Pub Date : 2024-07-26DOI: 10.1016/j.ajpath.2024.07.002
Lei Yang, Kien Pham, Yibo Xi, Shaoning Jiang, Keith Robertson, Chen Liu
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with high incidence and mortality worldwide. Despite diagnostic and therapeutic advancements, HCC remains poorly responsive to treatment, with a poor prognosis. Understanding the molecular mechanisms driving HCC is crucial for developing effective therapies. Emerging evidence indicates that dysregulated fatty acid metabolism contributes to HCC. Acyl-CoA medium-chain synthetase 5 (ACSM5), involved in fatty acid metabolism, is down-regulated in HCC; however, its role is not well understood. In this study, we analyzed ACSM5 expression in HCC patient samples and cell lines. Using newly established ACSM5-overexpressing HCC cell lines, Huh7-ACSM5 and Hepa1-6-ACSM5, we investigated the effects and regulatory mechanisms of ACSM5. Our results showed that ACSM5 was significantly down-regulated in HCC tumor tissues compared with nontumor tissues. ACSM5 expression was regulated by DNA methylation, with a DNMT1 inhibitor effectively increasing ACSM5 expression and reducing promoter region methylation. Overexpression of ACSM5 in Huh7 cells reduced fatty acid accumulation, decreased cell proliferation, migration, and invasion in vitro, and inhibited tumor growth in mouse xenografts. Furthermore, ACSM5 overexpression also decreased STAT3 phosphorylation, subsequently affecting downstream cytokine TGFB and FGF12 mRNA levels. Our findings suggest that ACSM5 down-regulation contributes to HCC progression, providing insights into its oncogenic role and highlighting its potential as a biomarker and therapeutic target for HCC.
{"title":"Acyl-CoA Synthetase Medium-Chain Family Member 5-Mediated Fatty Acid Metabolism Dysregulation Promotes the Progression of Hepatocellular Carcinoma.","authors":"Lei Yang, Kien Pham, Yibo Xi, Shaoning Jiang, Keith Robertson, Chen Liu","doi":"10.1016/j.ajpath.2024.07.002","DOIUrl":"10.1016/j.ajpath.2024.07.002","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with high incidence and mortality worldwide. Despite diagnostic and therapeutic advancements, HCC remains poorly responsive to treatment, with a poor prognosis. Understanding the molecular mechanisms driving HCC is crucial for developing effective therapies. Emerging evidence indicates that dysregulated fatty acid metabolism contributes to HCC. Acyl-CoA medium-chain synthetase 5 (ACSM5), involved in fatty acid metabolism, is down-regulated in HCC; however, its role is not well understood. In this study, we analyzed ACSM5 expression in HCC patient samples and cell lines. Using newly established ACSM5-overexpressing HCC cell lines, Huh7-ACSM5 and Hepa1-6-ACSM5, we investigated the effects and regulatory mechanisms of ACSM5. Our results showed that ACSM5 was significantly down-regulated in HCC tumor tissues compared with nontumor tissues. ACSM5 expression was regulated by DNA methylation, with a DNMT1 inhibitor effectively increasing ACSM5 expression and reducing promoter region methylation. Overexpression of ACSM5 in Huh7 cells reduced fatty acid accumulation, decreased cell proliferation, migration, and invasion in vitro, and inhibited tumor growth in mouse xenografts. Furthermore, ACSM5 overexpression also decreased STAT3 phosphorylation, subsequently affecting downstream cytokine TGFB and FGF12 mRNA levels. Our findings suggest that ACSM5 down-regulation contributes to HCC progression, providing insights into its oncogenic role and highlighting its potential as a biomarker and therapeutic target for HCC.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787021","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}
Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia/reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 inhibitor, and 2-deoxy-d-glucose, a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. Meanwhile, further studies suggested that lactate contributed to RIPC, rescuing I/R-induced autophagy deficiency by promoting transcription factor EB (TFEB) translocation to the nucleus through activating the AMPK-mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase-Akt pathway, thus reducing cardiomyocyte damage. Interestingly, we also found that lactate up-regulated the mRNA and protein expression of connexin 43 (CX43) by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, our research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via the AMPK-mTOR-TFEB-CX43 axis.
