Pub Date : 2024-08-31DOI: 10.1016/j.ajpath.2024.08.007
Qiang Du, Chun Zhang, Tianyu Qu, Xiao Zhou, Yingying Liu, Zhixuan Chen, Zilin Shen, Pingsheng Chen, Ruifeng Zhang
The dysregulation of N6-methyladenosine (m6A) RNA modification is widely recognized for its crucial roles in various diseases, including pulmonary hypertension (PH). Prior studies have highlighted the significant role of methyltransferase-like 3 (METTL3) in the pathogenesis of PH. Nevertheless, the potential and underlying mechanisms of METTL3 and its inhibitors as targets for PH treatment require further elucidation. In this study, we observed increased levels of METTL3 in various rodent models of PH. In vitro studies revealed that METTL3 silencing or treatment with STM2457, a specific METTL3 inhibitor, attenuated the proliferation and migration of pulmonary artery smooth muscle cells stimulated by platelet-derived growth factor-BB or hypoxia. Moreover, in vivo experiments using adeno-associated virus 9-mediated METTL3 silencing or STM2457 inhibition demonstrated improvement in SU5416/hypoxia-induced PH in mice. Additionally, m6A RNA immunoprecipitation analysis identified RBPJ as a gene regulated by METTL3 in rodent models of PH. Loss-of-function studies showed that silencing RBPJ could attenuate the changes in the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB or hypoxia. Further studies indicated that METTL3 and YTHDF1 regulate RBPJ mRNA expression in an m6A-dependent manner. These findings indicated that targeting METTL3 may be a promising therapeutic strategy for treating PH, and modulation of RBPJ could offer a potential intervention mechanism.
{"title":"Methyltransferase-Like 3-Driven N6-Methyladenosine Modification of RBPJ Promotes Vascular Remodeling in Pulmonary Hypertension.","authors":"Qiang Du, Chun Zhang, Tianyu Qu, Xiao Zhou, Yingying Liu, Zhixuan Chen, Zilin Shen, Pingsheng Chen, Ruifeng Zhang","doi":"10.1016/j.ajpath.2024.08.007","DOIUrl":"10.1016/j.ajpath.2024.08.007","url":null,"abstract":"<p><p>The dysregulation of N6-methyladenosine (m6A) RNA modification is widely recognized for its crucial roles in various diseases, including pulmonary hypertension (PH). Prior studies have highlighted the significant role of methyltransferase-like 3 (METTL3) in the pathogenesis of PH. Nevertheless, the potential and underlying mechanisms of METTL3 and its inhibitors as targets for PH treatment require further elucidation. In this study, we observed increased levels of METTL3 in various rodent models of PH. In vitro studies revealed that METTL3 silencing or treatment with STM2457, a specific METTL3 inhibitor, attenuated the proliferation and migration of pulmonary artery smooth muscle cells stimulated by platelet-derived growth factor-BB or hypoxia. Moreover, in vivo experiments using adeno-associated virus 9-mediated METTL3 silencing or STM2457 inhibition demonstrated improvement in SU5416/hypoxia-induced PH in mice. Additionally, m6A RNA immunoprecipitation analysis identified RBPJ as a gene regulated by METTL3 in rodent models of PH. Loss-of-function studies showed that silencing RBPJ could attenuate the changes in the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB or hypoxia. Further studies indicated that METTL3 and YTHDF1 regulate RBPJ mRNA expression in an m6A-dependent manner. These findings indicated that targeting METTL3 may be a promising therapeutic strategy for treating PH, and modulation of RBPJ could offer a potential intervention mechanism.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118819","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 : 2024-08-31DOI: 10.1016/j.ajpath.2024.08.006
Pouya Ahmadvand, Hossein Farahani, David Farnell, Amirali Darbandsari, James Topham, Joanna Karasinska, Jessica Nelson, Julia Naso, Steven J M Jones, Daniel Renouf, David F Schaeffer, Ali Bashashati
Delayed diagnosis and treatment resistance make pancreatic ductal adenocarcinoma (PDAC) mortality rates high. Identifying molecular subtypes can improve treatment, but current methods are costly and time-consuming. In this study, deep learning models were used to identify histologic features that classify PDAC molecular subtypes based on routine hematoxylin-eosin-stained histopathologic slides. A total of 97 histopathology slides associated with resectable PDAC from The Cancer Genome Atlas project were used to train a deep learning model and tested the performance on 44 needle biopsy material (110 slides) from a local annotated patient cohort. The model achieved balanced accuracy of 96.19% and 83.03% in identifying the classical and basal subtypes of PDAC in The Cancer Genome Atlas and the local cohort, respectively. This study provides a promising method to cost-effectively and rapidly classifying PDAC molecular subtypes based on routine hematoxylin-eosin-stained slides, potentially leading to more effective clinical management of this disease.
