The Journal of Pathology最新文献

{"title":"Integrated longitudinal circulating tumor DNA profiling predicts immunotherapy response of metastatic urothelial carcinoma in the POLARIS-03 trial","authors":"Jingyu Zang,&nbsp;Ruiyun Zhang,&nbsp;Di Jin,&nbsp;Feng Xie,&nbsp;Akezhouli Shahatiaili,&nbsp;Guangyu Wu,&nbsp;Yue Zhang,&nbsp;Zhixin Zhao,&nbsp;Pan Du,&nbsp;Shidong Jia,&nbsp;Haige Chen,&nbsp;Guanglei Zhuang","doi":"10.1002/path.6166","DOIUrl":"10.1002/path.6166","url":null,"abstract":"<p>Non-invasive biomarkers for immunotherapy response remain a compelling unmet medical need. POLARIS-03 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-programmed cell death 1) in refractory metastatic urothelial carcinoma (mUC). We assessed the predictive utility of longitudinal circulating tumor DNA (ctDNA) analysis from a single-institution biomarker cohort. Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled. Serial plasma specimens were obtained at baseline and then every two cycles during treatment. The 600-gene panel (PredicineATLAS™) liquid biopsy assay was applied to probe somatic variants and cancer cell fraction (CCF). Low-pass whole genome sequencing was used to determine the copy number abnormality (CNA) score. Across the entire cohort, we observed different degrees of concordance between somatic aberrations detected by ctDNA and those inferred by matched tumor samples. Although the baseline CCF or CNA had limited predictive value, early ctDNA response at week 8 was associated with toripalimab efficacy and prolonged patient survival. Integrating CCF and CNA decrease achieved a superior accuracy of 90.5% in classifying responders and non-responders and predicted long-term benefit from toripalimab. Dynamic changes in the CCF and CNA in blood exquisitely reflected radiographic assessment of malignant lesions, including those with <i>FGFR3</i>–<i>TACC3</i> gene fusion or microsatellite instability. This study demonstrates the feasibility and effectiveness of integrated longitudinal ctDNA profiling as a potential biomarker in mUC patients undergoing immunotherapy and supports further clinical evaluation of minimally invasive liquid biopsy assays for treatment stratification and therapy monitoring. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 2","pages":"198-209"},"PeriodicalIF":7.3,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5880422","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}

{"title":"Implications of tumour heterogeneity on cancer evolution and therapy resistance: lessons from breast cancer","authors":"Shefali Thakur,&nbsp;Syed Haider,&nbsp;Rachael Natrajan","doi":"10.1002/path.6158","DOIUrl":"10.1002/path.6158","url":null,"abstract":"<p>Tumour heterogeneity is pervasive amongst many cancers and leads to disease progression, and therapy resistance. In this review, using breast cancer as an exemplar, we focus on the recent advances in understanding the interplay between tumour cells and their microenvironment using single cell sequencing and digital spatial profiling technologies. Further, we discuss the utility of lineage tracing methodologies in pre-clinical models of breast cancer, and how these are being used to unravel new therapeutic vulnerabilities and reveal biomarkers of breast cancer progression. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 5","pages":"621-636"},"PeriodicalIF":7.3,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6158","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5653536","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}

{"title":"Recent Advances in Pathology: the 2023 Annual Review Issue of The Journal of Pathology","authors":"J Louise Jones,&nbsp;Richard Poulsom,&nbsp;Philip J Coates","doi":"10.1002/path.6192","DOIUrl":"10.1002/path.6192","url":null,"abstract":"<p>The 2023 Annual Review Issue of <i>The Journal of Pathology</i>, Recent Advances in Pathology, contains 12 invited reviews on topics of current interest in pathology. This year, our subjects include immuno-oncology and computational pathology approaches for diagnostic and research applications in human disease. Reviews on the tissue microenvironment include the effects of apoptotic cell-derived exosomes, how understanding the tumour microenvironment predicts prognosis, and the growing appreciation of the diverse functions of fibroblast subtypes in health and disease. We also include up-to-date reviews of modern aspects of the molecular basis of malignancies, and our final review covers new knowledge of vascular and lymphatic regeneration in cardiac disease. All of the reviews contained in this issue are written by expert groups of authors selected to discuss the recent progress in their particular fields and all articles are freely available online (https://pathsocjournals.onlinelibrary.wiley.com/journal/10969896). © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 5","pages":"495-497"},"PeriodicalIF":7.3,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5646487","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}

