The Journal of Pathology最新文献

{"title":"Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury","authors":"Jonay Poveda,&nbsp;Laura González-Lafuente,&nbsp;Sara Vázquez-Sánchez,&nbsp;Elisa Mercado-García,&nbsp;Elena Rodríguez-Sánchez,&nbsp;Inés García-Consuegra,&nbsp;Ana Belén Sanz,&nbsp;Julián Segura,&nbsp;María Fernández-Velasco,&nbsp;Fernando Liaño,&nbsp;Luis M Ruilope,&nbsp;Gema Ruiz-Hurtado","doi":"10.1002/path.6200","DOIUrl":"10.1002/path.6200","url":null,"abstract":"<p>Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca²⁺) handling alterations. Next, we investigated the role of the TWEAK–Fn14 axis in cardiomyocyte function following renal ischaemia–reperfusion (I/R) injury in mice. We observed that TWEAK–Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca²⁺ handling and arrhythmogenic Ca²⁺ events through an impairment in sarcoplasmic reticulum Ca²⁺-adenosine triphosphatase 2a pump (SERCA_2a) and ryanodine receptor (RyR₂) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca²⁺ cycling and arrhythmogenic events and prevented SERCA_2a and RyR₂ modifications. In conclusion, this study establishes the relevance of the TWEAK–Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca²⁺ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3. © 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 4","pages":"427-441"},"PeriodicalIF":7.3,"publicationDate":"2023-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093053","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":"Hedgehog signalling in Foxd1+ embryonic kidney stromal progenitors controls nephron formation via Cxcl12 and Wnt5a","authors":"Robert D'Cruz,&nbsp;Yun-Kyo Kim,&nbsp;Jaap Mulder,&nbsp;Neke Ibeh,&nbsp;Nan Jiang,&nbsp;Yilin Tian,&nbsp;Norman D Rosenblum","doi":"10.1002/path.6195","DOIUrl":"10.1002/path.6195","url":null,"abstract":"<p>Congenital anomalies of the kidney and urinary tract (CAKUT) are characterised by a spectrum of structural and histologic abnormalities and are the major cause of childhood kidney failure. During kidney morphogenesis, the formation of a critical number of nephrons is an embryonic process supported, in part, by signalling between nephrogenic precursors and <i>Foxd1</i>-positive stromal progenitor cells. Low nephron number and abnormal patterning of the stroma are signature pathological features among CAKUT phenotypes with decreased kidney function. Despite their critical contribution to CAKUT pathogenesis, the mechanisms that underlie a low nephron number and the functional contribution of a disorganised renal stroma to nephron number are both poorly defined. Here, we identify a primary pathogenic role for increased Hedgehog signalling in embryonic renal stroma in the genesis of congenital low nephron number. Pharmacologic activation of Hedgehog (Hh) signalling in human kidney organoid tissue decreased the number of nephrons and generated excess stroma. The mechanisms underlying these pathogenic effects were delineated in genetic mouse models in which Hh signalling was constitutively activated in a cell lineage-specific manner. Cre-mediated excision of <i>Ptch1</i> in <i>Foxd1</i>+ stromal progenitor cells, but not in <i>Six2</i>+ nephrogenic precursor cells, generated kidney malformation, identifying the stroma as a driver of low nephron number. Single-cell RNA sequencing analysis identified <i>Cxcl12</i> and <i>Wnt5a</i> as downstream targets of increased stromal Hh signalling, findings supported by analysis in human kidney organoids. <i>In vivo</i> deficiency of <i>Cxcl12</i> or <i>Wnt5a</i> in mice with increased stromal Hh signalling improved nephron endowment. These results demonstrate that dysregulated Hh signalling in embryonic renal stromal cells inhibits nephron formation in a manner dependent on <i>Cxcl12</i> and <i>Wnt5a</i>. © 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 4","pages":"385-400"},"PeriodicalIF":7.3,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41098013","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":"Conditional loss of Ube3d in the retinal pigment epithelium accelerates age-associated alterations in the retina of mice","authors":"Tianchang Tao,&nbsp;Ningda Xu,&nbsp;Jiarui Li,&nbsp;Mingwei Zhao,&nbsp;Xiaoxin Li,&nbsp;Lvzhen