The Journal of Pathology最新文献

{"title":"Macrophages producing chondroitin sulfate proteoglycan-4 induce neuro-cardiac junction impairment in Duchenne muscular dystrophy.","authors":"Marika Milan, Fabio Maiullari, Maila Chirivì, Maria Grazia Ceraolo, Rebecca Zigiotto, Andrea Soluri, Silvia Maiullari, Elisa Landoni, Dario Di Silvestre, Francesca Brambilla, Pierluigi Mauri, Veronica De Paolis, Nicole Fratini, Maria Cristina Crosti, Chiara Cordiglieri, Chiara Parisi, Antonella Calogero, Dror Seliktar, Yvan Torrente, Chiara Lanzuolo, Gianpietro Dotti, Mirco Toccafondi, Mauro Bombaci, Elena De Falco, Claudia Bearzi, Roberto Rizzi","doi":"10.1002/path.6362","DOIUrl":"https://doi.org/10.1002/path.6362","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is caused by the absence of the full form of the dystrophin protein, which is essential for maintaining the structural integrity of muscle cells, including those in the heart and respiratory system. Despite progress in understanding the molecular mechanisms associated with DMD, myocardial insufficiency persists as the primary cause of mortality, and existing therapeutic strategies remain limited. This study investigates the hypothesis that a dysregulation of the biological communication between infiltrating macrophages (MPs) and neurocardiac junctions exists in dystrophic cardiac tissue. In a mouse model of DMD (mdx), this phenomenon is influenced by the over-release of chondroitin sulfate proteoglycan-4 (CSPG4), a key inhibitor of nerve sprouting and a modulator of the neural function, by MPs infiltrating the cardiac tissue and associated with dilated cardiomyopathy, a hallmark of DMD. Givinostat, the histone deacetylase inhibitor under current development as a clinical treatment for DMD, is effective at both restoring a physiological microenvironment at the neuro-cardiac junction and cardiac function in mdx mice in addition to a reduction in cardiac fibrosis, MP-mediated inflammation, and tissue CSPG4 content. This study provides novel insight into the pathophysiology of DMD in the heart, identifying potential new biological targets. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613258","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":"AMIGO2 characterizes cancer-associated fibroblasts in metastatic colon cancer and induces the release of paracrine active tumorigenic secretomes.","authors":"Yongsong Yong, Richard Demmler, Bisan Abdalfatah Zohud, Qi Fang, Tong Zhang, Yonghua Zhou, Katja Petter, Christian Flierl, Tobias Gass, Carol I Geppert, Susanne Merkel, Vera S Schellerer, Elisabeth Naschberger, Michael Stürzl","doi":"10.1002/path.6363","DOIUrl":"https://doi.org/10.1002/path.6363","url":null,"abstract":"<p><p>Secretomes of cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC) contribute to malignancy. Detailed knowledge is available on the components and functions of CAF secretomes. Little is known about the regulation of CAF secretomes. Here, we searched for receptor-like membrane-bound molecules in CAFs, which may regulate the production and release of tumor-activating secretomes. The adhesion molecule with Ig-like domain 2 (AMIGO2) was significantly upregulated in cultivated CAFs compared to normal tissue-associated fibroblasts (NAFs), and this was confirmed in patient-derived tissues. AMIGO2 expression was low or absent in healthy colon, significantly increased in fibroblasts of primary CRC, and highest in the stromal tissues of CRC-derived liver metastases. AMIGO2 expression in CAFs correlated with a higher T-category, increased lymph node metastasis, progressed tumor stages and was associated with reduced survival in different