Pub Date : 2024-08-01DOI: 10.1016/j.ajpath.2024.04.006
Duchenne muscular dystrophy (DMD), caused by loss-of-function mutations in the dystrophin gene, results in progressive muscle weakness and early fatality. Impaired autophagy is one of the cellular hallmarks of DMD, contributing to the disease progression. Molecular mechanisms underlying the inhibition of autophagy in DMD are not well understood. In the current study, the DMD mouse model mdx was used for the investigation of signaling pathways leading to suppression of autophagy. Mammalian target of rapamycin complex 1 (mTORC1) was hyperactive in the DMD muscles, accompanying muscle weakness and autophagy impairment. Surprisingly, Akt, a well-known upstream regulator of mTORC1, was not responsible for mTORC1 activation or the dystrophic muscle phenotypes. Instead, leucyl-tRNA synthetase (LeuRS) was overexpressed in mdx muscles compared with the wild type. LeuRS activates mTORC1 in a noncanonical mechanism that involves interaction with RagD, an activator of mTORC1. Disrupting LeuRS interaction with RagD by the small-molecule inhibitor BC-LI-0186 reduced mTORC1 activity, restored autophagy, and ameliorated myofiber damage in the mdx muscles. Furthermore, inhibition of LeuRS by BC-LI-0186 improved dystrophic muscle strength in an autophagy-dependent manner. Taken together, our findings uncovered a noncanonical function of the housekeeping protein LeuRS as a potential therapeutic target in the treatment of DMD.
{"title":"Leucyl-tRNA Synthetase Contributes to Muscle Weakness through Mammalian Target of Rapamycin Complex 1 Activation and Autophagy Suppression in a Mouse Model of Duchenne Muscular Dystrophy","authors":"","doi":"10.1016/j.ajpath.2024.04.006","DOIUrl":"10.1016/j.ajpath.2024.04.006","url":null,"abstract":"<div><p>Duchenne muscular dystrophy (DMD), caused by loss-of-function mutations in the dystrophin gene, results in progressive muscle weakness and early fatality. Impaired autophagy is one of the cellular hallmarks of DMD, contributing to the disease progression. Molecular mechanisms underlying the inhibition of autophagy in DMD are not well understood. In the current study, the DMD mouse model <em>mdx</em> was used for the investigation of signaling pathways leading to suppression of autophagy. Mammalian target of rapamycin complex 1 (mTORC1) was hyperactive in the DMD muscles, accompanying muscle weakness and autophagy impairment. Surprisingly, Akt, a well-known upstream regulator of mTORC1, was not responsible for mTORC1 activation or the dystrophic muscle phenotypes. Instead, leucyl-tRNA synthetase (LeuRS) was overexpressed in <em>mdx</em> muscles compared with the wild type. LeuRS activates mTORC1 in a noncanonical mechanism that involves interaction with RagD, an activator of mTORC1. Disrupting LeuRS interaction with RagD by the small-molecule inhibitor BC-LI-0186 reduced mTORC1 activity, restored autophagy, and ameliorated myofiber damage in the <em>mdx</em> muscles. Furthermore, inhibition of LeuRS by BC-LI-0186 improved dystrophic muscle strength in an autophagy-dependent manner. Taken together, our findings uncovered a noncanonical function of the housekeeping protein LeuRS as a potential therapeutic target in the treatment of DMD.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 8","pages":"Pages 1571-1580"},"PeriodicalIF":4.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024001743/pdfft?md5=b3b0c202b5b66574aee539f13555e9bb&pid=1-s2.0-S0002944024001743-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955628","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 : 2024-08-01DOI: 10.1016/j.ajpath.2024.06.002
{"title":"The Impact of Generative Artificial Intelligence in Scientific Content Synthesis for Authors","authors":"","doi":"10.1016/j.ajpath.2024.06.002","DOIUrl":"10.1016/j.ajpath.2024.06.002","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 8","pages":"Pages 1406-1408"},"PeriodicalIF":4.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002001/pdfft?md5=07bff69436a8120452336470dbc57787&pid=1-s2.0-S0002944024002001-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327029","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 : 2024-07-26DOI: 10.1016/j.ajpath.2024.07.003
Wen-Yu Chuang , Chao-Wei Lee , Wen-Lang Fan , Tsung-Ta Liu , Zih-Han Lin , Kuo-Chih Wang , Po-Jung Huang , Yuan-Ming Yeh , Tsung-Chieh Lin
Wnt-5a is a protein encoded by the WNT5A gene and is a ligand for the receptor tyrosine kinase-like orphan receptor 2 (ROR2). However, its biological impact on clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, the prognostic significance of concurrent WNT5A and ROR2 expression levels was observed to predict unfavorable overall survival and disease-specific survival. High Wnt-5a expression was detected in a ccRCC cell line panel but not in HK-2 cells, a normal proximal tubular cell line. Inhibition of DNA methyltransferase by 5-azacytidine in 786-O and Caki-2 cells resulted in Wnt-5a up-regulation, indicating potential epigenetic modification. Furthermore, there was a repression of cell movement in vitro and metastatic colonization in vivo on WNT5A and ROR2 knockdown. Suppressions of angiogenesis in vivo and tubular-like structure formation in endothelial cells in vitro were also observed after silencing WNT5A and ROR2 expression. In addition, alteration in the downstream gene signature of the Wnt-5a–ROR2 signaling was similar to that in metastasis-associated gene 1–β-catenin axis. Moreover, prunetin treatment reversed the gene signature derived from Wnt-5a–ROR2 signaling activation and to abolish ccRCC cell migration and proliferation. Overall, this study demonstrates the clinical and functional significance of the Wnt-5a–ROR2 axis and identifies prunetin as a potential precision medicine for patients with ccRCC harboring aberrant Wnt-5a–ROR2 signaling pathways.