{"title":"A Deep Learning Approach for the Identification of the Molecular Subtypes of Pancreatic Ductal Adenocarcinoma Based on Whole Slide Pathology Images.","authors":"Pouya Ahmadvand, Hossein Farahani, David Farnell, Amirali Darbandsari, James Topham, Joanna Karasinska, Jessica Nelson, Julia Naso, Steven J M Jones, Daniel Renouf, David F Schaeffer, Ali Bashashati","doi":"10.1016/j.ajpath.2024.08.006","DOIUrl":"10.1016/j.ajpath.2024.08.006","url":null,"abstract":"<p><p>Delayed diagnosis and treatment resistance make pancreatic ductal adenocarcinoma (PDAC) mortality rates high. Identifying molecular subtypes can improve treatment, but current methods are costly and time-consuming. In this study, deep learning models were used to identify histologic features that classify PDAC molecular subtypes based on routine hematoxylin-eosin-stained histopathologic slides. A total of 97 histopathology slides associated with resectable PDAC from The Cancer Genome Atlas project were used to train a deep learning model and tested the performance on 44 needle biopsy material (110 slides) from a local annotated patient cohort. The model achieved balanced accuracy of 96.19% and 83.03% in identifying the classical and basal subtypes of PDAC in The Cancer Genome Atlas and the local cohort, respectively. This study provides a promising method to cost-effectively and rapidly classifying PDAC molecular subtypes based on routine hematoxylin-eosin-stained slides, potentially leading to more effective clinical management of this disease.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118816","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 : 2024-08-23DOI: 10.1016/j.ajpath.2024.05.013
Janice A. Dye , Helen H. Nguyen , Erica J. Stewart , Mette C.J. Schladweiler , Colette N. Miller
Air pollution exposure during pregnancy may affect fetal growth. Fetal growth restriction (FGR) is associated with reduced lung function in children that can persist into adulthood. Using an established model of asymmetrical FGR in Long-Evans rats, this study investigated sex differences in effects of early life ozone exposure on lung development and maturation. Adverse health effects for i) gestational exposure (with impacts on primary alveolarization), ii) peri-adolescent exposure (with impacts on secondary alveolarization), and iii) cumulative exposure across both periods were evaluated. Notably, female offspring were most affected by gestational ozone exposure, likely because of impaired angiogenesis and corresponding decreases in primary alveolarization. Females had diminished lung capacity, fewer mature alveoli, and medial hypertrophy of small and large pulmonary arteries. Males, especially FGR-prone offspring, were more affected by peri-adolescent ozone exposure. Males had increased ductal areas, likely due to disrupted secondary alveolarization. Altered lung development may increase risk of developing diseases, such as pulmonary arterial hypertension or chronic obstructive pulmonary disease. Pulmonary arterial hypertension disproportionately affects women. In the United States, chronic obstructive pulmonary disease prevalence is increasing, especially in women; and prevalence for both men and women is highest in urbanized areas. This investigation underlines the importance of evaluating results separately by sex, and provides biologic plausibility for later consequences of early-life exposure to ozone, a ubiquitous urban air pollutant.