cohorts of CRC patients. Interestingly, AMIGO2 expression was induced by transforming growth factor-β and higher in female patients, who exhibit a more aggressive disease course. In functional studies, conditioned media of NAFs with experimentally induced AMIGO2 overexpression enhanced proliferation and migration of different CRC tumor cells, while siRNA-mediated inhibition of AMIGO2 in CAFs attenuated these effects. Accordingly, therapeutic inhibition of the receptor-like AMIGO2 protein in CRC CAFs could prevent tumorigenic secretomes in CRC. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613255","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":"Consensus molecular subtype transition during progression of colorectal cancer","authors":"Simone van de Weerd,&nbsp;Arezo Torang,&nbsp;Liselotte W Zwager,&nbsp;Pim J Koelink,&nbsp;Jan Koster,&nbsp;Barbara AJ Bastiaansen,&nbsp;Veerle Lammers,&nbsp;Ciro Longobardi,&nbsp;Jeanine ML Roodhart,&nbsp;J Han van Krieken,&nbsp;Arantza Farina Sarasqueta,&nbsp;Evelien Dekker,&nbsp;Jan Paul Medema","doi":"10.1002/path.6176","DOIUrl":"10.1002/path.6176","url":null,"abstract":"<p>The consensus molecular subtype (CMS) classification divides colorectal cancer (CRC) into four distinct subtypes based on RNA expression profiles. The biological differences between CMSs are already present in CRC precursor lesions, but not all CMSs pose the same risk of malignant transformation. To fully understand the path to malignant transformation and to determine whether CMS is a fixed entity during progression, genomic and transcriptomic data from two regions of the same CRC lesion were compared: the precursor region and the carcinoma region. In total, 24 patients who underwent endoscopic removal of T1–2 CRC were included. Regions were subtyped for CMS and DNA mutation analysis was performed. Additionally, a set of 85 benign adenomas was CMS-subtyped. This analysis revealed that almost all benign adenomas were classified as CMS3 (91.8%). In contrast, CMS2 was the most prevalent subtype in precursor regions (66.7%), followed by CMS3 (29.2%). CMS4 was absent in precursor lesions and originated at the carcinoma stage. Importantly, CMS switching occurred in a substantial number of cases and almost all (six out of seven) CMS3 precursor regions showed a shift to a different subtype in the carcinoma part of the lesion, which in four cases was classified as CMS4. In conclusion, our data indicate that CMS3 is related to a more indolent type of precursor lesion that less likely progresses to CRC and when this occurs, it is often associated with a subtype change that includes the more aggressive mesenchymal CMS4. In contrast, an acquired CMS2 signature appeared to be rather fixed during early CRC development. Combined, our data show that subtype changes occur during progression and that CMS3 switching is related to changes in the genomic background through acquisition of a novel driver mutation (<i>TP53</i>) or selective expansion of a clone, but also occurred independently of such genetic changes. © 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":"298-308"},"PeriodicalIF":7.3,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10183938","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":"Integration of peripheral blood- and tissue-based biomarkers of response to immune checkpoint blockade in urothelial carcinoma","authors":"Rami S Vanguri,&nbsp;James W Smithy,&nbsp;Yanyun Li,&nbsp;Mingqiang Zhuang,&nbsp;Colleen A Maher,&nbsp;Nathaniel Aleynick,&nbsp;Xiyu Peng,&nbsp;Hikmat Al-Ahmadie,&nbsp;Samuel A Funt,&nbsp;Jonathan E Rosenberg,&nbsp;Gopa Iyer,&nbsp;Dean