{"title":"Computational pathology in cancer diagnosis, prognosis, and prediction – present day and prospects","authors":"Gregory Verghese,&nbsp;Jochen K Lennerz,&nbsp;Danny Ruta,&nbsp;Wen Ng,&nbsp;Selvam Thavaraj,&nbsp;Kalliopi P Siziopikou,&nbsp;Threnesan Naidoo,&nbsp;Swapnil Rane,&nbsp;Roberto Salgado,&nbsp;Sarah E Pinder,&nbsp;Anita Grigoriadis","doi":"10.1002/path.6163","DOIUrl":"10.1002/path.6163","url":null,"abstract":"<p>Computational pathology refers to applying deep learning techniques and algorithms to analyse and interpret histopathology images. Advances in artificial intelligence (AI) have led to an explosion in innovation in computational pathology, ranging from the prospect of automation of routine diagnostic tasks to the discovery of new prognostic and predictive biomarkers from tissue morphology. Despite the promising potential of computational pathology, its integration in clinical settings has been limited by a range of obstacles including operational, technical, regulatory, ethical, financial, and cultural challenges. Here, we focus on the pathologists’ perspective of computational pathology: we map its current translational research landscape, evaluate its clinical utility, and address the more common challenges slowing clinical adoption and implementation. We conclude by describing contemporary approaches to drive forward these techniques. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 5","pages":"551-563"},"PeriodicalIF":7.3,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6224514","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}

{"title":"Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers","authors":"Marta Persson,&nbsp;Mattias K Andersson,&nbsp;Per-Erik Sahlin,&nbsp;Yoshitsugu Mitani,&nbsp;Margaret S Brandwein-Weber,&nbsp;Henry F Frierson Jr,&nbsp;Christopher Moskaluk,&nbsp;Isabel Fonseca,&nbsp;Renata Ferrarotto,&nbsp;Werner Boecker,&nbsp;Thomas Loening,&nbsp;Adel K El-Naggar,&nbsp;Göran Stenman","doi":"10.1002/path.6172","DOIUrl":"10.1002/path.6172","url":null,"abstract":"<p>Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene <i>PARK2</i> (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (<i>n</i> = 20) had significantly shorter overall survival (OS) than those with one or no deletions (<i>p</i> &lt; 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (<i>p</i> = 0.02). Two pro-apoptotic genes, <i>TP73</i> and <i>KIF1B</i>, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. <i>PARK2</i> expression was markedly reduced in tumors with 6q deletions, and <i>PARK2</i> knockdown increased spherogenesis and decreased apoptosis, indicating that <i>PARK2</i> is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of <i>TP73</i>. Taken together, the results indicate that <i>TP73</i> and <i>PARK2</i> are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 3","pages":"256-268"},"PeriodicalIF":7.3,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10346308","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}

{"title":"Cytoplasmic SIRT1 promotes paclitaxel resistance in ovarian carcinoma through increased formation and survival of polyploid giant cancer cells","authors":"Hong Xu,&nbsp;Shujun Zeng,&nbsp;Yingmei Wang,&nbsp;Tong Yang,&nbsp;Minmin Wang,&nbsp;Xuan Li,&nbsp;Yejun He,&nbsp;Xin Peng,&nbsp;Xia Li,&nbsp;Qing Qiao,&nbsp;Jing Zhang","doi":"10.1002/path.6167","DOIUrl":"10.1002/path.6167","url":null,"abstract":"<p>Therapeutic resistance is a notable cause of death in patients with ovarian carcinoma. Polyploid giant cancer cells (PGCCs), commonly arising in tumor tissues following chemotherapy, have recently been considered to contribute to drug resistance. As a type III deacetylase, Sirtuin1 (SIRT1) plays essential roles in the cell cycle, cellular senescence, and drug resistance. Accumulating evidence has suggested that alteration in its subcellular localization via nucleocytoplasmic shuttling is a critical process influencing the functions of SIRT1. However, the roles of SIRT1 subcellular localization in PGCC formation and subsequent senescence escape remain unclear. In this study, we compared the differences in the polyploid cell population and senescence state of PGCCs following paclitaxel treatment between tumor cells overexpressing wild-type SIRT1 (WT SIRT1) and those expressing nuclear localization sequence (NLS)-mutated SIRT1 (SIRT1^NLSmt). We investigated the involvement of cytoplasmic SIRT1 in biological processes and signaling pathways, including the cell cycle and cellular senescence, in ovarian carcinoma cells' response to paclitaxel treatment. We found that the SIRT1^NLSmt tumor cell population contained more polyploid cells and fewer senescent PGCCs than the SIRT1-overexpressing tumor cell population. Comparative proteomic analyses using co-immunoprecipitation (Co-IP) combined with liquid chromatography–mass spectrometry (LC-MS)/MS showed the differences in the differentially expressed proteins related to PGCC formation, cell growth, and death, including CDK1 and CDK2, between SIRT1^NLSmt and SIRT1 cells or PGCCs. Our results suggested that ovarian carcinoma cells utilize polyploidy formation as a survival mechanism during exposure to paclitaxel-based treatment via the effect of cytoplasmic SIRT1 on PGCC formation and survival, thereby boosting paclitaxel resistance. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 2","pages":"210-226"},"PeriodicalIF":7.3,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6199124","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}

