-RNA sequencing data from nontumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to controls (NOK-Ø) revealed differential expression of >100 miRNAs being half-regulated by p53. The expression of miR-205 was down-regulated, and miR-296 was up-regulated, in NOK-SK2 cells; however, cells with SK2 knockdown and p53 overexpression showed an opposite profile. Proteins involved in miRNA biogenesis were increased in NOK-SK2 cells, while levels were decreased in NOK-SK2 cells with p53 overexpression. Transfection with miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and the number of cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 regulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor-formation capacity, and NOK-SK2 cells abrogated tumor growth in mice. The results indicate crosstalk between SK2 and p53 in regulating miRNAs 205 and 296, which could be potential therapeutic targets in the treatment of HNSCC.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 321-333"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ajpath.2024.10.005
Yuting Wu , Jinyu Ma , Jing Chen , Xiaoyu Liu , Zhe Wang , Lan Luo , Cheng Sun
CD44 is a transmembrane protein that plays an essential role in transducing extracellular stimuli into intracellular signaling cascades, especially in cancer cells. Recent studies have shown that CD44 contributes to metabolic regulation. However, the effect of CD44 on adipogenesis in white adipose tissue (WAT) remains unclear. Herein, the expression of CD44 was largely increased in the inguinal and epididymal WAT of obese mice. Ablation or neutralization of CD44 inhibited adipogenesis in cultured adipocytes. CD44-deficient mice were resistant to high-fat diet–induced obesity and metabolic dysfunction. RNA-sequencing, together with functional studies, revealed that reduced expression of tryptophan 5-hydroxylase 2 (Tph2) in WAT was responsible for the repressed adipogenesis in the absence of CD44. The application of 5-hydroxytryptamine, a product of TPH2, rescued the repressed adipogenesis induced by CD44 neutralization. Moreover, the inhibition of TPH2 by p-chlorophenylalanine recapitulated the beneficial phenotypes observed in CD44-deficient mice. Taken together, these data indicate that CD44 plays a pivotal role in adipogenesis in WAT. In this regard, CD44 and its downstream target TPH2 may hold great therapeutic potential for treating excessive adiposity-related metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes.
{"title":"Ablation of CD44 Attenuates Adipogenesis in White Adipocytes via the Tryptophan 5-Hydroxylase 2/5-Hydroxytryptamine Axis to Protect Mice from High-Fat Diet–Induced Obesity","authors":"Yuting Wu , Jinyu Ma , Jing Chen , Xiaoyu Liu , Zhe Wang , Lan Luo , Cheng Sun","doi":"10.1016/j.ajpath.2024.10.005","DOIUrl":"10.1016/j.ajpath.2024.10.005","url":null,"abstract":"<div><div>CD44 is a transmembrane protein that plays an essential role in transducing extracellular stimuli into intracellular signaling cascades, especially in cancer cells. Recent studies have shown that CD44 contributes to metabolic regulation. However, the effect of CD44 on adipogenesis in white adipose tissue (WAT) remains unclear. Herein, the expression of CD44 was largely increased in the inguinal and epididymal WAT of obese mice. Ablation or neutralization of CD44 inhibited adipogenesis in cultured adipocytes. CD44-deficient mice were resistant to high-fat diet–induced obesity and metabolic dysfunction. RNA-sequencing, together with functional studies, revealed that reduced expression of tryptophan 5-hydroxylase 2 (<em>Tph2</em>) in WAT was responsible for the repressed adipogenesis in the absence of CD44. The application of 5-hydroxytryptamine, a product of TPH2, rescued the repressed adipogenesis induced by CD44 neutralization. Moreover, the inhibition of TPH2 by p-chlorophenylalanine recapitulated the beneficial phenotypes observed in CD44-deficient mice. Taken together, these data indicate that CD44 plays a pivotal role in adipogenesis in WAT. In this regard, CD44 and its downstream target TPH2 may hold great therapeutic potential for treating excessive adiposity-related metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 247-264"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ajpath.2024.10.008
Tong Yang , Ping Li , Bo Liu , Yuchun Lv , Dage Fan , Yuling Fan , Peizhong Liu , Yaping Ni
Endometrial cancer has the second highest incidence of malignant tumors in the female reproductive system. Accurate and efficient analysis of endometrial cancer pathology images is one of the important research components of computer-aided diagnosis. However, endometrial cancer pathology images have challenges such as smaller solid tumors, lesion areas varying in morphology, and difficulty distinguishing solid and nonsolid tumors, which would affect the accuracy of subsequent pathologic analyses. An Endometrial Cancer Multi-class Transformer Network (ECMTrans-net) is therefore proposed herein to improve the segmentation accuracy of endometrial cancer pathology images. An ECM-Attention module can sequentially infer attention maps along three separate dimensions (channel, local spatial, and global spatial) and multiply the attention maps and the input feature map for adaptive feature refinement. This approach may solve the problems of the small size of solid tumors and similar characteristics of solid tumors to nonsolid tumors and further improve the accuracy of segmentation of solid tumors. In addition, an ECM-Transformer module is proposed, which can fuse multi-class feature information and dynamically adjust the receptive field, solving the issue of complex tumor features. Experiments on the Solid Tumor Endometrial Cancer Pathological (ST-ECP) data set found that performance of the ECMTrans-net was superior to state-of-the-art image segmentation methods, and the average values of accuracy, Mean Intersection over Union, precision, and Dice coefficients were 0.952, 0.927, 0.931, and 0.901, respectively.