{"title":"Sex Differences in Impacts of Early Gestational and Peri-Adolescent Ozone Exposure on Lung Development in Rats","authors":"Janice A. Dye , Helen H. Nguyen , Erica J. Stewart , Mette C.J. Schladweiler , Colette N. Miller","doi":"10.1016/j.ajpath.2024.05.013","DOIUrl":"10.1016/j.ajpath.2024.05.013","url":null,"abstract":"<div><p>Air pollution exposure during pregnancy may affect fetal growth. Fetal growth restriction (FGR) is associated with reduced lung function in children that can persist into adulthood. Using an established model of asymmetrical FGR in Long-Evans rats, this study investigated sex differences in effects of early life ozone exposure on lung development and maturation. Adverse health effects for i) gestational exposure (with impacts on primary alveolarization), ii) peri-adolescent exposure (with impacts on secondary alveolarization), and iii) cumulative exposure across both periods were evaluated. Notably, female offspring were most affected by gestational ozone exposure, likely because of impaired angiogenesis and corresponding decreases in primary alveolarization. Females had diminished lung capacity, fewer mature alveoli, and medial hypertrophy of small and large pulmonary arteries. Males, especially FGR-prone offspring, were more affected by peri-adolescent ozone exposure. Males had increased ductal areas, likely due to disrupted secondary alveolarization. Altered lung development may increase risk of developing diseases, such as pulmonary arterial hypertension or chronic obstructive pulmonary disease. Pulmonary arterial hypertension disproportionately affects women. In the United States, chronic obstructive pulmonary disease prevalence is increasing, especially in women; and prevalence for both men and women is highest in urbanized areas. This investigation underlines the importance of evaluating results separately by sex, and provides biologic plausibility for later consequences of early-life exposure to ozone, a ubiquitous urban air pollutant.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 9","pages":"Pages 1636-1663"},"PeriodicalIF":4.7,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054695","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 : 2024-08-23DOI: 10.1016/j.ajpath.2024.07.006
Jin Chu, Domenico Praticò
{"title":"Retraction notice to “Pharmacologic Blockade of 5-Lipoxygenase Improves the Amyloidotic Phenotype of an Alzheimer's Disease Transgenic Mouse Model: Involvement of γ-Secretase” [Am J Pathol 178 (2011) 1762–1769]","authors":"Jin Chu, Domenico Praticò","doi":"10.1016/j.ajpath.2024.07.006","DOIUrl":"10.1016/j.ajpath.2024.07.006","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 9","pages":"Page 1799"},"PeriodicalIF":4.7,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002487/pdfft?md5=aa082668392dc040e86274c51430baca&pid=1-s2.0-S0002944024002487-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054694","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 : 2024-08-22DOI: 10.1016/j.ajpath.2024.08.003
Mwense Leya , Hyuneui Jeong , Daram Yang , Tien Huyen Ton Nu Bao , Prakash Raj Pandeya , Sang-Ik Oh , Yoon-Seok Roh , Jong-Won Kim , Bumseok Kim
Casein kinase 1 epsilon (CK1ε), a member of the serine/threonine protein kinase family, phosphorylates a broad range of substrates. However, its role in the development of chronic liver diseases remains elusive. This study aimed to investigate the role of CK1ε in the development and progression of metabolic dysfunction–associated steatohepatitis (MASH). Hepatocyte-specific CK1ε knockout (CK1εΔHEP) mice were generated by crossbreeding mice with floxed CK1ε alleles (CK1εfl/fl) and Cre-expressing albumin mice. Mice were fed either a Western diet (WD) or a methionine- and choline-deficient diet to induce MASH. CK1εΔHEP was associated with a decreased severity of WD- or methionine- and choline-deficient diet–induced MASH, as confirmed by reduced incidence of hepatic lesions and significantly lower levels of alanine aminotransferase, aspartate aminotransferase, and proinflammatory cytokine tumor necrosis factor (TNF)-α. CK1εΔHEP WD-fed mice exhibited significant amelioration of total cholesterol, triglycerides, and de novo lipogenic genes, indicating that CK1ε could influence lipid metabolism. CK1εΔHEP WD-fed mice showed significantly down-regulated TNF receptor–associated factor (TRAF) 3, phosphorylated (p) transforming growth factor-β–activated kinase 1, p–TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1), and p-AKT levels, thereby affecting downstream mitogen-activated protein kinase signaling, indicating a potential mechanism for the observed rescue. Finally, pharmacologic inhibition of CK1ε with PF670462 improved palmitic acid–induced steatohepatitis in vitro and attenuated WD-induced metabolic profile in vivo. In conclusion, CK1ε up-regulates TNF receptor–associated factor 3, which, in turn, causes transforming growth factor-β–activated kinase 1–dependent signaling, amplifies downstream mitogen-activated protein kinase signaling, modifies p-c-Jun levels, and exacerbates inflammation, all of which are factors in WD-induced metabolic dysfunction–associated steatotic liver disease.