Huang","doi":"10.1002/path.6201","DOIUrl":"10.1002/path.6201","url":null,"abstract":"<p>Several studies have suggested a correlation between the ubiquitin-proteasome system (UPS) and age-related macular degeneration (AMD), with its phenotypic severity ranging from mild visual impairment to blindness, but the mechanism for UPS dysfunction contributing to disease progression is unclear. In this study, we investigated the role of ubiquitin protein ligase E3D (UBE3D) in aging and degeneration in mouse retina. Conditional knockout of <i>Ube3d</i> in the retinal pigment epithelium (RPE) of mice led to progressive and irregular fundus lesions, attenuation of the retinal vascular system, and age-associated deterioration of rod and cone responses. Simultaneously, RPE-specific <i>Ube3d</i> knockout mice also presented morphological changes similar to the histopathological characteristics of human AMD, in which a defective UPS led to RPE abnormalities such as phagocytosis or degradation of metabolites, the interaction with photoreceptor outer segment, and the transport of nutrients or waste products with choroidal capillaries via Bruch's membrane. Moreover, conditional loss of <i>Ube3d</i> resulted in aberrant molecular characterizations associated with the autophagy–lysosomal pathway, oxidative stress damage, and cell-cycle regulation, which are implicated in AMD pathology. Thus, our findings strengthen and expand the impact of UPS dysfunction on retinal pathophysiology during aging, indicating that genetic <i>Ube3d</i> deficiency in the RPE could lead to the abnormal formation of pigment deposits and secondary fundus alterations. © 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 4","pages":"442-454"},"PeriodicalIF":7.3,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41094951","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":"Hourglass, a rapid analysis framework for heterogeneous bioimaging data, identifies sex disparity in IL-6/STAT3-associated immune phenotypes in pancreatic cancer","authors":"Kazeera Aliar,&nbsp;Henry R Waterhouse,&nbsp;Foram Vyas,&nbsp;Niklas Krebs,&nbsp;Bowen Zhang,&nbsp;Emily Poulton,&nbsp;Nathan Chan,&nbsp;Ricardo Gonzalez,&nbsp;Gun Ho Jang,&nbsp;Peter Bronsert,&nbsp;Sandra E Fischer,&nbsp;Steven Gallinger,&nbsp;Barbara T Grünwald,&nbsp;Rama Khokha","doi":"10.1002/path.6199","DOIUrl":"10.1002/path.6199","url":null,"abstract":"<p>Integration and mining of bioimaging data remains a challenge and lags behind the rapidly expanding digital pathology field. We introduce Hourglass, an open-access analytical framework that streamlines biology-driven visualization, interrogation, and statistical assessment of multiparametric datasets. Cognizant of tissue and clinical heterogeneity, Hourglass systematically organizes observations across spatial and global levels and within patient subgroups. Applied to an extensive bioimaging dataset, Hourglass promptly consolidated a breadth of known interleukin-6 (IL-6) functions via its downstream effector STAT3 and uncovered a so-far unknown sexual dimorphism in the IL-6/STAT3-linked intratumoral T-cell response in human pancreatic cancer. As an R package and cross-platform application, Hourglass facilitates knowledge extraction from multi-layered bioimaging datasets for users with or without computational proficiency and provides unique and widely accessible analytical means to harness insights hidden within heterogeneous tissues at the sample and patient level. © 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 4","pages":"413-426"},"PeriodicalIF":7.3,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41090589","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":"‘Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants’","authors":"","doi":"10.1002/path.6215","DOIUrl":"10.1002/path.6215","url":null,"abstract":"<p>By Alberto Valenzuela-Palomo, Elena Bueno-Martínez, Lara Sanoguera-Miralles, Víctor Lorca, Eugenia Fraile-Bethencourt, Ada Esteban-Sánchez, Susana Gómez-Barrero, Sara Carvalho, Jamie Allen, Alicia García-Álvarez, Pedro Pérez-Segura, Leila Dorling, Douglas F Easton, Peter Devilee, Maaike PG Vreeswijk, Miguel de la Hoya^† and Eladio A Velasco^†, <i>J Pathol</i> 2022; <b>256:</b> 321–334. https://doi.org/10.1002/path.5839. ^†Senior authors.