{"title":"Forward genetics and functional analysis highlight Itga11 as a modulator of murine psoriasiform dermatitis","authors":"Katja Bieber,&nbsp;Siegfried Bezdek,&nbsp;Yask Gupta,&nbsp;Artem Vorobyev,&nbsp;Tanya Sezin,&nbsp;Natalie Gross,&nbsp;Jasper Prüssmann,&nbsp;Jean-Paul Sayegh,&nbsp;Mareike Becker,&nbsp;Sadegh Mousavi,&nbsp;Ashref Hdnah,&nbsp;Sven Künzel,&nbsp;Saleh M Ibrahim,&nbsp;Ralf J Ludwig,&nbsp;Donald Gullberg,&nbsp;Christian D Sadik","doi":"10.1002/path.6162","DOIUrl":"10.1002/path.6162","url":null,"abstract":"<p>Psoriasis is a chronic inflammatory skin condition. Repeated epicutaneous application of Aldara® (imiquimod) cream results in psoriasiform dermatitis in mice. The Aldara®-induced psoriasiform dermatitis (AIPD) mouse model has been used to examine the pathogenesis of psoriasis. Here, we used a forward genetics approach in which we compared AIPD that developed in 13 different inbred mouse strains to identify genes and pathways that modulated disease severity. Among our primary results, we found that the severity of AIPD differed substantially between different strains of inbred mice and that these variations were associated with polymorphisms in <i>Itga11</i>. The <i>Itga11</i> gene encodes the integrin α11 subunit that heterodimerizes with the integrin β1 subunit to form integrin α11β1. Less information is available about the function of ITGA11 in skin inflammation; however, a role in the regulation of cutaneous wound healing, specifically the development of dermal fibrosis, has been described. Experiments performed with <i>Itga11</i> gene-deleted (<i>Itga11</i>^{<i>−/−</i>}) mice revealed that the integrin α11 subunit contributes substantially to the clinical phenotype as well as the histopathological and molecular findings associated with skin inflammation characteristic of AIPD. Although the skin transcriptomes of <i>Itga11</i>^−/− and WT mice do not differ from one another under physiological conditions, distinct transcriptomes emerge in these strains in response to the induction of AIPD. Most of the differentially expressed genes contributed to extracellular matrix organization, immune system, and metabolism of lipids pathways. Consistent with these findings, we detected a reduced number of fibroblasts and inflammatory cells, including macrophages, T cells, and tissue-resident memory T cells in skin samples from <i>Itga11</i>^−/− mice in response to AIPD induction. Collectively, our results reveal that <i>Itga11</i> plays a critical role in promoting skin inflammation in AIPD and thus might be targeted for the development of novel therapeutics for psoriasiform skin conditions. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 2","pages":"184-197"},"PeriodicalIF":7.3,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6199125","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}