{"title":"Multi-Class Segmentation Network Based on Tumor Tissue in Endometrial Cancer Pathology Images","authors":"Tong Yang , Ping Li , Bo Liu , Yuchun Lv , Dage Fan , Yuling Fan , Peizhong Liu , Yaping Ni","doi":"10.1016/j.ajpath.2024.10.008","DOIUrl":"10.1016/j.ajpath.2024.10.008","url":null,"abstract":"<div><div>Endometrial cancer has the second highest incidence of malignant tumors in the female reproductive system. Accurate and efficient analysis of endometrial cancer pathology images is one of the important research components of computer-aided diagnosis. However, endometrial cancer pathology images have challenges such as smaller solid tumors, lesion areas varying in morphology, and difficulty distinguishing solid and nonsolid tumors, which would affect the accuracy of subsequent pathologic analyses. An Endometrial Cancer Multi-class Transformer Network (ECMTrans-net) is therefore proposed herein to improve the segmentation accuracy of endometrial cancer pathology images. An ECM-Attention module can sequentially infer attention maps along three separate dimensions (channel, local spatial, and global spatial) and multiply the attention maps and the input feature map for adaptive feature refinement. This approach may solve the problems of the small size of solid tumors and similar characteristics of solid tumors to nonsolid tumors and further improve the accuracy of segmentation of solid tumors. In addition, an ECM-Transformer module is proposed, which can fuse multi-class feature information and dynamically adjust the receptive field, solving the issue of complex tumor features. Experiments on the Solid Tumor Endometrial Cancer Pathological (ST-ECP) data set found that performance of the ECMTrans-net was superior to state-of-the-art image segmentation methods, and the average values of accuracy, Mean Intersection over Union, precision, and Dice coefficients were 0.952, 0.927, 0.931, and 0.901, respectively.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 232-246"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gastrointestinal motility disturbances are a hallmark of inflammatory bowel disease (IBD); however, their mechanisms remain unclear. This study used a dextran sulfate sodium–induced colitis mouse model, deficient in mature B and T lymphocytes, to assess intestinal motility and the role of the adaptive immune system in health and IBD. In healthy mice, the absence of adaptive lymphocytes reduced acetylcholine (ACh) sensitivity in the ileum. During colitis, it decreases motility by reducing the intensity and frequency of spontaneous contractions while increasing cholinergic responsiveness. In the proximal colon, adaptive immunity deficiency led to increased contractility and reduced ACh sensitivity in homeostasis, whereas colitis reduced contractile capacity. In the mid colon, immune-deficient mice had reduced ACh sensitivity in homeostasis and exacerbated contractile responses during colitis. In the distal colon, adaptive immunity loss reduced contractility in health and cholinergic responsiveness during colitis. These motility alterations were associated with altered acetylcholinesterase and M2/M3 muscarinic receptor expression. Notably, adaptive lymphocyte deficiency resulted in reduced tissue damage and lower tumor necrosis factor-α expression in the colon during colitis, paralleling intestinal motility changes. Overall, the adaptive immune system critically regulates motility and inflammation across different intestinal segments in IBD.