</p><p>The senior authors of this article, first published on 30 November 2021 in Wiley Online Library (wileyonlinelibrary.com), have informed the editors of an unintentional mistake that they wish to correct, and they explain why below.</p><p>In our manuscript, we described minigene splicing read-outs for 42 <i>PALB2</i> variants. Two of them, c.1685-2A&gt;C and c.1685-2A&gt;G (acceptor site of exon 5), displayed a complex pattern of five anomalous transcripts: ∆(E5p139), ∆(E5p5), ▼(E5p88), ∆(E5p10) and ∆(E5p97) (Table 1 and Figure 2B of the original manuscript).</p><p>Therefore, Δ(E5p510) represents roughly 18% and 25% of the overall minigene expression of c.1685-2A&gt;C and c.1685-2A&gt;G, respectively.</p><p>In the light of our new data, we re-evaluated the ACMG-AMP point-based system classification of both variants.</p><p>Since all the initially minigene-detected transcripts were PTC_NMD (∆(E5p139), ▼(E5p88), ∆(E5p10), ∆(E5p97) and ∆(E5p5)), we had previously assigned PS3_VS (+8) to both variants (supplementary material, Table S2, and Table 2). Yet, ∆(E5p510) makes a substantial contribution to the overall expression. Moreover, this transcript encodes for an in-frame protein deletion, p.(Lys563_Gly732del), which removes &gt;10% of the protein sequence but does not target known critical PALB2 domains, so that ∆(E5p510) finally qualifies for a PS3 code.</p><p><b>Figure C1.</b> Fluorescent fragment analysis of the wild type minigene mgPALB2_ex4-6 and variants c.1685-2A&gt;C and c.1685-2A&gt;G. FAM-labeled products (blue peaks) were run with LIZ-1200 (orange peaks) as size standards. The <i>x</i>-axis indicates size in bp (electropherogram on the top) and the <i>y</i>-axis represents relative fluorescence units (RFU). FL, minigene full-length transcript. As indicated in Materials and methods, cDNA was amplified with primers RTPB2_EX4-FW (5’-CACAAATATCAGCACGAAAA-3’) and FAM-RTPB2_EX6-RV (full-length size: 918 nt).</p><p>The authors apologise for any inconvenience this mistake may have caused.</p><p>The editors apologise for the time taken to process the request for this corrigendum and approve it.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 3","pages":"372-373"},"PeriodicalIF":7.3,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6215","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41145946","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":"Canonical Kaiso target genes define a functional signature that associates with breast cancer survival and the invasive lobular carcinoma histological type","authors":"Thijmen Sijnesael,&nbsp;François Richard,&nbsp;Max AK Rätze,&nbsp;Thijs Koorman,&nbsp;Blessing Bassey-Archibong,&nbsp;Christa Rohof,&nbsp;Juliet Daniel,&nbsp;Christine Desmedt,&nbsp;Patrick WB Derksen","doi":"10.1002/path.6205","DOIUrl":"10.1002/path.6205","url":null,"abstract":"<p>Invasive lobular carcinoma (ILC) is a low- to intermediate-grade histological breast cancer type caused by mutational inactivation of E-cadherin function, resulting in the acquisition of anchorage independence (anoikis resistance). Most ILC cases express estrogen receptors, but options are limited in relapsed endocrine-refractory disease as ILC tends to be less responsive to standard chemotherapy. Moreover, ILC can relapse after &gt;15 years, an event that currently cannot be predicted. E-cadherin inactivation leads to p120-catenin-dependent relief of the transcriptional repressor Kaiso (ZBTB33) and activation of canonical Kaiso target genes. Here, we examined whether an anchorage-independent and ILC-specific transcriptional program correlated with clinical parameters in breast cancer. Based on the presence of a canonical Kaiso-binding consensus sequence (cKBS) in the promoters of genes that are upregulated under anchorage-independent conditions, we defined an ILC-specific anoikis resistance transcriptome (ART). Converting the ART genes into human orthologs and adding published Kaiso target genes resulted in the Kaiso-specific ART (KART) 33-gene signature, used subsequently to study correlations with histological and clinical variables in primary breast cancer. Using publicly available data for ER^POSHer2^NEG breast cancer, we found that expression of KART was positively associated with the histological ILC breast cancer type (<i>p</i> &lt; 2.7E-07). KART