{"title":"Buds, clusters, and transitions in 21st century colorectal carcinoma: revolution or reinvention?†","authors":"Roger M Feakins,&nbsp;Maurice B Loughrey,&nbsp;Andrew Silver","doi":"10.1002/path.6173","DOIUrl":"10.1002/path.6173","url":null,"abstract":"<p>Tumour budding (TB) describes single or small groups of neoplastic cells that lack continuity with an advancing tumour front. Poorly differentiated clusters (PDCs) are larger and qualitatively different. TB grade and PDCs may predict a worse outcome in colorectal carcinoma and other cancers and fall into the category of ‘invasive front prognostic markers’ that also includes intratumoural stroma type. Epithelial–mesenchymal transition (EMT) allows the adoption by epithelial cells of mesenchymal characteristics such as dyscohesion, migration, and stromal invasion. TB and PDCs harbor alterations in EMT-related proteins and RNAs and may be morphological manifestations of EMT. However, persistence of epithelioid features and absence of a full complement of typical alterations in TB and PDCs may indicate ‘partial EMT’, i.e. an intermediate/hybrid state. Recently, Pavlič <i>et al</i> asserted that TB and PDCs in colorectal cancer represent different manifestations of partial EMT and, perhaps controversially, that TB is closer than PDCs to complete transition. In clinical practice, low inter-observer agreement for invasive front prognostic markers is a potential problem. The UK colorectal cancer pathology dataset advises assessment of TB and recommends the use of an international consensus system, but time will tell if we are adopting reliable prognostic markers or reinventing the wheel. Additional studies of TB, PDCs, and EMT will presumably allow greater insight into their role in tumour development and progression. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 2","pages":"121-124"},"PeriodicalIF":7.3,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6199134","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}

{"title":"Intestinal overgrowth of Candida albicans exacerbates bleomycin-induced pulmonary fibrosis in mice with dysbiosis","authors":"Takahiro Yamada,&nbsp;Taku Nakashima,&nbsp;Takeshi Masuda,&nbsp;Shinjiro Sakamoto,&nbsp;Kakuhiro Yamaguchi,&nbsp;Yasushi Horimasu,&nbsp;Shintaro Miyamoto,&nbsp;Hiroshi Iwamoto,&nbsp;Kazunori Fujitaka,&nbsp;Hironobu Hamada,&nbsp;Nobuhiko Kamada,&nbsp;Noboru Hattori","doi":"10.1002/path.6169","DOIUrl":"10.1002/path.6169","url":null,"abstract":"Increasing evidence indicates an interaction between the intestinal microbiota and diseases in distal organs. However, the relationship between pulmonary fibrosis and the intestinal microbiota, especially intestinal fungal microbiota, is poorly understood. Thus, this study aimed to determine the effects of changes in the intestinal fungal microbiota on the pathogenesis of pulmonary fibrosis. Mice with intestinal overgrowth of Candida albicans, which was established by oral administration of antibiotics plus C. albicans, showed accelerated bleomycin‐induced pulmonary fibrosis relative to the control mice (i.e. without C. albicans treatment). In addition, the mice with intestinal overgrowth of C. albicans showed enhanced Th17‐type immunity, and treatment with IL‐17A‐neutralizing antibody alleviated pulmonary fibrosis in these mice but not in the control mice. This result indicates that IL‐17A is involved in the pathogenesis of C. albicans‐exacerbated pulmonary fibrosis. Even before bleomycin treatment, the expression of Rorc, the master regulator of Th17, was already upregulated in the pulmonary lymphocytes of the mice with intestinal overgrowth of C. albicans. Subsequent administration of bleomycin triggered these Th17‐skewed lymphocytes to produce IL‐17A, which enhanced endothelial–mesenchymal transition. These results suggest that intestinal overgrowth of C. albicans exacerbates pulmonary fibrosis via IL‐17A‐mediated endothelial–mesenchymal transition. Thus, it might be a potential therapeutic target in pulmonary fibrosis. This study may serve as a basis for using intestinal fungal microbiota as novel therapeutic targets in pulmonary fibrosis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 2","pages":"227-237"},"PeriodicalIF":7.3,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6186224","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}

{"title":"Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade","authors":"Sandra Rayego-Mateos,&nbsp;José Luis Morgado-Pascual,&nbsp;Cristina García-Caballero,&nbsp;Iolanda Lazaro,&nbsp;Aleix Sala-Vila,&nbsp;Lucas Opazo-Rios,&nbsp;Sebastian Mas-Fontao,&nbsp;Jesús Egido,&nbsp;Marta Ruiz-Ortega,&nbsp;Juan Antonio Moreno","doi":"10.1002/path.6161","DOIUrl":"10.1002/path.6161","url":null,"abstract":"<p>Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 2","pages":"169-183"},"PeriodicalIF":7.3,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6200559","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}