{"title":"Hepatocyte-Specific Casein Kinase 1 Epsilon Ablation Ameliorates Metabolic Dysfunction–Associated Steatohepatitis by Up-Regulating Tumor Necrosis Factor Receptor–Associated Factor 3 in Mice","authors":"Mwense Leya , Hyuneui Jeong , Daram Yang , Tien Huyen Ton Nu Bao , Prakash Raj Pandeya , Sang-Ik Oh , Yoon-Seok Roh , Jong-Won Kim , Bumseok Kim","doi":"10.1016/j.ajpath.2024.08.003","DOIUrl":"10.1016/j.ajpath.2024.08.003","url":null,"abstract":"<div><div>Casein kinase 1 epsilon (CK1ε), a member of the serine/threonine protein kinase family, phosphorylates a broad range of substrates. However, its role in the development of chronic liver diseases remains elusive. This study aimed to investigate the role of CK1ε in the development and progression of metabolic dysfunction–associated steatohepatitis (MASH). Hepatocyte-specific CK1ε knockout (CK1ε<sup>ΔHEP</sup>) mice were generated by crossbreeding mice with floxed CK1ε alleles (CK1ε<sup>fl/fl</sup>) and <em>Cre-</em>expressing albumin mice. Mice were fed either a Western diet (WD) or a methionine- and choline-deficient diet to induce MASH. CK1ε<sup>ΔHEP</sup> was associated with a decreased severity of WD- or methionine- and choline-deficient diet–induced MASH, as confirmed by reduced incidence of hepatic lesions and significantly lower levels of alanine aminotransferase, aspartate aminotransferase, and proinflammatory cytokine tumor necrosis factor (TNF)-α. CK1ε<sup>ΔHEP</sup> WD-fed mice exhibited significant amelioration of total cholesterol, triglycerides, and <em>de novo</em> lipogenic genes, indicating that CK1ε could influence lipid metabolism. CK1ε<sup>ΔHEP</sup> WD-fed mice showed significantly down-regulated TNF receptor–associated factor (TRAF) 3, phosphorylated (p) transforming growth factor-β–activated kinase 1, p–TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1), and p-AKT levels, thereby affecting downstream mitogen-activated protein kinase signaling, indicating a potential mechanism for the observed rescue. Finally, pharmacologic inhibition of CK1ε with PF670462 improved palmitic acid–induced steatohepatitis <em>in vitro</em> and attenuated WD-induced metabolic profile <em>in vivo</em>. In conclusion, CK1ε up-regulates TNF receptor–associated factor 3, which, in turn, causes transforming growth factor-β–activated kinase 1–dependent signaling, amplifies downstream mitogen-activated protein kinase signaling, modifies p-c-Jun levels, and exacerbates inflammation, all of which are factors in WD-induced metabolic dysfunction–associated steatotic liver disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2106-2127"},"PeriodicalIF":4.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046120","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 : 2024-08-19DOI: 10.1016/j.ajpath.2024.07.019
Maximilian P. Brandt , Olesya Vakhrusheva , Hubert Hackl , Tamas Daher , Katrin Tagscherer , Wilfried Roth , Igor Tsaur , Florian Handle , Andrea Eigentler , Zoran Culig , Christian Thomas , Holger H.H. Erb , Axel Haferkamp , Eva Jüngel , Martin Puhr
Resistance to antiandrogens and chemotherapy (Cx) limits therapeutic options for patients with metastatic hormone-sensitive (mHSPC) and metastatic castration-resistant (mCRPC) prostate cancer. In this context, up-regulation of the glucocorticoid receptor is identified as a potential bypass mechanism in mCRPC. A combination of docetaxel and mifepristone (Doc + RU-486), an inhibitor of the glucocorticoid receptor, re-sensitizes docetaxel-resistant cell models to Cx. This study was designed to elucidate the molecular mechanisms responsible for this phenomenon. RNA sequencing was performed in docetaxel-resistant prostate cancer cell models after Doc + RU-486 treatment with consecutive functional assays. Expression of selected proteins was verified in prostatic tissue from prostate cancer patients with progressive disease. Treatment