{"title":"Wnt-5a–Receptor Tyrosine Kinase-Like Orphan Receptor 2 Signaling Provokes Metastatic Colonization and Angiogenesis in Renal Cell Carcinoma, and Prunetin Supresses the Axis Activation","authors":"Wen-Yu Chuang , Chao-Wei Lee , Wen-Lang Fan , Tsung-Ta Liu , Zih-Han Lin , Kuo-Chih Wang , Po-Jung Huang , Yuan-Ming Yeh , Tsung-Chieh Lin","doi":"10.1016/j.ajpath.2024.07.003","DOIUrl":"10.1016/j.ajpath.2024.07.003","url":null,"abstract":"<div><div>Wnt-5a is a protein encoded by the <em>WNT5A</em> gene and is a ligand for the receptor tyrosine kinase-like orphan receptor 2 (ROR2). However, its biological impact on clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, the prognostic significance of concurrent <em>WNT5A</em> and <em>ROR2</em> expression levels was observed to predict unfavorable overall survival and disease-specific survival. High Wnt-5a expression was detected in a ccRCC cell line panel but not in HK-2 cells, a normal proximal tubular cell line. Inhibition of DNA methyltransferase by 5-azacytidine in 786-O and Caki-2 cells resulted in Wnt-5a up-regulation, indicating potential epigenetic modification. Furthermore, there was a repression of cell movement <em>in vitro</em> and metastatic colonization <em>in vivo</em> on <em>WNT5A</em> and <em>ROR2</em> knockdown. Suppressions of angiogenesis <em>in vivo</em> and tubular-like structure formation in endothelial cells <em>in vitro</em> were also observed after silencing <em>WNT5A</em> and <em>ROR2</em> expression. In addition, alteration in the downstream gene signature of the Wnt-5a–ROR2 signaling was similar to that in metastasis-associated gene 1–β-catenin axis. Moreover, prunetin treatment reversed the gene signature derived from Wnt-5a–ROR2 signaling activation and to abolish ccRCC cell migration and proliferation. Overall, this study demonstrates the clinical and functional significance of the Wnt-5a–ROR2 axis and identifies prunetin as a potential precision medicine for patients with ccRCC harboring aberrant Wnt-5a–ROR2 signaling pathways.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1967-1985"},"PeriodicalIF":4.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787068","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.2024.07.002
Lei Yang , Kien Pham , Yibo Xi , Shaoning Jiang , Keith D. 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. This study was used to analyze ACSM5 expression in HCC patient samples and cell lines. The newly established ACSM5-overexpressing HCC cell lines, Huh7-ACSM5 and Hepa1-6–ACSM5, were used to investigate the effects and regulatory mechanisms of ACSM5. The results showed that ACSM5 was significantly down-regulated in HCC tumor tissues compared with non-tumor tissues. ACSM5 expression was regulated by DNA methylation, with a DNA methyltransferase 1 (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. These 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 D. Robertson , Chen Liu","doi":"10.1016/j.ajpath.2024.07.002","DOIUrl":"10.1016/j.ajpath.2024.07.002","url":null,"abstract":"<div><div>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. This study was used to analyze ACSM5 expression in HCC patient samples and cell lines. The newly established ACSM5-overexpressing HCC cell lines, Huh7-ACSM5 and Hepa1-6–ACSM5, were used to investigate the effects and regulatory mechanisms of ACSM5. The results showed that ACSM5 was significantly down-regulated in HCC tumor tissues compared with non-tumor tissues. ACSM5 expression was regulated by DNA methylation, with a DNA methyltransferase 1 (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 <em>in vitro</em>, and inhibited tumor growth in mouse xenografts. Furthermore, ACSM5 overexpression also decreased STAT3 phosphorylation, subsequently affecting downstream cytokine <em>TGFB</em> and <em>FGF12</em> mRNA levels. These 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.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1951-1966"},"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}
Pub Date : 2024-07-26DOI: 10.1016/j.ajpath.2024.07.005
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
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. 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 AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase–Akt pathway, thus reducing cardiomyocyte damage. Interestingly, 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 that lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, this 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 AMP-Activated Protein Kinase–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":"<div><div>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-<span>d</span>-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 <em>in vitro</em> hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. 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 AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase–Akt pathway, thus reducing cardiomyocyte damage. Interestingly, 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 that lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, this research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via the AMPK-mTOR-TFEB-CX43 axis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1857-1878"},"PeriodicalIF":4.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002475/pdfft?md5=2f9808ac48a129915482c71e9a5dfb06&pid=1-s2.0-S0002944024002475-main.pdf","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":"OA","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