{"title":"Lactate Contributes to Remote Ischemic Preconditioning-Mediated Protection Against Myocardial Ischemia Reperfusion Injury by Facilitating Autophagy via the AMPK-Mammalian Target of Rapamycin-Transcription Factor EB-Connexin 43 Axis.","authors":"Zhang-Jian Yang, Wei-Fang Zhang, Qing-Qing Jin, Zhi-Rong Wu, Yun-Yan Du, Hao Shi, Zhen-Sheng Qu, Xiao-Jian Han, Li-Ping Jiang","doi":"10.1016/j.ajpath.2024.07.005","DOIUrl":"10.1016/j.ajpath.2024.07.005","url":null,"abstract":"<p><p>Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia/reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 inhibitor, and 2-deoxy-d-glucose, a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. Meanwhile, further studies suggested that lactate contributed to RIPC, rescuing I/R-induced autophagy deficiency by promoting transcription factor EB (TFEB) translocation to the nucleus through activating the AMPK-mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase-Akt pathway, thus reducing cardiomyocyte damage. Interestingly, we also found that lactate up-regulated the mRNA and protein expression of connexin 43 (CX43) by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, our research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via the AMPK-mTOR-TFEB-CX43 axis.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787022","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 : 2024-07-26DOI: 10.1016/j.ajpath.2024.07.004
Xu Han, Ali Zhang, Pan Wang, Honghao Bi, Kehan Ren, Ermin Li, Ximing Yang, Inci Aydemir, Kara Tao, Jeffrey Lin, Sarki A Abdulkadir, Jing Yang, Peng Ji
Phosphatidylinositol 3-kinase (PI3K)-AKT and androgen receptor (AR) pathways are commonly activated in prostate cancers. Their reciprocal regulation makes advanced prostate cancers difficult to treat. The current study shows that pleckstrin-2 (PLEK-2, a proto-oncoprotein involved in the activation and stabilization of AKT, connects these two pathways. Genetic evidence is provided that suggests that Plek2 deficiency largely reverted tumorigenesis in Pten prostate-specific knockout mice and that overexpression of PLEK2 promoted the proliferation and colony formation of prostate cancer cells in vitro. In addition, it was found that PLEK2 was negatively regulated by AR, that AR transcriptionally repressed PLEK2 through binding to the PLEK2 promoter region, and that overexpression of AR reduced PLEK2 expression, which inactivated AKT. Conversely, knockdown of AR in prostate cancer cells increased PLEK2 expression and activated the AKT pathway. This reciprocal inhibitory loop can be pharmacologically targeted using the PLEK2 inhibitor. It is shown that the PLEK2 inhibitor dose-dependently inhibited prostate cancer cell proliferation with the inactivation of AKT. Overall, the current study uncovers the crucial role of PLEK2 in prostate cancer proliferation and provides the rationale for targeting PLEK2 to treat prostate cancers.
{"title":"Pleckstrin-2 Mediates the Activation of AKT in Prostate Cancer and Is Repressed by Androgen Receptor.","authors":"Xu Han, Ali Zhang, Pan Wang, Honghao Bi, Kehan Ren, Ermin Li, Ximing Yang, Inci Aydemir, Kara Tao, Jeffrey Lin, Sarki A Abdulkadir, Jing Yang, Peng Ji","doi":"10.1016/j.ajpath.2024.07.004","DOIUrl":"10.1016/j.ajpath.2024.07.004","url":null,"abstract":"<p><p>Phosphatidylinositol 3-kinase (PI3K)-AKT and androgen receptor (AR) pathways are commonly activated in prostate cancers. Their reciprocal regulation makes advanced prostate cancers difficult to treat. The current study shows that pleckstrin-2 (PLEK-2, a proto-oncoprotein involved in the activation and stabilization of AKT, connects these two pathways. Genetic evidence is provided that suggests that Plek2 deficiency largely reverted tumorigenesis in Pten prostate-specific knockout mice and that overexpression of PLEK2 promoted the proliferation and colony formation of prostate cancer cells in vitro. In addition, it was found that PLEK2 was negatively regulated by AR, that AR transcriptionally repressed PLEK2 through binding to the PLEK2 promoter region, and that overexpression of AR reduced PLEK2 expression, which inactivated AKT. Conversely, knockdown of AR in prostate cancer cells increased PLEK2 expression and activated the AKT pathway. This reciprocal inhibitory loop can be pharmacologically targeted using the PLEK2 inhibitor. It is shown that the PLEK2 inhibitor dose-dependently inhibited prostate cancer cell proliferation with the inactivation of AKT. Overall, the current study uncovers the crucial role of PLEK2 in prostate cancer proliferation and provides the rationale for targeting PLEK2 to treat prostate cancers.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787023","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}