胃肠道运动障碍是炎症性肠病（IBD）的一个特征；然而，其机制仍不清楚。本研究利用缺乏成熟 B 淋巴细胞和 T 淋巴细胞的右旋糖酐硫酸钠（DSS）诱导结肠炎小鼠模型来评估肠道运动以及适应性免疫系统在健康和 IBD 中的作用。在健康小鼠中，适应性淋巴细胞的缺失会降低回肠对乙酰胆碱（ACh）的敏感性。在结肠炎期间，适应性淋巴细胞会降低自发收缩的强度和频率，同时增加胆碱能反应性，从而降低运动能力。在近端结肠，适应性免疫缺陷导致收缩力增加，ACh 敏感性在平衡状态下降低，而结肠炎则会降低收缩能力。在结肠中部，免疫缺陷小鼠在平衡状态下对 ACh 的敏感性降低，而在结肠炎时收缩反应加剧。在结肠远端，适应性免疫丧失降低了健康时的收缩能力和结肠炎时的胆碱能反应能力。这些运动能力的改变与乙酰胆碱酯酶和 M2/M3 毒蕈碱受体表达的改变有关。值得注意的是，在结肠炎期间，适应性淋巴细胞缺乏会导致结肠组织损伤减少，TNF-α表达降低，与肠道运动变化同步。总之，适应性免疫系统对 IBD 不同肠段的运动和炎症起着关键性的调节作用。
{"title":"Segmental Regulation of Intestinal Motility by Colitis and the Adaptive Immune System in the Mouse Ileum and Colon","authors":"Raquel Gomez-Bris , Pilar Rodríguez-Rodríguez , Marina Ortega-Zapero , Santiago Ruvira , Raquel Castillo-González , María-Jesús Fernández-Aceñero , Aránzazu Cruz-Adalia , Angela Saez , Silvia-Magdalena Arribas , Jose-Maria Gonzalez-Granado","doi":"10.1016/j.ajpath.2024.10.020","DOIUrl":"10.1016/j.ajpath.2024.10.020","url":null,"abstract":"<div><div>Gastrointestinal motility disturbances are a hallmark of inflammatory bowel disease (IBD); however, their mechanisms remain unclear. This study used a dextran sulfate sodium–induced colitis mouse model, deficient in mature B and T lymphocytes, to assess intestinal motility and the role of the adaptive immune system in health and IBD. In healthy mice, the absence of adaptive lymphocytes reduced acetylcholine (ACh) sensitivity in the ileum. During colitis, it decreases motility by reducing the intensity and frequency of spontaneous contractions while increasing cholinergic responsiveness. In the proximal colon, adaptive immunity deficiency led to increased contractility and reduced ACh sensitivity in homeostasis, whereas colitis reduced contractile capacity. In the mid colon, immune-deficient mice had reduced ACh sensitivity in homeostasis and exacerbated contractile responses during colitis. In the distal colon, adaptive immunity loss reduced contractility in health and cholinergic responsiveness during colitis. These motility alterations were associated with altered acetylcholinesterase and M2/M3 muscarinic receptor expression. Notably, adaptive lymphocyte deficiency resulted in reduced tissue damage and lower tumor necrosis factor-α expression in the colon during colitis, paralleling intestinal motility changes. Overall, the adaptive immune system critically regulates motility and inflammation across different intestinal segments in IBD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 204-220"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Salivary gland neoplasms (SGNs) represent a group of human neoplasms characterized by a remarkable cytomorphologic diversity, which frequently poses diagnostic challenges. Accurate histologic categorization of salivary gland tumors is crucial to make precise diagnoses and guide decisions regarding patient management. Within the scope of this study, a computer-aided diagnosis model using Vision Transformer (ViT), a cutting-edge deep learning model in computer vision, was developed to accurately classify the most prevalent subtypes of SGNs. These subtypes include pleomorphic adenoma, myoepithelioma, Warthin tumor, basal cell adenoma, oncocytic adenoma, cystadenoma, mucoepidermoid carcinoma, and salivary adenoid cystic carcinoma. The data set comprised 3046 whole slide images of histologically confirmed salivary gland tumors, encompassing nine distinct tissue categories. SGN-ViT exhibited impressive performance in classifying the eight salivary gland tumors, achieving an accuracy of 0.9966, an area under the receiver operating characteristic curve value of 0.9899, precision of 0.9848, recall of 0.9848, and an F1 score of 0.9848. Diagnostic performance of SGN-ViT surpassed that of benchmark models. In a subset of 100 whole slide images, SGN-ViT demonstrated comparable diagnostic performance to that of the chief pathologist while significantly reducing the diagnosis time. These observations indicate that SGN-ViT holds the potential to serve as a valuable computer-aided diagnostic tool for salivary gland tumors, enhancing the diagnostic accuracy of junior pathologists.