expression associated with younger patients in all invasive breast cancers and smaller tumors in invasive ductal carcinoma of no special type (IDC-NST) (&lt;2 cm, <i>p</i> &lt; 6.3E-10). We observed associations with favorable long-term prognosis in both ILC (hazard ratio [HR] = 0.51, 95% CI = 0.29–0.91, <i>p</i> &lt; 3.4E-02) and IDC-NST (HR = 0.79, 95% CI = 0.66–0.93, <i>p</i> &lt; 1.2E-04). Our analysis thus defines a new mRNA expression signature for human breast cancer based on canonical Kaiso target genes that are upregulated in E-cadherin deficient ILC. The KART signature may enable a deeper understanding of ILC biology and etiology. © 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 4","pages":"477-489"},"PeriodicalIF":7.3,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093950","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":"Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration","authors":"Mohamed Elnagdy,&nbsp;Yali Wang,&nbsp;Walter Rodriguez,&nbsp;JingWen Zhang,&nbsp;Philip Bauer,&nbsp;Daniel W Wilkey,&nbsp;Michael Merchant,&nbsp;Jianmin Pan,&nbsp;Zainab Farooqui,&nbsp;Robert Cannon,&nbsp;Shesh Rai,&nbsp;Claudio Maldonado,&nbsp;Shirish Barve,&nbsp;Craig J McClain,&nbsp;Leila Gobejishvili","doi":"10.1002/path.6194","DOIUrl":"10.1002/path.6194","url":null,"abstract":"<p>Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho-specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho-associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization. GEF exchange protein directly activated by cAMP 1 (EPAC1) has been implicated in modulating TGFβ1 and Rho signaling; however, its role in HSC migration has never been examined. The aim of this study was to evaluate the role of cAMP-degrading phosphodiesterase 4 (PDE4) enzymes in regulating EPAC1 signaling, HSC migration, and fibrogenesis. We show that PDE4 protein expression is increased in activated HSCs expressing alpha smooth muscle actin and active myosin light chain (MLC) in fibrotic tissues of human nonalcoholic steatohepatitis cirrhosis livers and mouse livers exposed to carbon tetrachloride. In human livers, TGFβ1 levels were highly correlated with PDE4 expression. TGFβ1 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC-specific agonist decreased TGFβ1-mediated cell migration <i>in vitro</i>. <i>In vivo</i>, targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis-related genes, and HSC activation. Proteomic analysis of mouse liver tissues identified the regulation of actin cytoskeleton by the kinase effectors of Rho GTPases as a major pathway impacted by rolipram. Western blot analyses confirmed that PDE4 inhibition decreased active MLC and endothelin 1 levels, key proteins involved in cytoskeleton remodeling and contractility. The current study, for the first time, demonstrates that PDE4 enzymes are expressed in hepatic myofibroblasts and promote cytoskeleton remodeling and HSC migration. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 3","pages":"361-371"},"PeriodicalIF":7.3,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41145942","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":"The collagen landscape in cancer: profiling collagens in tumors and in circulation reveals novel markers of cancer-associated fibroblast subtypes","authors":"Jeppe Thorlacius-Ussing,&nbsp;Christina Jensen,&nbsp;Neel I Nissen,&nbsp;Thomas R Cox,&nbsp;Raghu Kalluri,&nbsp;Morten Karsdal,&nbsp;Nicholas Willumsen","doi":"10.1002/path.6207","DOIUrl":"10.1002/path.6207","url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs) deposit and remodel collagens in the tumor stroma, impacting cancer progression and efficacy of interventions. CAFs are the focus of new therapeutics with the aim of normalizing the tumor microenvironment. To do this, a better understanding of CAF heterogeneity and collagen composition in cancer is needed. In this study, we sought to profile the expression of collagens at multiple levels with the goal of identifying cancer biomarkers. We investigated the collagen expression pattern in various cell types and CAF subtypes in a publicly available single-cell RNA sequencing (RNA-seq) dataset of pancreatic ductal adenocarcinoma. Next, we investigated the collagen expression profile in tumor samples across cancer types