Four subtypes of ovarian high-grade serous carcinoma (HGSC) have previously been identified, each with different prognoses and drug sensitivities. However, the accuracy of classification depended on the assessor's experience. This study aimed to develop a universal algorithm for HGSC-subtype classification using deep learning techniques. An artificial intelligence (AI)-based classification algorithm, which replicates the consensus diagnosis of pathologists, was formulated to analyze the morphological patterns and tumor-infiltrating lymphocyte counts for each tile extracted from whole slide images of ovarian HGSC available in The Cancer Genome Atlas (TCGA) data set. The accuracy of the algorithm was determined using the validation set from the Japanese Gynecologic Oncology Group 3022A1 (JGOG3022A1) and Kindai and Kyoto University (Kindai/Kyoto) cohorts. The algorithm classified the four HGSC-subtypes with mean accuracies of 0.933, 0.910, and 0.862 for the TCGA, JGOG3022A1, and Kindai/Kyoto cohorts, respectively. To compare mesenchymal transition (MT) with non-MT groups, overall survival analysis was performed in the TCGA data set. The AI-based prediction of HGSC-subtype classification in TCGA cases showed that the MT group had a worse prognosis than the non-MT group (P = 0.017). Furthermore, Cox proportional hazard regression analysis identified AI-based MT subtype classification prediction as a contributing factor along with residual disease after surgery, stage, and age. In conclusion, a robust AI-based HGSC-subtype classification algorithm was established using virtual slides of ovarian HGSC.
{"title":"Artificial Intelligence-Based Histopathological Subtyping of High-Grade Serous Ovarian Cancer.","authors":"Akihiko Ueda, Hidekatsu Nakai, Chiho Miyagawa, Tomoyuki Otani, Manabu Yoshida, Ryusuke Murakami, Shinichi Komiyama, Terumi Tanigawa, Takeshi Yokoi, Hirokuni Takano, Tsukasa Baba, Kiyonori Miura, Muneaki Shimada, Junzo Kigawa, Takayuki Enomoto, Junzo Hamanishi, Aikou Okamoto, Yasushi Okuno, Masaki Mandai, Noriomi Matsumura","doi":"10.1016/j.ajpath.2024.06.010","DOIUrl":"10.1016/j.ajpath.2024.06.010","url":null,"abstract":"<p><p>Four subtypes of ovarian high-grade serous carcinoma (HGSC) have previously been identified, each with different prognoses and drug sensitivities. However, the accuracy of classification depended on the assessor's experience. This study aimed to develop a universal algorithm for HGSC-subtype classification using deep learning techniques. An artificial intelligence (AI)-based classification algorithm, which replicates the consensus diagnosis of pathologists, was formulated to analyze the morphological patterns and tumor-infiltrating lymphocyte counts for each tile extracted from whole slide images of ovarian HGSC available in The Cancer Genome Atlas (TCGA) data set. The accuracy of the algorithm was determined using the validation set from the Japanese Gynecologic Oncology Group 3022A1 (JGOG3022A1) and Kindai and Kyoto University (Kindai/Kyoto) cohorts. The algorithm classified the four HGSC-subtypes with mean accuracies of 0.933, 0.910, and 0.862 for the TCGA, JGOG3022A1, and Kindai/Kyoto cohorts, respectively. To compare mesenchymal transition (MT) with non-MT groups, overall survival analysis was performed in the TCGA data set. The AI-based prediction of HGSC-subtype classification in TCGA cases showed that the MT group had a worse prognosis than the non-MT group (P = 0.017). Furthermore, Cox proportional hazard regression analysis identified AI-based MT subtype classification prediction as a contributing factor along with residual disease after surgery, stage, and age. In conclusion, a robust AI-based HGSC-subtype classification algorithm was established using virtual slides of ovarian HGSC.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733311","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 : 2024-07-18DOI: 10.1016/j.ajpath.2024.06.004
Sourabh Soni, Laura Antonescu, Kaylin Ro, Jeffrey C Horowitz, Yohannes A Mebratu, Richard S Nho
Respiratory tract infections represent a significant global public health concern, disproportionately affecting vulnerable populations such as children, the elderly, and immunocompromised individuals. RNA viruses, particularly influenza viruses and coronaviruses, significantly contribute to respiratory illnesses, especially in immunosuppressed and elderly individuals. Influenza A viruses (IAVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to pose global health threats due to their capacity to cause annual epidemics, with profound implications for public health. In addition, the increase in global life expectancy is influencing the dynamics and outcomes of respiratory viral infections. Understanding the molecular mechanisms by which IAVs and SARS-CoV-2 contribute to lung disease progression is therefore crucial. The aim of this review was to comprehensively explore the impact of IAVs and SARS-CoV-2 on chronic lung diseases, with a specific focus on pulmonary fibrosis in the elderly. It also outlines potential preventive and therapeutic strategies and suggests directions for future research.