{"title":"A Recognition System for Diagnosing Salivary Gland Neoplasms Based on Vision Transformer","authors":"Mao Li , Ze-liang Shen , Hong-chun Xian , Zhi-jian Zheng , Zhen-wei Yu , Xin-hua Liang , Rui Gao , Ya-ling Tang , Zhong Zhang","doi":"10.1016/j.ajpath.2024.09.010","DOIUrl":"10.1016/j.ajpath.2024.09.010","url":null,"abstract":"<div><div>Salivary gland neoplasms (SGNs) represent a group of human neoplasms characterized by a remarkable cytomorphologic diversity, which frequently poses diagnostic challenges. Accurate histologic categorization of salivary gland tumors is crucial to make precise diagnoses and guide decisions regarding patient management. Within the scope of this study, a computer-aided diagnosis model using Vision Transformer (ViT), a cutting-edge deep learning model in computer vision, was developed to accurately classify the most prevalent subtypes of SGNs. These subtypes include pleomorphic adenoma, myoepithelioma, Warthin tumor, basal cell adenoma, oncocytic adenoma, cystadenoma, mucoepidermoid carcinoma, and salivary adenoid cystic carcinoma. The data set comprised 3046 whole slide images of histologically confirmed salivary gland tumors, encompassing nine distinct tissue categories. SGN-ViT exhibited impressive performance in classifying the eight salivary gland tumors, achieving an accuracy of 0.9966, an area under the receiver operating characteristic curve value of 0.9899, precision of 0.9848, recall of 0.9848, and an F1 score of 0.9848. Diagnostic performance of SGN-ViT surpassed that of benchmark models. In a subset of 100 whole slide images, SGN-ViT demonstrated comparable diagnostic performance to that of the chief pathologist while significantly reducing the diagnosis time. These observations indicate that SGN-ViT holds the potential to serve as a valuable computer-aided diagnostic tool for salivary gland tumors, enhancing the diagnostic accuracy of junior pathologists.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 221-231"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ajpath.2024.10.019
Sydney O. Idahosa , Rokia Diarra , Hernoor K. Ranu , Raidah H. Nasiri , Sei Higuchi
Bidirectional communication between the brain and gastrointestinal tract, called the gut-brain axis, is linked with our emotions. Intestinal lipids, hormones, and molecules, such as bile acids (BAs), impact our mood, motivation, and emotions via the gut-brain axis. BAs are synthesized from cholesterol in the liver and serve as a regulator of lipid metabolism and hormonal secretion in the intestine. Human studies have indicated that the alteration of plasma BA levels is associated with depression and anxiety. Several possible mechanisms, such as BA receptor-dependent and receptor-independent mechanisms, have been reported for emotional control. Animal studies have indicated that the deletion of BA receptors shows behavioral abnormalities. BAs regulate gut hormones, glucagon-like peptide-1 secretion, bioactive lipids, oleoylethanolamide, and the immune system function, which influences neural activities. Thus, BAs act as an emotional regulator. This review aims to summarize the following: clinical evidence of BA concentration linked to mental disorders, including depression and anxiety; and animal studies of BA-related signaling correlated with its neurobehavioral effect supporting its mechanism. We will also discuss future research required for further neurobehavioral treatment.
大脑和胃肠道之间的双向交流，即肠道-大脑轴，与我们的情绪息息相关。众所周知，肠道脂质、激素和胆汁酸（BA）等分子会通过肠脑轴影响我们的情绪、动力和情感。胆汁酸在肝脏中由胆固醇合成，是肠道中脂质代谢和激素分泌的调节剂。人体研究表明，血浆 BA 水平的改变与抑郁和焦虑有关。据报道，情绪控制可能有多种机制，如 BA 受体依赖机制和独立机制。动物研究表明，删除 BA 受体会导致行为异常。BAs 可调节肠道激素、GLP-1 分泌、生物活性脂质、油酰乙醇酰胺（OEA）和免疫系统功能，从而影响神经活动。因此，BAs 被认为是一种情绪调节剂。本综述旨在总结：1）BA 浓度与精神障碍（包括抑郁和焦虑）相关的临床证据；2）BA 相关信号传导与其神经行为效应相关的动物研究，以支持其机制。在这篇综述中，我们将讨论进一步的神经行为治疗所需的未来研究。
{"title":"Evidence and Mechanism of Bile Acid–Mediated Gut-Brain Axis in Anxiety and Depression","authors":"Sydney O. Idahosa , Rokia Diarra , Hernoor K. Ranu , Raidah H. Nasiri , Sei Higuchi","doi":"10.1016/j.ajpath.2024.10.019","DOIUrl":"10.1016/j.ajpath.2024.10.019","url":null,"abstract":"<div><div>Bidirectional communication between the brain and gastrointestinal tract, called the gut-brain axis, is linked with our emotions. Intestinal lipids, hormones, and molecules, such as bile acids (BAs), impact our mood, motivation, and emotions via the gut-brain axis. BAs are synthesized from cholesterol in the liver and serve as a regulator of lipid metabolism and hormonal secretion in the intestine. Human studies have indicated that the alteration of plasma BA levels is associated with depression and anxiety. Several possible mechanisms, such as BA receptor-dependent and receptor-independent mechanisms, have been reported for emotional control. Animal studies have indicated that the deletion of BA receptors shows behavioral abnormalities. BAs regulate gut hormones, glucagon-like peptide-1 secretion, bioactive lipids, oleoylethanolamide, and the immune system function, which influences neural activities. Thus, BAs act as an emotional regulator. This review aims to summarize the following: clinical evidence of BA concentration linked to mental disorders, including depression and anxiety; and animal studies of BA-related signaling correlated with its neurobehavioral effect supporting its mechanism. We will also discuss future research required for further neurobehavioral treatment.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 163-173"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号