Bajorin,&nbsp;James C Mathews,&nbsp;Saad Nadeem,&nbsp;Katherine S Panageas,&nbsp;Ronglai Shen,&nbsp;Margaret K Callahan,&nbsp;Travis J Hollmann","doi":"10.1002/path.6197","DOIUrl":"10.1002/path.6197","url":null,"abstract":"<p>As predictive biomarkers of response to immune checkpoint inhibitors (ICIs) remain a major unmet clinical need in patients with urothelial carcinoma (UC), we sought to identify tissue-based immune biomarkers of clinical benefit to ICIs using multiplex immunofluorescence and to integrate these findings with previously identified peripheral blood biomarkers of response. Fifty-five pretreatment and 12 paired on-treatment UC specimens were identified from patients treated with nivolumab with or without ipilimumab. Whole tissue sections were stained with a 12-plex mIF panel, including CD8, PD-1/CD279, PD-L1/CD274, CD68, CD3, CD4, FoxP3, TCF1/7, Ki67, LAG-3, MHC-II/HLA-DR, and pancytokeratin+SOX10 to identify over three million cells. Immune tissue densities were compared to progression-free survival (PFS) and best overall response (BOR) by RECIST version 1.1. Correlation coefficients were calculated between tissue-based and circulating immune populations. The frequency of intratumoral CD3⁺LAG-3⁺ cells was higher in responders compared to nonresponders (<i>p</i> = 0.0001). LAG-3⁺ cellular aggregates were associated with response, including CD3⁺LAG-3⁺ in proximity to CD3⁺ (<i>p</i> = 0.01). Exploratory multivariate modeling showed an association between intratumoral CD3⁺LAG-3⁺ cells and improved PFS independent of prognostic clinical factors (log HR −7.0; 95% confidence interval [CI] −12.7 to −1.4), as well as established biomarkers predictive of ICI response (log HR −5.0; 95% CI −9.8 to −0.2). Intratumoral LAG-3⁺ immune cell populations warrant further study as a predictive biomarker of clinical benefit to ICIs. Differences in LAG-3⁺ lymphocyte populations across the intratumoral and peripheral compartments may provide complementary information that could inform the future development of multimodal composite biomarkers of ICI response. © 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":"349-360"},"PeriodicalIF":7.3,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10145534","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":"A new FGF15/19-mediated gut-to-heart axis controls cardiac hypertrophy","authors":"Samantha Morón-Ros,&nbsp;Albert Blasco-Roset,&nbsp;Artur Navarro-Gascon,&nbsp;Celia Rupérez,&nbsp;Monica Zamora,&nbsp;Fatima Crispi,&nbsp;Iker Uriarte,&nbsp;Maite G Fernández-Barrena,&nbsp;Matias Avila,&nbsp;Gemma Ferrer-Curriu,&nbsp;Josep Lupón,&nbsp;Antoni Bayés-Genis,&nbsp;Francesc Villarroya,&nbsp;Aleix Gavaldà-Navarro,&nbsp;Anna Planavila","doi":"10.1002/path.6193","DOIUrl":"10.1002/path.6193","url":null,"abstract":"<p>FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in <i>Fgf15</i>-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (<i>Nppa</i>) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in <i>Fgf15</i>-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy <i>in vivo</i>, without changes in <i>Nppa</i> and up-regulation of metabolic genes. Finally, <i>in vitro</i> studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 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":"335-348"},"PeriodicalIF":7.3,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10184663","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":"STING1 deficiency ameliorates immune-mediated crescentic glomerulonephritis in mice","authors":"Jorge García-Giménez,&nbsp;Gina Córdoba-David,&nbsp;Sandra Rayego-Mateos,&nbsp;Pablo Cannata-Ortiz,&nbsp;Susana Carrasco,&nbsp;Marta