from The Cancer Genome Atlas (TCGA) database and evaluated if specific patterns of collagen expression were associated with prognosis. Finally, we profiled circulating collagen peptides using a panel of immunoassays to measure collagen fragments in the serum of cancer patients. We found that pancreatic stellate cells and fibroblasts were the primary producers of collagens in the pancreas. <i>COL1A1</i>, <i>COL3A1</i>, <i>COL5A1</i>, <i>COL6A1</i> were expressed in all CAF subtypes, whereas <i>COL8A1</i>, <i>COL10A1</i>, <i>COL11A1</i>, <i>COL12A1</i> were specific to myofibroblast CAFs (myCAF) and <i>COL14A1</i> specific to inflammatory CAFs (iCAF). In TCGA database, myCAF collagens <i>COL10A1</i> and <i>COL11A1</i> were elevated across solid tumor types, and multiple associations between high expression and worse survival were found. Finally, circulating collagen biomarkers were elevated in the serum of patients with cancer relative to healthy controls with COL11A1 (myCAF) having the best diagnostic accuracy of the markers measured. In conclusion, CAFs express a noncanonical collagen profile with specific collagen subtypes associated with iCAFs and myCAFs in PDAC. These collagens are deregulated at the cellular, tumor, and systemic levels across different solid tumors and associate with survival. These findings could lead to new discoveries such as novel biomarkers and therapeutic targets. © 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":"262 1","pages":"22-36"},"PeriodicalIF":7.3,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6207","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41096701","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":"Reducing the risks of nuclear war – the role of health professionals","authors":"Kamran Abbasi,&nbsp;Parveen Ali,&nbsp;Virginia Barbour,&nbsp;Kirsten Bibbins-Domingo,&nbsp;Marcel GM Olde Rikkert,&nbsp;Andy Haines,&nbsp;Ira Helfand,&nbsp;Richard Horton,&nbsp;Bob Mash,&nbsp;Arun Mitra,&nbsp;Carlos Monteiro,&nbsp;Elena N Naumova,&nbsp;Eric J Rubin,&nbsp;Tilman Ruff,&nbsp;Peush Sahni,&nbsp;James Tumwine,&nbsp;Paul Yonga,&nbsp;Chris Zielinski","doi":"10.1002/path.6203","DOIUrl":"10.1002/path.6203","url":null,"abstract":"&lt;p&gt;In January 2023, the Science and Security Board of the Bulletin of Atomic Scientists moved the hands of the Doomsday Clock forward to 90 s before midnight, reflecting the growing risk of nuclear war [&lt;span&gt;1&lt;/span&gt;]. In August 2022, UN Secretary-General António Guterres warned that the world is now in ‘a time of nuclear danger not seen since the height of the Cold War’ [&lt;span&gt;2&lt;/span&gt;]. The danger has been underlined by growing tensions between many nuclear-armed states [&lt;span&gt;1, 3&lt;/span&gt;]. As editors of health and medical journals worldwide, we call on health professionals to alert the public and our leaders to this major danger to public health and the essential life support systems of the planet, and we urge action to prevent it.&lt;/p&gt;&lt;p&gt;Current nuclear arms control and non-proliferation efforts are inadequate to protect the world's population against the threat of nuclear war by design, error or miscalculation. The Treaty on the Non-Proliferation of Nuclear Weapons (NPT) commits each of the 190 participating nations to pursue negotiations in good faith on effective measures relating to the cessation of the nuclear arms race at an early date and to nuclear disarmament and on a treaty on general and complete disarmament under strict and effective international control [&lt;span&gt;4&lt;/span&gt;]. Progress has been disappointingly slow, and the most recent NPT review conference in 2022 ended without an agreed statement [&lt;span&gt;5&lt;/span&gt;]. Many examples of near disasters have exposed the risks of depending on nuclear deterrence for the indefinite future [&lt;span&gt;6&lt;/span&gt;]. Modernisation of nuclear arsenals could increase risks: for example, hypersonic missiles decrease the time available to distinguish between an attack and a false alarm, increasing the likelihood of rapid escalation.