{"title":"Influenza, SARS-CoV-2, and Their Impact on Chronic Lung Diseases and Fibrosis: Exploring Therapeutic Options.","authors":"Sourabh Soni, Laura Antonescu, Kaylin Ro, Jeffrey C Horowitz, Yohannes A Mebratu, Richard S Nho","doi":"10.1016/j.ajpath.2024.06.004","DOIUrl":"10.1016/j.ajpath.2024.06.004","url":null,"abstract":"<p><p>Respiratory tract infections represent a significant global public health concern, disproportionately affecting vulnerable populations such as children, the elderly, and immunocompromised individuals. RNA viruses, particularly influenza viruses and coronaviruses, significantly contribute to respiratory illnesses, especially in immunosuppressed and elderly individuals. Influenza A viruses (IAVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to pose global health threats due to their capacity to cause annual epidemics, with profound implications for public health. In addition, the increase in global life expectancy is influencing the dynamics and outcomes of respiratory viral infections. Understanding the molecular mechanisms by which IAVs and SARS-CoV-2 contribute to lung disease progression is therefore crucial. The aim of this review was to comprehensively explore the impact of IAVs and SARS-CoV-2 on chronic lung diseases, with a specific focus on pulmonary fibrosis in the elderly. It also outlines potential preventive and therapeutic strategies and suggests directions for future research.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733314","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 : 2024-07-18DOI: 10.1016/j.ajpath.2024.06.008
Leslie M Ogilvie, Luca J Delfinis, Bridget Coyle-Asbil, Vignesh Vudatha, Razan Alshamali, Bianca Garlisi, Madison Pereira, Kathy Matuszewska, Madison C Garibotti, Shivam Gandhi, Keith R Brunt, Geoffrey A Wood, Jose G Trevino, Christopher G R Perry, Jim Petrik, Jeremy A Simpson
Muscle atrophy and weakness are prevalent features of cancer. Although extensive research has characterized skeletal muscle wasting in cancer cachexia, limited studies have investigated how cardiac structure and function are affected by therapy-naive cancer. Here, the authors used orthotopic, syngeneic models of epithelial ovarian cancer and pancreatic ductal adenocarcinoma, and a patient-derived pancreatic xenograft model, to define the impacts of malignancy on cardiac structure, function, and metabolism. Tumor-bearing mice develop cardiac atrophy and intrinsic systolic and diastolic dysfunction, with arterial hypotension and exercise intolerance. In hearts of ovarian tumor-bearing mice, fatty acid-supported mitochondrial respiration decreased, and carbohydrate-supported respiration increased-showcasing a substrate shift in cardiac metabolism that is characteristic of heart failure. Epithelial ovarian cancer decreased cytoskeletal and cardioprotective gene expression, which was paralleled by down-regulation of transcription factors that regulate cardiomyocyte size and function. Patient-derived pancreatic xenograft tumor-bearing mice show altered myosin heavy chain isoform expression-also a molecular phenotype of heart failure. Markers of autophagy and ubiquitin-proteasome system were upregulated by cancer, providing evidence of catabolic signaling that promotes cardiac wasting. Together, the authors cross-validate with two cancer types, evidence of the structural, functional, and metabolic cancer-induced cardiomyopathy, thus providing translational evidence that could impact future medical management strategies for improved cancer recovery in patients.