Ruiz-Ortega,&nbsp;Beatriz Fernandez-Fernandez,&nbsp;Alberto Ortiz,&nbsp;Adrián M Ramos","doi":"10.1002/path.6177","DOIUrl":"10.1002/path.6177","url":null,"abstract":"<p>Rapidly progressive/crescentic glomerulonephritis (RPGN/CGN) involves the formation of glomerular crescents by maladaptive differentiation of parietal epithelial cells that leads to rapid loss of renal function. The molecular mechanisms of crescent formation are poorly understood. Therefore, new insights into molecular mechanisms could identify alternative therapeutic targets for RPGN/CGN. Analysis of kidney biopsies from patients with RPGN revealed increased interstitial, glomerular, and tubular expression of STING1, an accessory protein of the c-GAS-dependent DNA-sensing pathway, which was also observed in murine nephrotoxic nephritis induced by an anti-GBM antibody. STING1 was expressed by key cell types involved in RPGN and crescent formation such as glomerular parietal epithelial cells, and tubular cells as well as by inflammation accessory cells. In functional <i>in vivo</i> studies, <i>Sting1</i>^{<i>−/−</i>} mice with nephrotoxic nephritis had lower kidney cytokine expression, milder kidney infiltration by innate and adaptive immune cells, and decreased disease severity. Pharmacological STING1 inhibition mirrored these findings. Direct STING1 agonism in parietal and tubular cells activated the NF-κB-dependent cytokine response and the interferon-induced genes (ISGs) program. These responses were also triggered in a STING1-dependent manner by the pro-inflammatory cytokine TWEAK. These results identify STING1 activation as a pathological mechanism in RPGN/CGN and TWEAK as an activator of STING1. Pharmacological strategies targeting STING1, or upstream regulators may therefore be potential alternatives to treat RPGN. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 3","pages":"309-322"},"PeriodicalIF":7.3,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10122632","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":"Genome-wide and panel-based cell-free DNA characterization of patients with resectable esophageal adenocarcinoma","authors":"Tom van den Ende,&nbsp;Ymke van der Pol,&nbsp;Aafke Creemers,&nbsp;Norbert Moldovan,&nbsp;Dries Boers,&nbsp;Mark I van Berge Henegouwen,&nbsp;Maarten CCM Hulshof,&nbsp;Saskia AGM Cillessen,&nbsp;Nicole CT van Grieken,&nbsp;D Michiel Pegtel,&nbsp;Sarah Derks,&nbsp;Maarten F Bijlsma,&nbsp;Florent Mouliere,&nbsp;Hanneke WM van Laarhoven","doi":"10.1002/path.6175","DOIUrl":"10.1002/path.6175","url":null,"abstract":"<p>Circulating tumor DNA (ctDNA) holds promise in resectable esophageal adenocarcinoma (EAC) to predict patient outcome but is not yet sensitive enough to be clinically applicable. Our aim was to combine ctDNA mutation data with shallow whole-genome sequencing (sWGS)-derived copy number tumor fraction estimates (ichorCNA) to improve pathological response and survival prediction in EAC. In total, 111 stage II/III EAC patients with baseline (<i>n</i> = 111), post-neoadjuvant chemoradiotherapy (nCRT) (<i>n</i> = 68), and pre-surgery (<i>n</i> = 92) plasma samples were used for ctDNA characterization. sWGS (&lt;5× coverage) was performed on all time-point samples, and copy number aberrations were estimated using ichorCNA. Baseline and pre-surgery samples were sequenced using a custom amplicon panel for mutation detection. Detection of baseline ctDNA was successful in 44.3% of patients by amplicon sequencing and 10.5% by ichorCNA. Combining both, ctDNA could be detected in 50.5% of patients. Baseline ctDNA positivity was related to higher T stage (cT3, 4) (<i>p</i> = 0.017). There