with Doc + RU-486 significantly reduced cancer cell viability, and RNA sequencing revealed sterol regulatory element of binding transcription factor 1 (SREBF-1), a transcription factor of cholesterol and lipid biosynthesis, as a significantly down-regulated target. Functional assays confirmed that SREBF-1 down-regulation is partially responsible for this observation. In concordance, SREBF-1 knockdown and pharmacologic sterol regulatory element binding protein inhibition, together with other key enzymes in the cholesterol pathway, showed similar results. Furthermore, SREBF-1 expression is significantly elevated in advanced prostate cancer tissues, showing its potential involvement in tumor progression and emerging therapy resistance. Therefore, specific inhibition of cholesterol and lipid biosynthesis might also target Cx-resistant cancer cells and represents a potential additive future therapeutic option to improve mCRPC therapy.
{"title":"Inhibition of the Sterol Regulatory Element Binding Protein SREBF-1 Overcomes Docetaxel Resistance in Advanced Prostate Cancer","authors":"Maximilian P. Brandt , Olesya Vakhrusheva , Hubert Hackl , Tamas Daher , Katrin Tagscherer , Wilfried Roth , Igor Tsaur , Florian Handle , Andrea Eigentler , Zoran Culig , Christian Thomas , Holger H.H. Erb , Axel Haferkamp , Eva Jüngel , Martin Puhr","doi":"10.1016/j.ajpath.2024.07.019","DOIUrl":"10.1016/j.ajpath.2024.07.019","url":null,"abstract":"<div><div>Resistance to antiandrogens and chemotherapy (Cx) limits therapeutic options for patients with metastatic hormone-sensitive (mHSPC) and metastatic castration-resistant (mCRPC) prostate cancer. In this context, up-regulation of the glucocorticoid receptor is identified as a potential bypass mechanism in mCRPC. A combination of docetaxel and mifepristone (Doc + RU-486), an inhibitor of the glucocorticoid receptor, re-sensitizes docetaxel-resistant cell models to Cx. This study was designed to elucidate the molecular mechanisms responsible for this phenomenon. RNA sequencing was performed in docetaxel-resistant prostate cancer cell models after Doc + RU-486 treatment with consecutive functional assays. Expression of selected proteins was verified in prostatic tissue from prostate cancer patients with progressive disease. Treatment with Doc + RU-486 significantly reduced cancer cell viability, and RNA sequencing revealed sterol regulatory element of binding transcription factor 1 (SREBF-1), a transcription factor of cholesterol and lipid biosynthesis, as a significantly down-regulated target. Functional assays confirmed that SREBF-1 down-regulation is partially responsible for this observation. In concordance, SREBF-1 knockdown and pharmacologic sterol regulatory element binding protein inhibition, together with other key enzymes in the cholesterol pathway, showed similar results. Furthermore, SREBF-1 expression is significantly elevated in advanced prostate cancer tissues, showing its potential involvement in tumor progression and emerging therapy resistance. Therefore, specific inhibition of cholesterol and lipid biosynthesis might also target Cx-resistant cancer cells and represents a potential additive future therapeutic option to improve mCRPC therapy.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2150-2162"},"PeriodicalIF":4.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016036","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 : 2024-08-19DOI: 10.1016/j.ajpath.2024.07.018
Huimei Lu , Yuan Wang , Shipra Chaudhary , Varshita Balaga , Hua Ke , Fuqian Shi , Jingmei Liu , Yanying Huo , Peter J. Romanienko , Bing Xia , Subhajyoti De , Chang S. Chan , Zhiyuan Shen
Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. Whether ablation of Brca2 and Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas was explored here. Conditional knockout mouse models of these HR genes and a conditional knockdown of Bccip (shBccip-KD) were established. Deletion of any of these genes led to microcephaly and neurologic defects, with Brca1– and Bccip– producing the worst defects. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency but exhibited limited impact on Bccip– mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Despite shBccip-CKD being highly penetrative, Bccip/Trp53 deletions failed to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. Although there were widespread up-regulations of cell proliferative pathways, most of the tumors expressed biomarkers of the sonic hedgehog subgroup. The medulloblastomas developed from Brca1–, Palb2–, and Brca2– mice were highly sensitive to a poly (ADP-ribose) polymerase inhibitor but not the ones from shBccip-CKD mice. These models recapitulate the spontaneous medulloblastoma development with high penetrance and a narrow time window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR-defective and HR-proficient tumors.
{"title":"Medulloblastomas Initiated by Homologous Recombination Defects in Mice","authors":"Huimei Lu , Yuan Wang , Shipra Chaudhary , Varshita Balaga , Hua Ke , Fuqian Shi , Jingmei Liu , Yanying Huo , Peter J. Romanienko , Bing Xia , Subhajyoti De , Chang S. Chan , Zhiyuan Shen","doi":"10.1016/j.ajpath.2024.07.018","DOIUrl":"10.1016/j.ajpath.2024.07.018","url":null,"abstract":"<div><div>Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. Whether ablation of <em>Brca2</em> and <em>Palb2</em>, and their related <em>Brca1</em> and <em>Bccip</em> genes, in the mouse brain can differentially initiate medulloblastomas was explored here. Conditional knockout mouse models of these HR genes and a conditional knockdown of <em>Bccip</em> (<em>shBccip-KD</em>) were established. Deletion of any of these genes led to microcephaly and neurologic defects, with <em>Brca1</em><sup><em>–</em></sup> and <em>Bccip</em><sup><em>–</em></sup> producing the worst defects. <em>Trp53</em> co-deletion significantly rescued the microcephaly with <em>Brca1</em>, <em>Palb2</em>, and <em>Brca2</em> deficiency but exhibited limited impact on <em>Bccip</em><sup>–</sup> mice. For the first time, inactivation of either <em>Brca1</em> or <em>Palb2</em> with <em>Trp53</em> was found to induce medulloblastomas. Despite <em>shBccip-CKD</em> being highly penetrative, <em>Bccip/Trp53</em> deletions failed to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. Although there were widespread up-regulations of cell proliferative pathways, most of the tumors expressed biomarkers of the sonic hedgehog subgroup. The medulloblastomas developed from <em>Brca1</em><sup><em>–</em></sup><em>, Palb2</em><sup><em>–</em></sup><em>,</em> and <em>Brca2</em><sup>–</sup> mice were highly sensitive to a poly (ADP-ribose) polymerase inhibitor but not the ones from <em>shBccip-CKD</em> mice. These models recapitulate the spontaneous medulloblastoma development with high penetrance and a narrow time window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR-defective and HR-proficient tumors.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2007-2022"},"PeriodicalIF":4.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016037","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 : 2024-08-19DOI: 10.1016/j.ajpath.2024.07.020
Hui Zhang , Si Lei , Hui Zhuo , Yan Xu , Yun Ye , Yingquan Luo