{"title":"Cardiac Atrophy, Dysfunction, and Metabolic Impairments: A Cancer-Induced Cardiomyopathy Phenotype.","authors":"Leslie M Ogilvie, Luca J Delfinis, Bridget Coyle-Asbil, Vignesh Vudatha, Razan Alshamali, Bianca Garlisi, Madison Pereira, Kathy Matuszewska, Madison C Garibotti, Shivam Gandhi, Keith R Brunt, Geoffrey A Wood, Jose G Trevino, Christopher G R Perry, Jim Petrik, Jeremy A Simpson","doi":"10.1016/j.ajpath.2024.06.008","DOIUrl":"10.1016/j.ajpath.2024.06.008","url":null,"abstract":"<p><p>Muscle atrophy and weakness are prevalent features of cancer. Although extensive research has characterized skeletal muscle wasting in cancer cachexia, limited studies have investigated how cardiac structure and function are affected by therapy-naive cancer. Here, the authors used orthotopic, syngeneic models of epithelial ovarian cancer and pancreatic ductal adenocarcinoma, and a patient-derived pancreatic xenograft model, to define the impacts of malignancy on cardiac structure, function, and metabolism. Tumor-bearing mice develop cardiac atrophy and intrinsic systolic and diastolic dysfunction, with arterial hypotension and exercise intolerance. In hearts of ovarian tumor-bearing mice, fatty acid-supported mitochondrial respiration decreased, and carbohydrate-supported respiration increased-showcasing a substrate shift in cardiac metabolism that is characteristic of heart failure. Epithelial ovarian cancer decreased cytoskeletal and cardioprotective gene expression, which was paralleled by down-regulation of transcription factors that regulate cardiomyocyte size and function. Patient-derived pancreatic xenograft tumor-bearing mice show altered myosin heavy chain isoform expression-also a molecular phenotype of heart failure. Markers of autophagy and ubiquitin-proteasome system were upregulated by cancer, providing evidence of catabolic signaling that promotes cardiac wasting. Together, the authors cross-validate with two cancer types, evidence of the structural, functional, and metabolic cancer-induced cardiomyopathy, thus providing translational evidence that could impact future medical management strategies for improved cancer recovery in patients.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733312","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 : 2024-07-18DOI: 10.1016/j.ajpath.2024.06.009
Yumei Cao, Lei Qiao, Yingying Song, Yuanye Yan, Yewen Ni, Huiyu Xi, Jiayu Chen, Suyan Li, Haiyang Liu
Retinal detachment (RD) is a sight-threatening condition that occurs in several retinal diseases. Microglia that reside in retina are activated after RD and are involved in the death of photoreceptor cells. The involvement of microglial pyroptosis in the early pathological process of RD is still unclear. It has been shown that VX-765, an inhibitor of caspase-1, may exert neuroprotective effects by targeting microglial pyroptosis in nervous system disease; however, whether it plays a role in RD is uncertain. This study detected and localized pyroptosis to specific cells by immunofluorescence co-staining and flow cytometry in rat RD models. The majority of gasdermin D N-terminal (GSDMD-N)-positive cells exhibited IBA1-positive or P2RY12-positive microglia in the early stage of RD, indicating the pyroptosis of microglia. Administration of VX-765 shifted the microglia phenotype from M1 to M2, inhibited microglial migration toward the outer nuclear layer (ONL) post-RD, and most importantly, inhibited microglial pyroptosis. The thickness of ONL increased with VX-765 administration, and the photoreceptors were more structured and orderly under hematoxylin and eosin staining and transmission electron microscopy, revealing the protective effects of VX-765 on photoreceptors. Overall, this study demonstrates that inflammation induced by pyroptosis of microglia is the early pathological process of RD. VX-765 may serve as a candidate therapeutic approach for the treatment of RD by targeting microglia.