was no relationship between pathological response and baseline ctDNA positivity. However, baseline ctDNA metrics (variant allele frequency &gt; 1% or ichorCNA &gt; 3%) were associated with a high risk of disease progression [HR = 2.23 (95% CI 1.22–4.07), <i>p</i> = 0.007]. The non-clearance of a baseline variant or ichorCNA &gt; 3% in pre-surgery samples was related to early progression [HR = 4.58 (95% CI 2.22–9.46), <i>p</i> &lt; 0.001]. Multi-signal analysis improves detection of ctDNA and can be used for prognostication of resectable EAC patients. Future studies should explore the potential of multi-modality sequencing for risk stratification and treatment adaptation based on ctDNA results. © 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":"286-297"},"PeriodicalIF":7.3,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10116451","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":"Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer","authors":"Jeppe Thagaard,&nbsp;Glenn Broeckx,&nbsp;David B Page,&nbsp;Chowdhury Arif Jahangir,&nbsp;Sara Verbandt,&nbsp;Zuzana Kos,&nbsp;Rajarsi Gupta,&nbsp;Reena Khiroya,&nbsp;Khalid Abduljabbar,&nbsp;Gabriela Acosta Haab,&nbsp;Balazs Acs,&nbsp;Guray Akturk,&nbsp;Jonas S Almeida,&nbsp;Isabel Alvarado-Cabrero,&nbsp;Mohamed Amgad,&nbsp;Farid Azmoudeh-Ardalan,&nbsp;Sunil Badve,&nbsp;Nurkhairul Bariyah Baharun,&nbsp;Eva Balslev,&nbsp;Enrique R Bellolio,&nbsp;Vydehi Bheemaraju,&nbsp;Kim RM Blenman,&nbsp;Luciana Botinelly Mendonça Fujimoto,&nbsp;Najat Bouchmaa,&nbsp;Octavio Burgues,&nbsp;Alexandros Chardas,&nbsp;Maggie Chon U Cheang,&nbsp;Francesco Ciompi,&nbsp;Lee AD Cooper,&nbsp;An Coosemans,&nbsp;Germán Corredor,&nbsp;Anders B Dahl,&nbsp;Flavio Luis Dantas Portela,&nbsp;Frederik Deman,&nbsp;Sandra Demaria,&nbsp;Johan Doré Hansen,&nbsp;Sarah N Dudgeon,&nbsp;Thomas Ebstrup,&nbsp;Mahmoud Elghazawy,&nbsp;Claudio Fernandez-Martín,&nbsp;Stephen B Fox,&nbsp;William M Gallagher,&nbsp;Jennifer M Giltnane,&nbsp;Sacha Gnjatic,&nbsp;Paula I Gonzalez-Ericsson,&nbsp;Anita Grigoriadis,&nbsp;Niels Halama,&nbsp;Matthew G Hanna,&nbsp;Aparna Harbhajanka,&nbsp;Steven N Hart,&nbsp;Johan Hartman,&nbsp;Søren Hauberg,&nbsp;Stephen Hewitt,&nbsp;Akira I Hida,&nbsp;Hugo M Horlings,&nbsp;Zaheed Husain,&nbsp;Evangelos Hytopoulos,&nbsp;Sheeba Irshad,&nbsp;Emiel AM Janssen,&nbsp;Mohamed Kahila,&nbsp;Tatsuki R Kataoka,&nbsp;Kosuke Kawaguchi,&nbsp;Durga Kharidehal,&nbsp;Andrey I Khramtsov,&nbsp;Umay Kiraz,&nbsp;Pawan Kirtani,&nbsp;Liudmila L Kodach,&nbsp;Konstanty Korski,&nbsp;Anikó Kovács,&nbsp;Anne-Vibeke Laenkholm,&nbsp;Corinna Lang-Schwarz,&nbsp;Denis Larsimont,&nbsp;Jochen K Lennerz,&nbsp;Marvin Lerousseau,&nbsp;Xiaoxian Li,&nbsp;Amy Ly,&nbsp;Anant Madabhushi,&nbsp;Sai K Maley,&nbsp;Vidya Manur Narasimhamurthy,&nbsp;Douglas K Marks,&nbsp;Elizabeth S McDonald,&nbsp;Ravi Mehrotra,&nbsp;Stefan Michiels,&nbsp;Fayyaz ul Amir Afsar Minhas,&nbsp;Shachi Mittal,&nbsp;David A Moore,&nbsp;Shamim Mushtaq,&nbsp;Hussain Nighat,&nbsp;Thomas Papathomas,&nbsp;Frederique Penault-Llorca,&nbsp;Rashindrie D Perera,&nbsp;Christopher J Pinard,&nbsp;Juan Carlos Pinto-Cardenas,&nbsp;Giancarlo Pruneri,&nbsp;Lajos Pusztai,&nbsp;Arman Rahman,&nbsp;Nasir Mahmood Rajpoot,&nbsp;Bernardo Leon Rapoport,&nbsp;Tilman T Rau,&nbsp;Jorge S Reis-Filho,&nbsp;Joana M Ribeiro,&nbsp;David Rimm,&nbsp;Anne Roslind,&nbsp;Anne Vincent-Salomon,&nbsp;Manuel Salto-Tellez,&nbsp;Joel Saltz,&nbsp;Shahin Sayed,&nbsp;Ely Scott,&nbsp;Kalliopi P Siziopikou,&nbsp;Christos Sotiriou,&nbsp;Albrecht Stenzinger,&nbsp;Maher A Sughayer,&nbsp;Daniel Sur,&nbsp;Susan Fineberg,&nbsp;Fraser Symmans,&nbsp;Sunao Tanaka,&nbsp;Timothy