Obstructive sleep apnea syndrome (OSAS) is associated with the development and progression of metabolic dysfunction–associated steatotic liver disease (MASLD). Tripartite motif containing 24 (TRIM24) deficiency causes hepatic lipid accumulation and hepatitis. However, the expression, function, and mechanism of TRIM24 in OSAS and MASLD remain unclear. Herein, an OSAS and MASLD mouse model was established by intermittent hypoxia (IH) and high-fat diet. IH- and 1% free fatty acid–induced mouse liver cells served as an in vitro model. TRIM24 and HIF1A were up-regulated under the IH condition. HIF1A enhanced the transcriptional activity of TRIM24. Overexpression of TRIM24 reduced hepatic lipid accumulation, decreased serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and increased serum levels of high-density lipoprotein cholesterol in OSAS and MASLD mice. Additionally, overexpression of TRIM24 alleviated inflammation and oxidative stress, and modulated aberrant lipid metabolism. Mechanically, TRIM24 up-regulated the expression of ORM2, a key regulator of hepatic lipogenesis, by binding to H3K27ac and recruiting retinoic acid receptor-α to ORM2 promoter. The cell rescue model was used to verify that ORM2 mediated the hepatoprotective effects of TRIM24. The current study reveals the important role of TRIM24 as an epigenetic coregulator of transcription in OSAS and MASLD, providing additional insights into understanding the pathogenesis and preventing the development of OSAS and MASLD.
{"title":"TRIM24 Up-Regulates ORM2 to Alleviate Abnormal Lipid Metabolism, Inflammation, and Oxidative Stress in Mice with Obstructive Sleep Apnea Syndrome and Metabolic Dysfunction–Associated Steatotic Liver Disease","authors":"Hui Zhang , Si Lei , Hui Zhuo , Yan Xu , Yun Ye , Yingquan Luo","doi":"10.1016/j.ajpath.2024.07.020","DOIUrl":"10.1016/j.ajpath.2024.07.020","url":null,"abstract":"<div><div>Obstructive sleep apnea syndrome (OSAS) is associated with the development and progression of metabolic dysfunction–associated steatotic liver disease (MASLD). Tripartite motif containing 24 (<em>TRIM24</em>) deficiency causes hepatic lipid accumulation and hepatitis. However, the expression, function, and mechanism of <em>TRIM24</em> in OSAS and MASLD remain unclear. Herein, an OSAS and MASLD mouse model was established by intermittent hypoxia (IH) and high-fat diet. IH- and 1% free fatty acid–induced mouse liver cells served as an <em>in vitro</em> model. <em>TRIM24</em> and <em>HIF1A</em> were up-regulated under the IH condition. <em>HIF1A</em> enhanced the transcriptional activity of <em>TRIM24</em>. Overexpression of <em>TRIM24</em> reduced hepatic lipid accumulation, decreased serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and increased serum levels of high-density lipoprotein cholesterol in OSAS and MASLD mice. Additionally, overexpression of <em>TRIM24</em> alleviated inflammation and oxidative stress, and modulated aberrant lipid metabolism. Mechanically, <em>TRIM24</em> up-regulated the expression of <em>ORM2</em>, a key regulator of hepatic lipogenesis, by binding to H3K27ac and recruiting retinoic acid receptor-α to <em>ORM2</em> promoter. The cell rescue model was used to verify that <em>ORM2</em> mediated the hepatoprotective effects of <em>TRIM24</em>. The current study reveals the important role of <em>TRIM24</em> as an epigenetic coregulator of transcription in OSAS and MASLD, providing additional insights into understanding the pathogenesis and preventing the development of OSAS and MASLD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2091-2105"},"PeriodicalIF":4.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016038","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 : 2024-08-17DOI: 10.1016/j.ajpath.2024.07.021
Phuong M. Le , Mary J. Mattapallil , Rachel R. Caspi , Mary Ann Stepp , A. Sue Menko
Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, an immunolocalization approach combined with high-resolution confocal microscopy was used to investigate whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule, such as regulatory T cells [forkhead box P3 (FoxP3)+CD4+] and M2 macrophages (CD68+ arginase 1+IL-10+), included those with putative anti-inflammatory, proresolution roles. The frequency of these lens capsule–associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. These results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU.