{"title":"Caspase-1 Inhibition Ameliorates Photoreceptor Damage Following Retinal Detachment by Inhibiting Microglial Pyroptosis.","authors":"Yumei Cao, Lei Qiao, Yingying Song, Yuanye Yan, Yewen Ni, Huiyu Xi, Jiayu Chen, Suyan Li, Haiyang Liu","doi":"10.1016/j.ajpath.2024.06.009","DOIUrl":"10.1016/j.ajpath.2024.06.009","url":null,"abstract":"<p><p>Retinal detachment (RD) is a sight-threatening condition that occurs in several retinal diseases. Microglia that reside in retina are activated after RD and are involved in the death of photoreceptor cells. The involvement of microglial pyroptosis in the early pathological process of RD is still unclear. It has been shown that VX-765, an inhibitor of caspase-1, may exert neuroprotective effects by targeting microglial pyroptosis in nervous system disease; however, whether it plays a role in RD is uncertain. This study detected and localized pyroptosis to specific cells by immunofluorescence co-staining and flow cytometry in rat RD models. The majority of gasdermin D N-terminal (GSDMD-N)-positive cells exhibited IBA1-positive or P2RY12-positive microglia in the early stage of RD, indicating the pyroptosis of microglia. Administration of VX-765 shifted the microglia phenotype from M1 to M2, inhibited microglial migration toward the outer nuclear layer (ONL) post-RD, and most importantly, inhibited microglial pyroptosis. The thickness of ONL increased with VX-765 administration, and the photoreceptors were more structured and orderly under hematoxylin and eosin staining and transmission electron microscopy, revealing the protective effects of VX-765 on photoreceptors. Overall, this study demonstrates that inflammation induced by pyroptosis of microglia is the early pathological process of RD. VX-765 may serve as a candidate therapeutic approach for the treatment of RD by targeting microglia.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733313","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 : 2024-07-18DOI: 10.1016/j.ajpath.2024.06.007
Areej Alsaafin, Peyman Nejat, Abubakr Shafique, Jibran Khan, Saghir Alfasly, Ghazal Alabtah, Hamid R Tizhoosh
Digital pathology and the integration of artificial intelligence (AI) models have revolutionized histopathology, opening new opportunities. With the increasing availability of whole-slide images (WSIs), demand is growing for efficient retrieval, processing, and analysis of relevant images from vast biomedical archives. However, processing WSIs presents challenges due to their large size and content complexity. Full computer digestion of WSIs is impractical, and processing all patches individually is prohibitively expensive. In this article, we propose an unsupervised patching algorithm, Sequential Patching Lattice for Image Classification and Enquiry (SPLICE). This novel approach condenses a histopathology WSI into a compact set of representative patches, forming a collage of WSI while minimizing redundancy. SPLICE prioritizes patch quality and uniqueness by sequentially analyzing a WSI and selecting nonredundant representative features. We evaluated SPLICE for search and match applications, showing its improved accuracy, reduced computation time, and storage requirements compared with existing state-of-the-art methods. As an unsupervised method, SPLICE effectively reduces storage requirements for representing tissue images by 50%. This reduction enables numerous algorithms in computational pathology to operate much more efficiently, paving the way for accelerated adoption of digital pathology.