Taxter,&nbsp;Sabine Tejpar,&nbsp;Jonas Teuwen,&nbsp;E Aubrey Thompson,&nbsp;Trine Tramm,&nbsp;William T Tran,&nbsp;Jeroen van der Laak,&nbsp;Paul J van Diest,&nbsp;Gregory E Verghese,&nbsp;Giuseppe Viale,&nbsp;Michael Vieth,&nbsp;Noorul Wahab,&nbsp;Thomas Walter,&nbsp;Yannick Waumans,&nbsp;Hannah Y Wen,&nbsp;Wentao Yang,&nbsp;Yinyin Yuan,&nbsp;Reena Md Zin,&nbsp;Sylvia Adams,&nbsp;John Bartlett,&nbsp;Sibylle Loibl,&nbsp;Carsten Denkert,&nbsp;Peter Savas,&nbsp;Sherene Loi,&nbsp;Roberto Salgado,&nbsp;Elisabeth Specht Stovgaard","doi":"10.1002/path.6155","DOIUrl":"10.1002/path.6155","url":null,"abstract":"<p>The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 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":"498-513"},"PeriodicalIF":7.3,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5770540","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":"Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer","authors":"David B Page,&nbsp;Glenn Broeckx,&nbsp;Chowdhury Arif Jahangir,&nbsp;Sara Verbandt,&nbsp;Rajarsi R Gupta,&nbsp;Jeppe Thagaard,&nbsp;Reena Khiroya,&nbsp;Zuzana Kos,&nbsp;Khalid Abduljabbar,&nbsp;Gabriela Acosta Haab,&nbsp;Balazs Acs,&nbsp;Guray Akturk,&nbsp;Jonas S Almeida,&nbsp;Isabel Alvarado-Cabrero,&nbsp;Farid Azmoudeh-Ardalan,&nbsp;Sunil Badve,&nbsp;Nurkhairul Bariyah Baharun,&nbsp;Enrique R Bellolio,&nbsp;Vydehi Bheemaraju,&nbsp;Kim RM Blenman,&nbsp;Luciana Botinelly Mendonça Fujimoto,&nbsp;Najat Bouchmaa,&nbsp;Octavio Burgues,&nbsp;Maggie Chon U Cheang,&nbsp;Francesco Ciompi,&nbsp;Lee AD Cooper,&nbsp;An Coosemans,&nbsp;Germán Corredor,&nbsp;Flavio Luis Dantas Portela,&nbsp;Frederik Deman,&nbsp;Sandra Demaria,&nbsp;Sarah N Dudgeon,&nbsp;Mahmoud Elghazawy,&nbsp;Scott Ely,&nbsp;Claudio Fernandez-Martín,&nbsp;Susan Fineberg,&nbsp;Stephen B Fox,&nbsp;William M Gallagher,&nbsp;Jennifer M Giltnane,&nbsp;Sacha Gnjatic,&nbsp;Paula I Gonzalez-Ericsson,&nbsp;Anita Grigoriadis,&nbsp;Niels Halama,&nbsp;Matthew G Hanna,&nbsp;Aparna Harbhajanka,&nbsp;Alexandros Hardas,&nbsp;Steven N Hart,&nbsp;Johan Hartman,&nbsp;Stephen Hewitt,&nbsp;Akira I Hida,&nbsp;Hugo M Horlings,&nbsp;Zaheed Husain,&nbsp;Evangelos Hytopoulos,&nbsp;Sheeba Irshad,&nbsp;Emiel AM Janssen,&nbsp;Mohamed Kahila,&nbsp;Tatsuki R Kataoka,&nbsp;Kosuke Kawaguchi,&nbsp;Durga Kharidehal,&nbsp;Andrey I Khramtsov,&nbsp;Umay Kiraz,&nbsp;Pawan Kirtani,&nbsp;Liudmila L Kodach,&nbsp;Konstanty Korski,&nbsp;Anikó Kovács,&nbsp;Anne-Vibeke Laenkholm,&nbsp;Corinna Lang-Schwarz,&nbsp;Denis Larsimont,&nbsp;Jochen K Lennerz,&nbsp;Marvin Lerousseau,&nbsp;Xiaoxian Li,&nbsp;Amy Ly,&nbsp;Anant Madabhushi,&nbsp;Sai K Maley,&nbsp;Vidya Manur Narasimhamurthy,&nbsp;Douglas K Marks,&nbsp;Elizabeth S McDonald,&nbsp;Ravi Mehrotra,&nbsp;Stefan Michiels,&nbsp;Fayyaz ul Amir Afsar Minhas,&nbsp;Shachi Mittal,&nbsp;David A Moore,&nbsp;Shamim Mushtaq,&nbsp;Hussain Nighat,&nbsp;Thomas Papathomas,&nbsp;Frederique Penault-Llorca,&nbsp;Rashindrie D Perera,&nbsp;Christopher J Pinard,&nbsp;Juan Carlos Pinto-Cardenas,&nbsp;Giancarlo Pruneri,&nbsp;Lajos Pusztai,&nbsp;Arman Rahman,&nbsp;Nasir Mahmood Rajpoot,&nbsp;Bernardo Leon Rapoport,&nbsp;Tilman T Rau,&nbsp;Jorge S Reis-Filho,&nbsp;Joana M Ribeiro,&nbsp;David Rimm,&nbsp;Anne Vincent-Salomon,&nbsp;Manuel Salto-Tellez,&nbsp;Joel Saltz,&nbsp;Shahin Sayed,&nbsp;Kalliopi P Siziopikou,&nbsp;Christos Sotiriou,&nbsp;Albrecht Stenzinger,&nbsp;Maher A Sughayer,&nbsp;Daniel Sur,&nbsp;Fraser Symmans,&nbsp;Sunao Tanaka,&nbsp;Timothy Taxter,&nbsp;Sabine Tejpar,&nbsp;Jonas Teuwen,&nbsp;E Aubrey Thompson,&nbsp;Trine Tramm,&nbsp;William T Tran,&nbsp;Jeroen van der Laak,&nbsp;Paul J van Diest,&nbsp;Gregory E Verghese,&nbsp;Giuseppe