Phosphoinositide 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 (PLEK2), a proto-oncoprotein involved in the activation and stabilization of AKT, connects these two pathways. Genetic evidence provided herein 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, PLEK2 was negatively regulated by AR, AR transcriptionally repressed PLEK2 through binding to the PLEK2 promoter region, and 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. PLEK2 inhibitor dose-dependently inhibited prostate cancer cell proliferation with the inactivation of AKT. Overall, the current study uncovered a crucial role of PLEK2 in prostate cancer proliferation and provided 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":"<div><div>Phosphoinositide 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 (PLEK2), a proto-oncoprotein involved in the activation and stabilization of AKT, connects these two pathways. Genetic evidence provided herein suggests that Plek2 deficiency largely reverted tumorigenesis in <em>Pten</em> prostate-specific knockout mice and that overexpression of PLEK2 promoted the proliferation and colony formation of prostate cancer cells <em>in vitro</em>. In addition, PLEK2 was negatively regulated by AR, AR transcriptionally repressed <em>PLEK2</em> through binding to the <em>PLEK2</em> promoter region, and 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. PLEK2 inhibitor dose-dependently inhibited prostate cancer cell proliferation with the inactivation of AKT. Overall, the current study uncovered a crucial role of PLEK2 in prostate cancer proliferation and provided the rationale for targeting PLEK2 to treat prostate cancers.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1986-1996"},"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":"<div><div>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 (<em>P</em> = 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.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1913-1923"},"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.2024.06.008
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. Herein, orthotopic, syngeneic models of epithelial ovarian cancer and pancreatic ductal adenocarcinoma, and a patient-derived pancreatic xenograft model, were used to define the impact of malignancy on cardiac structure, function, and metabolism. Tumor-bearing mice developed 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, two cancer types were used to cross-validate 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","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":"<div><div>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. Herein, orthotopic, syngeneic models of epithelial ovarian cancer and pancreatic ductal adenocarcinoma, and a patient-derived pancreatic xenograft model, were used to define the impact of malignancy on cardiac structure, function, and metabolism. Tumor-bearing mice developed 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, two cancer types were used to cross-validate 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.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1823-1843"},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002414/pdfft?md5=2b3550697bfc233232b9bdf55581d136&pid=1-s2.0-S0002944024002414-main.pdf","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":"OA","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 play a role in the death of photoreceptor cells. The involvement of microglial pyroptosis in the early pathological process of RD is still unclear. 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 demonstrated 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":"<div><div>Retinal detachment (RD) is a sight-threatening condition that occurs in several retinal diseases. Microglia that reside in retina are activated after RD and play a role in the death of photoreceptor cells. The involvement of microglial pyroptosis in the early pathological process of RD is still unclear. 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 demonstrated 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.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1924-1937"},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002426/pdfft?md5=b47bc1de32cf108f260e7adf3d118fb0&pid=1-s2.0-S0002944024002426-main.pdf","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":"OA","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 is 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","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":"<div><div>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 is 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.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1807-1822"},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002359/pdfft?md5=61c329fee97e91f660fccea1512054cc&pid=1-s2.0-S0002944024002359-main.pdf","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":"OA","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