数字病理学和人工智能(AI)模型的整合彻底改变了组织病理学,带来了新的机遇。随着整张切片图像(WSI)的可用性不断提高,从庞大的生物医学档案中高效检索、处理和分析相关图像的需求也日益增长。然而,由于 WSIs 体积庞大、内容复杂,处理 WSIs 是一项挑战。完全用计算机消化 WSI 是不切实际的,而单独处理所有补丁又过于昂贵。在本文中,我们提出了一种无监督修补算法--用于图像分类和查询的序列修补网格(SPLICE)。这种新方法将组织病理学 WSI 浓缩为一组紧凑的代表性补丁,形成 WSI 的 "拼贴",同时最大限度地减少冗余。SPLICE 通过顺序分析 WSI 并选择非冗余的代表性特征,优先考虑斑块的质量和独特性。我们对 SPLICE 的搜索和匹配应用进行了评估,结果表明,与现有的先进方法相比,SPLICE 提高了准确性,减少了计算时间和存储要求。作为一种无监督方法,SPLICE 能有效地将表示组织图像的存储要求降低 50%。这种减少使计算病理学中的许多算法能更有效地运行,为加快数字病理学的应用铺平了道路。
{"title":"SPLICE: Streamlining Digital Pathology Image Processing.","authors":"Areej Alsaafin, Peyman Nejat, Abubakr Shafique, Jibran Khan, Saghir Alfasly, Ghazal Alabtah, Hamid R Tizhoosh","doi":"10.1016/j.ajpath.2024.06.007","DOIUrl":"10.1016/j.ajpath.2024.06.007","url":null,"abstract":"<p><p>Digital pathology and the integration of artificial intelligence (AI) models have revolutionized histopathology, opening new opportunities. With the increasing availability of whole-slide images (WSIs), demand is growing for efficient retrieval, processing, and analysis of relevant images from vast biomedical archives. However, processing WSIs presents challenges due to their large size and content complexity. Full computer digestion of WSIs is impractical, and processing all patches individually is prohibitively expensive. In this article, we propose an unsupervised patching algorithm, Sequential Patching Lattice for Image Classification and Enquiry (SPLICE). This novel approach condenses a histopathology WSI into a compact set of representative patches, forming a collage of WSI while minimizing redundancy. SPLICE prioritizes patch quality and uniqueness by sequentially analyzing a WSI and selecting nonredundant representative features. We evaluated SPLICE for search and match applications, showing its improved accuracy, reduced computation time, and storage requirements compared with existing state-of-the-art methods. As an unsupervised method, SPLICE effectively reduces storage requirements for representing tissue images by 50%. This reduction enables numerous algorithms in computational pathology to operate much more efficiently, paving the way for accelerated adoption of digital pathology.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733316","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 : 2024-07-18DOI: 10.1016/j.ajpath.2024.06.006
Khun Zaw Latt, Teruhiko Yoshida, Shashi Shrivastav, Amin Abedini, Jeff M Reece, Zeguo Sun, Hewang Lee, Koji Okamoto, Pradeep Dagur, Yu Ishimoto, Jurgen Heymann, Yongmei Zhao, Joon-Yong Chung, Stephen Hewitt, Pedro A Jose, Kyung Lee, John Cijiang He, Cheryl A Winkler, Mark A Knepper, Tomoshige Kino, Avi Z Rosenberg, Katalin Susztak, Jeffrey B Kopp
Although hyponatremia and salt wasting are common in patients with HIV/AIDS, the understanding of their contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the sodium-chloride cotransporter (which is responsible for sodium reabsorption in distal nephron segments), single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr transgenic (Vpr Tg) mice. The results show that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05); in Vpr Tg mice, Slc12a3 expression was not significantly different in DCT cells. The Pvalb+ DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT mice (P < 0.01). Immunohistochemistry revealed fewer Slc12a3+Pvalb+ DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT samples in the DCT cluster showed down-regulation of the Ier3 gene, which is an inhibitor of apoptosis. The in vitro knockdown of Ier3 by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by Ier3 down-regulation in DCT1 cells and loss of Slc12a3+Pvalb+ DCT1 segments.