Viale,&nbsp;Michael Vieth,&nbsp;Noorul Wahab,&nbsp;Thomas Walter,&nbsp;Yannick Waumans,&nbsp;Hannah Y Wen,&nbsp;Wentao Yang,&nbsp;Yinyin Yuan,&nbsp;Sylvia Adams,&nbsp;John Mark Seaverns Bartlett,&nbsp;Sibylle Loibl,&nbsp;Carsten Denkert,&nbsp;Peter Savas,&nbsp;Sherene Loi,&nbsp;Roberto Salgado,&nbsp;Elisabeth Specht Stovgaard","doi":"10.1002/path.6165","DOIUrl":"10.1002/path.6165","url":null,"abstract":"<p>Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 5","pages":"514-532"},"PeriodicalIF":7.3,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5783472","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":"C/EBPβ isoform-specific regulation of podocyte pyroptosis in lupus nephritis-induced renal injury","authors":"Huimei Zou,&nbsp;Min Chen,&nbsp;Xiuhong Wang,&nbsp;Jie Yu,&nbsp;Xiaoying Li,&nbsp;Ying Xie,&nbsp;Jun Liu,&nbsp;Miao Liu,&nbsp;Lifen Xu,&nbsp;Qiong Zhang,&nbsp;Xiaoxue Tian,&nbsp;Fan Zhang,&nbsp;Bing Guo","doi":"10.1002/path.6174","DOIUrl":"10.1002/path.6174","url":null,"abstract":"<p>As an essential factor in the prognosis of systemic lupus erythematosus (SLE), lupus nephritis (LN) can accelerate the rate at which patients with SLE can transition to chronic kidney disease or even end-stage renal disease. Podocytes now appear to be a possible direct target in LN in addition to being prone to collateral damage from glomerular capillary lesions induces by immune complexes and inflammatory processes. The NLRP3 inflammasome is regulated by CCAAT/enhancer-binding protein β (C/EBPβ), which is involved in the pathogenesis of SLE. However, the role and mechanism of C/EBPβ in LN remain unclear. In this investigation, glomerular podocytes treated with LN serum and MRL/lpr mice were employed as <i>in vivo</i> and <i>in vitro</i> models of LN, respectively. <i>In vivo</i>, the expression of C/EBPβ isoforms was detected in kidney specimens of humans and mice with LN. Then we assessed the effect of C/EBPβ inhibition on renal structure and function by injecting RNAi adeno-associated virus of C/EBPβ shRNA into MRL/lpr mice. <i>In vitro</i>, glomerular podocytes were treated with LN serum and C/EBPβ siRNA to explore the role of C/EBPβ in the activation of the AIM2 inflammasome and podocyte injury. C/EBPβ-LAP and C/EBPβ-LIP were significantly overexpressed in kidney tissue samples from LN patients and mice, and C/EBPβ inhibition significantly alleviated renal function damage and ameliorated renal structural deficiencies. Inflammatory pathways downstream from the AIM2 inflammasome could be suppressed by C/EBPβ knockdown. Furthermore, the upregulation of C/EBPβ-LAP could activate the AIM2 inflammasome and podocyte pyroptosis by binding to the promoters of <i>AIM2</i> and <i>CASPASE1</i> to enhance their expression, and the knockdown of AIM2 or (and) caspase-1 reversed the effects of C/EBPβ-LAP overexpression. Interestingly, C/EBPβ-LIP overexpression could transcriptionally inhibit IRAG and promote Ca²⁺ release-mediated activation of the AIM2 inflammasome. This finding suggests that C/EBPβ is not only involved in the regulation of the expression of key proteins of the AIM2 inflammasome but also affects the polymerization of key proteins of the AIM2 inflammasome through the regulation of Ca²⁺ release. In conclusion, this study provides a new idea for studying the regulatory mechanism of C/EBPβ and provides a theoretical basis for the early diagnosis and treatment of LN in the future. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 3","pages":"269-285"},"PeriodicalIF":7.3,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10406816","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}