&lt;/p&gt;&lt;p&gt;Any use of nuclear weapons would be catastrophic for humanity. Even a ‘limited’ nuclear war involving only 250 of the 13,000 nuclear weapons in the world could kill 120 million people outright and cause global climate disruption leading to a nuclear famine, putting two billion people at risk [&lt;span&gt;7, 8&lt;/span&gt;]. A large-scale nuclear war between the USA and Russia could kill 200 million people or more in the near term and potentially cause a global ‘nuclear winter’ that could kill five to six billion people, threatening the survival of humanity [&lt;span&gt;7, 8&lt;/span&gt;]. Once a nuclear weapon is detonated, escalation to all-out nuclear war could occur rapidly. The prevention of any use of nuclear weapons is therefore an urgent public health priority, and fundamental steps must also be taken to address the root cause of the problem – by abolishing nuclear weapons.&lt;/p&gt;&lt;p&gt;The health community has played a crucial role in efforts to reduce the risk of nuclear war and must continue to do so in the future [&lt;span&gt;9&lt;/span&gt;]. In the 1980s, the efforts of health professionals, led by International Physicians for the Prevention of Nuclear War (IPPNW), helped to end the Cold War arms race by","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 3","pages":"253-255"},"PeriodicalIF":7.3,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093398","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":"Single-cell profiling identifies distinct hormonal, immunologic, and inflammatory signatures of endometriosis-constituting cells","authors":"Sun Shin,&nbsp;Youn-Jee Chung,&nbsp;Seong Won Moon,&nbsp;Eun Ji Choi,&nbsp;Mee-Ran Kim,&nbsp;Yeun-Jun Chung,&nbsp;Sug Hyung Lee","doi":"10.1002/path.6178","DOIUrl":"10.1002/path.6178","url":null,"abstract":"<p>Endometriosis consists of ectopic endometrial epithelial cells (EEECs) and ectopic endometrial stromal cells (EESCs) mixed with heterogeneous stromal cells. To address how endometriosis-constituting cells are different from normal endometrium and among endometriosis subtypes and how their molecular signatures are related to phenotypic manifestations, we analyzed ovarian endometrial cyst (OEC), superficial peritoneal endometriosis (SPE), and deep infiltrating endometriosis (DIE) from 12 patients using single-cell RNA-sequencing (scRNA-seq). We identified 11 cell clusters, including EEEC, EESC, fibroblasts, inflammatory/immune, endothelial, mesothelial, and Schwann cells. For hormonal signatures, EESCs, but not EEECs, showed high estrogen signatures (estrogen response scores and <i>HOXA</i> downregulation) and low progesterone signatures (<i>DKK1</i> downregulation) compared to normal endometrium. In EEECs, we found <i>MUC5B</i>⁺ <i>TFF3</i>^<i>low</i> cells enriched in endometriosis. In lymphoid cells, evidence for both immune activation (high cytotoxicity in NK) and exhaustion (high checkpoint genes in NKT and cytotoxic T) was identified in endometriosis. Signatures and subpopulations of macrophages were remarkably different among endometriosis subtypes with increased monocyte-derived macrophages and <i>IL1B</i> expression in DIE. The scRNA-seq predicted <i>NRG1</i> (macrophage)-<i>ERBB3</i> (Schwann cell) interaction in endometriosis, expressions of which were validated by immunohistochemistry. Myofibroblast subpopulations differed according to the location (OECs from fibroblasts and SPE/DIEs from mesothelial cells and fibroblasts). Endometriosis endothelial cells displayed proinflammation, angiogenesis, and leaky permeability signatures that were enhanced in DIE. Collectively, our study revealed that (1) many cell types—endometrial, lymphoid, macrophage, fibroblast, and endothelial cells—are altered in endometriosis; (2) endometriosis cells show estrogen responsiveness, immunologic cytotoxicity and exhaustion, and proinflammation signatures that are different in endometriosis subtypes; and (3) novel endometriosis-specific findings of <i>MUC5B</i>^<i>+</i> EEECs, mesothelial cell-derived myofibroblasts, and <i>NRG1-ERBB3</i> interaction may underlie the pathogenesis of endometriosis. Our results may help extend pathologic insights, dissect aggressive diseases, and discover therapeutic targets in endometriosis. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 3","pages":"323-334"},"PeriodicalIF":7.3,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41145945","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}