{"title":"Immunoregulatory Properties of Immune Cells that Associate with the Lens Capsule Surface during Acute and Resolution Phases of Experimental Autoimmune Uveitis","authors":"Phuong M. Le , Mary J. Mattapallil , Rachel R. Caspi , Mary Ann Stepp , A. Sue Menko","doi":"10.1016/j.ajpath.2024.07.021","DOIUrl":"10.1016/j.ajpath.2024.07.021","url":null,"abstract":"<div><div>Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, an immunolocalization approach combined with high-resolution confocal microscopy was used to investigate whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule, such as regulatory T cells [forkhead box P3 (FoxP3)<sup>+</sup>CD4<sup>+</sup>] and M2 macrophages (CD68<sup>+</sup> arginase 1<sup>+</sup>IL-10<sup>+</sup>), included those with putative anti-inflammatory, proresolution roles. The frequency of these lens capsule–associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. These results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2194-2211"},"PeriodicalIF":4.7,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003414","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 : 2024-08-13DOI: 10.1016/j.ajpath.2024.07.017
Lauren Pickel , Soo Jin Kim , Sabiha Hacibekiroglu , Andras Nagy , Junyeop Lee , Hoon-Ki Sung
Biological processes throughout the body are orchestrated in time through the regulation of local circadian clocks. The retina is among the most metabolically active tissues, with demands depending greatly on the light/dark cycle. Most cell types within the rodent retina are known to express the circadian clock; however, retinal clock expression in humans has not previously been localized. Moreover, the effect of local circadian clock dysfunction on retinal homeostasis is incompletely understood. The current study indicated an age-dependent decline in circadian clock gene and protein expression in the human retina. An animal model of targeted Bmal1 deficiency was used to identify the circadian clock of the retinal Müller glia as essential for neuronal survival, vascular integrity, and retinal function. These results suggest a potential role for the local retinal circadian clock within the Müller glia in age-related retinal disease and retinal degeneration.
{"title":"The Circadian Clock of Müller Glia Is Necessary for Retinal Homeostasis and Neuronal Survival","authors":"Lauren Pickel , Soo Jin Kim , Sabiha Hacibekiroglu , Andras Nagy , Junyeop Lee , Hoon-Ki Sung","doi":"10.1016/j.ajpath.2024.07.017","DOIUrl":"10.1016/j.ajpath.2024.07.017","url":null,"abstract":"<div><div>Biological processes throughout the body are orchestrated in time through the regulation of local circadian clocks. The retina is among the most metabolically active tissues, with demands depending greatly on the light/dark cycle. Most cell types within the rodent retina are known to express the circadian clock; however, retinal clock expression in humans has not previously been localized. Moreover, the effect of local circadian clock dysfunction on retinal homeostasis is incompletely understood. The current study indicated an age-dependent decline in circadian clock gene and protein expression in the human retina. An animal model of targeted <em>Bmal1</em> deficiency was used to identify the circadian clock of the retinal Müller glia as essential for neuronal survival, vascular integrity, and retinal function. These results suggest a potential role for the local retinal circadian clock within the Müller glia in age-related retinal disease and retinal degeneration.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2179-2193"},"PeriodicalIF":4.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987247","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