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}
Pub Date : 2025-02-01DOI: 10.1016/j.ajpath.2024.11.001
Michael S. Goligorsky
{"title":"Highlights of the First 100 Years of Publications on Kidney Disease in The American Journal of Pathology","authors":"Michael S. Goligorsky","doi":"10.1016/j.ajpath.2024.11.001","DOIUrl":"10.1016/j.ajpath.2024.11.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 158-162"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045579","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.2024.09.008
Gretchen E. Bollar , Johnathan D. Keith , Denise D. Stanford , Ashley M. Oden , S. Vamsee Raju , T. Spencer Poore , Susan E. Birket
Cystic fibrosis (CF) respiratory outcomes are heavily influenced by complications of infection. Pseudomonas aeruginosa and Staphylococcus aureus are the most common colonizers of the cystic fibrosis lung, and frequently overlap to cause chronic and persistent coinfections associated with severe disease. However, the dynamics of P. aeruginosa and S. aureus coinfection and its impacts on the development of CF lung structural damage are poorly understood. Additionally, small colony variants (SCVs) of S. aureus have been associated with P. aeruginosa infections in people with CF, but their role in disease progression is largely unknown. In this work, the CF rat was used to model chronic lung coinfection with P. aeruginosa and S. aureus, using clinically and laboratory-derived normal colony and SCV strains of S. aureus to evaluate the impact of phenotype on clinical outcomes. Rats coinfected with clinically derived S. aureus of both phenotypes experienced increased inflammation in the lung. However, only the combination of P. aeruginosa and clinically normal colony S. aureus led to lung structural decline, including mucus obstruction and bronchiectasis. Regression analyses showed that the damage was associated with a higher burden of P. aeruginosa. These data indicate that chronic coinfection with normal colony S. aureus and P. aeruginosa may support the progression CF lung decline driven by P. aeruginosa, which might be avoided when coinfecting S. aureus exhibits the SCV phenotype.
{"title":"Chronic Coinfection with Pseudomonas aeruginosa and Normal Colony Staphylococcus aureus Causes Lung Structural Damage in the Cystic Fibrosis Rat","authors":"Gretchen E. Bollar , Johnathan D. Keith , Denise D. Stanford , Ashley M. Oden , S. Vamsee Raju , T. Spencer Poore , Susan E. Birket","doi":"10.1016/j.ajpath.2024.09.008","DOIUrl":"10.1016/j.ajpath.2024.09.008","url":null,"abstract":"<div><div>Cystic fibrosis (CF) respiratory outcomes are heavily influenced by complications of infection. <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em> are the most common colonizers of the cystic fibrosis lung, and frequently overlap to cause chronic and persistent coinfections associated with severe disease. However, the dynamics of <em>P. aeruginosa</em> and <em>S. aureus</em> coinfection and its impacts on the development of CF lung structural damage are poorly understood. Additionally, small colony variants (SCVs) of <em>S. aureus</em> have been associated with <em>P. aeruginosa</em> infections in people with CF, but their role in disease progression is largely unknown. In this work, the CF rat was used to model chronic lung coinfection with <em>P. aeruginosa</em> and <em>S. aureus</em>, using clinically and laboratory-derived normal colony and SCV strains of <em>S. aureus</em> to evaluate the impact of phenotype on clinical outcomes. Rats coinfected with clinically derived <em>S. aureus</em> of both phenotypes experienced increased inflammation in the lung. However, only the combination of <em>P. aeruginosa</em> and clinically normal colony <em>S. aureus</em> led to lung structural decline, including mucus obstruction and bronchiectasis. Regression analyses showed that the damage was associated with a higher burden of <em>P. aeruginosa</em>. These data indicate that chronic coinfection with normal colony <em>S. aureus</em> and <em>P. aeruginosa</em> may support the progression CF lung decline driven by <em>P. aeruginosa</em>, which might be avoided when coinfecting <em>S. aureus</em> exhibits the SCV phenotype.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 174-187"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543135","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.2024.10.015
Feiyu Jin, Yuanye Yan, Ziyang Ye, Lisong Wang, Can Deng, Jiazhen Jiang, Kai Dong
Retinal detachment (RD) is the separation of the neural retina from the retinal pigment epithelium, with photoreceptor degeneration being a major cause of irreversible vision loss. Herein, ischemia and hypoxia after RD decreased the level of miR-7a-5p (miR-7) and promoted the expression of its main target, α-synuclein (α-syn), which activated the parthanatos pathway and led to photoreceptor damage. Circular RNA CDR1as is an antisense transcript of cerebellar degeneration–associated protein 1, which functions as a “sponge” for miR-7, thereby regulating the abundance and activity of miR-7. In this study, CDR1as expression was elevated after RD. Adeno-associated virus serotype 9 vector containing the shRNA-CDR1as sequence was used to inhibit CDR1as expression via subretinal injection. Hematoxylin and eosin staining and transmission electron microscopy revealed that the morphology and outer nuclear layer thickness of the retina were preserved and photoreceptor cell death was decreased after experimental RD in mice. Mechanistically, CDR1as deficiency significantly increased the expression of miR-7, then decreased the expression of α-syn, poly (ADP-ribose) polymerase 1, apoptosis-inducing factor, and migration inhibitory factor. Furthermore, visual function was improved as shown by Morris water maze experiments in the mouse model of RD. These findings suggest a surprisingly neuroprotective role for CDR1as deficiency, which is probably mediated by enhancing miR-7 activity and inhibiting α-syn/poly (ADP-ribose) polymerase 1/apoptosis-inducing factor pathway, thereby preventing photoreceptor degeneration.
{"title":"CDR1as Deficiency Prevents Photoreceptor Degeneration by Regulating miR-7a-5p/α-syn/Parthanatos Pathway in Retinal Detachment","authors":"Feiyu Jin, Yuanye Yan, Ziyang Ye, Lisong Wang, Can Deng, Jiazhen Jiang, Kai Dong","doi":"10.1016/j.ajpath.2024.10.015","DOIUrl":"10.1016/j.ajpath.2024.10.015","url":null,"abstract":"<div><div>Retinal detachment (RD) is the separation of the neural retina from the retinal pigment epithelium, with photoreceptor degeneration being a major cause of irreversible vision loss. Herein, ischemia and hypoxia after RD decreased the level of miR-7a-5p (miR-7) and promoted the expression of its main target, α-synuclein (α-syn), which activated the parthanatos pathway and led to photoreceptor damage. Circular RNA CDR1as is an antisense transcript of cerebellar degeneration–associated protein 1, which functions as a “sponge” for miR-7, thereby regulating the abundance and activity of miR-7. In this study, CDR1as expression was elevated after RD. Adeno-associated virus serotype 9 vector containing the shRNA-CDR1as sequence was used to inhibit CDR1as expression via subretinal injection. Hematoxylin and eosin staining and transmission electron microscopy revealed that the morphology and outer nuclear layer thickness of the retina were preserved and photoreceptor cell death was decreased after experimental RD in mice. Mechanistically, CDR1as deficiency significantly increased the expression of miR-7, then decreased the expression of α-syn, poly (ADP-ribose) polymerase 1, apoptosis-inducing factor, and migration inhibitory factor. Furthermore, visual function was improved as shown by Morris water maze experiments in the mouse model of RD. These findings suggest a surprisingly neuroprotective role for CDR1as deficiency, which is probably mediated by enhancing miR-7 activity and inhibiting α-syn/poly (ADP-ribose) polymerase 1/apoptosis-inducing factor pathway, thereby preventing photoreceptor degeneration.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 293-305"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680641","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}
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