{"title":"Single-Nucleus RNA Sequencing Reveals Loss of Distal Convoluted Tubule 1 Renal Tubules in HIV Viral Protein R Transgenic Mice.","authors":"Khun Zaw Latt, Teruhiko Yoshida, Shashi Shrivastav, Amin Abedini, Jeff M Reece, Zeguo Sun, Hewang Lee, Koji Okamoto, Pradeep Dagur, Yu Ishimoto, Jurgen Heymann, Yongmei Zhao, Joon-Yong Chung, Stephen Hewitt, Pedro A Jose, Kyung Lee, John Cijiang He, Cheryl A Winkler, Mark A Knepper, Tomoshige Kino, Avi Z Rosenberg, Katalin Susztak, Jeffrey B Kopp","doi":"10.1016/j.ajpath.2024.06.006","DOIUrl":"10.1016/j.ajpath.2024.06.006","url":null,"abstract":"<p><p>Although hyponatremia and salt wasting are common in patients with HIV/AIDS, the understanding of their contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the sodium-chloride cotransporter (which is responsible for sodium reabsorption in distal nephron segments), single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr transgenic (Vpr Tg) mice. The results show that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05); in Vpr Tg mice, Slc12a3 expression was not significantly different in DCT cells. The Pvalb<sup>+</sup> DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT mice (P < 0.01). Immunohistochemistry revealed fewer Slc12a3<sup>+</sup>Pvalb<sup>+</sup> DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT samples in the DCT cluster showed down-regulation of the Ier3 gene, which is an inhibitor of apoptosis. The in vitro knockdown of Ier3 by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by Ier3 down-regulation in DCT1 cells and loss of Slc12a3<sup>+</sup>Pvalb<sup>+</sup> DCT1 segments.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733315","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 : 2024-07-18DOI: 10.1016/j.ajpath.2024.06.003
Emma Geister, Dalton Ard, Heer Patel, Alyssa Findley, Godfrey DeSouza, Lyndsay Martin, Henry Knox, Natasha Gavara, Aurelia Lugea, Maria Eugenia Sabbatini
In a healthy pancreas, pancreatic stellate cells (PaSCs) synthesize the basement membrane, which is mainly composed of type IV collagen and laminin. In chronic pancreatitis (CP), PaSCs are responsible for the production of a rigid extracellular matrix (ECM) that is mainly composed of fibronectin and type I/III collagen. Reactive oxygen species evoke the formation of the rigid ECM by PaSCs. One source of reactive oxygen species is NADPH oxidase (Nox) enzymes. Nox1 up-regulates the expression of Twist1 and matrix metalloproteinase-9 (MMP-9) in PaSCs from mice with CP. This study determined the functional relationship between Twist1 and MMP-9, and other PaSC-produced proteins, and the extent to which Twist1 regulates digestion of ECM proteins in CP. Twist1 induced the expression of MMP-9 in mouse PaSCs. The action of Twist1 was not selective to MMP-9 because Twist1 induced the expression of types I and IV collagen, fibronectin, transforming growth factor, and α-smooth muscle actin. Using luciferase assay, Twist1 in human primary PaSCs increased the expression of MMP-9 at the transcriptional level in an NF-κB dependent manner. The digestion of type I/III collagen by MMP-9 secreted by PaSCs from mice with CP depended on Twist1. Thus, Twist1 in PaSCs from mice with CP induces rigid ECM production and MMP-9 transcription in an NF-κB-dependent mechanism that selectively displays proteolytic activity toward type I/III collagen.
{"title":"The Role of Twist1 in Chronic Pancreatitis-Associated Pancreatic Stellate Cells.","authors":"Emma Geister, Dalton Ard, Heer Patel, Alyssa Findley, Godfrey DeSouza, Lyndsay Martin, Henry Knox, Natasha Gavara, Aurelia Lugea, Maria Eugenia Sabbatini","doi":"10.1016/j.ajpath.2024.06.003","DOIUrl":"10.1016/j.ajpath.2024.06.003","url":null,"abstract":"<p><p>In a healthy pancreas, pancreatic stellate cells (PaSCs) synthesize the basement membrane, which is mainly composed of type IV collagen and laminin. In chronic pancreatitis (CP), PaSCs are responsible for the production of a rigid extracellular matrix (ECM) that is mainly composed of fibronectin and type I/III collagen. Reactive oxygen species evoke the formation of the rigid ECM by PaSCs. One source of reactive oxygen species is NADPH oxidase (Nox) enzymes. Nox1 up-regulates the expression of Twist1 and matrix metalloproteinase-9 (MMP-9) in PaSCs from mice with CP. This study determined the functional relationship between Twist1 and MMP-9, and other PaSC-produced proteins, and the extent to which Twist1 regulates digestion of ECM proteins in CP. Twist1 induced the expression of MMP-9 in mouse PaSCs. The action of Twist1 was not selective to MMP-9 because Twist1 induced the expression of types I and IV collagen, fibronectin, transforming growth factor, and α-smooth muscle actin. Using luciferase assay, Twist1 in human primary PaSCs increased the expression of MMP-9 at the transcriptional level in an NF-κB dependent manner. The digestion of type I/III collagen by MMP-9 secreted by PaSCs from mice with CP depended on Twist1. Thus, Twist1 in PaSCs from mice with CP induces rigid ECM production and MMP-9 transcription in an NF-κB-dependent mechanism that selectively displays proteolytic activity toward type I/III collagen.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733317","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}