The Journal of Pathology最新文献

{"title":"Integrated spatial and multimodal single-cell transcriptomics reveal patient-dependent cell heterogeneity in splenic marginal zone lymphoma","authors":"Juan Pablo Cerapio,&nbsp;Pauline Gravelle,&nbsp;Anne Quillet-Mary,&nbsp;Carine Valle,&nbsp;Frederic Martins,&nbsp;Don-Marc Franchini,&nbsp;Charlotte Syrykh,&nbsp;Pierre Brousset,&nbsp;Alexandra Traverse-Glehen,&nbsp;Loic Ysebaert,&nbsp;Jean-Jacques Fournie,&nbsp;Camille Laurent","doi":"10.1002/path.6296","DOIUrl":"10.1002/path.6296","url":null,"abstract":"<p>Biological hallmarks of splenic marginal zone lymphoma (SMZL) remain poorly described. Herein, we performed in-depth SMZL characterization through multimodal single-cell analyses of paired blood/spleen samples. The 3’-single-cell RNA-sequencing, Cellular Indexing of Transcriptomes and Epitopes by sequencing, and 5’-V(D)J single-cell RNA-sequencing datasets were integrated to characterize SMZL transcriptome profiles, including B-cell receptor and T-cell receptor repertoires. Hyperexpanded B-cell clones in the spleen were at a memory-like stage, whereas recirculating tumor B-cells in blood encompassed multiple differentiation stages, indicating an unexpected desynchronization of the B-cell maturation program in SMZL cells. Spatial transcriptomics showed the enrichment of T-effector and T-follicular helper (T_FH) signatures in the nodular subtype of SMZL. This latter also exhibited gene-based cell–cell interactions suggestive of dynamic crosstalk between T_FH and cancer cells in transcriptomics, further substantiated by using imaging mass cytometry. Our findings provide a comprehensive high-resolution description of SMZL biological hallmarks and characterize, for the first time <i>in situ</i>, inter- and intra-patient heterogeneity at both transcriptomic and protein levels. © 2024 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":"263 4-5","pages":"442-453"},"PeriodicalIF":5.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198618","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":"Multiplex imaging reveals spatially resolved DNA-damage response neighborhoods in TP53-mutated myelodysplastic neoplasms","authors":"Tony Yeung,&nbsp;Yi Zhang,&nbsp;Bridget Kennedy,&nbsp;Cara Walsh,&nbsp;Tanzy Love,&nbsp;Daniel Xia,&nbsp;Anindro Bhattacharya,&nbsp;Rahul G Krishnan,&nbsp;David Head,&nbsp;Richard Burack","doi":"10.1002/path.6292","DOIUrl":"10.1002/path.6292","url":null,"abstract":"<p>While increased DNA damage is a well-described feature of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), it is unclear whether all lineages and all regions of the marrow are homogeneously affected. In this study, we performed immunohistochemistry on formalin-fixed, paraffin-embedded whole-section bone marrow biopsies using a well-established antibody to detect pH2A.X (phosphorylated histone variant H2A.X) that recognizes DNA double-strand breaks. Focusing on <i>TP53</i>-mutated and complex karyotype MDS/AML, we find a greater pH2A.X+ DNA damage burden compared to <i>TP53</i> wild-type neoplastic cases and non-neoplastic controls. To understand how double-strand breaks vary between lineages and spatially in <i>TP53-</i>mutated specimens, we applied a low-multiplex immunofluorescence staining and spatial analysis protocol to visualize pH2A.X+ cells with p53 protein staining and lineage markers. pH2A.X marked predominantly mid- to late-stage erythroids, whereas early erythroids and CD34+ blasts were relatively spared. In a prototypical example, these pH2A.X+ erythroids were organized locally as distinct colonies, and each colony displayed pH2A.X+ puncta at a synchronous level. This highly coordinated immunophenotypic expression was also seen for p53 protein staining and among presumed early myeloid colonies. Neighborhood clustering analysis showed distinct marrow regions differentially enriched in pH2A.X+/p53+ erythroid or myeloid colonies, indicating spatial heterogeneity of DNA-damage response and p53 protein expression. The lineage and architectural context within which DNA damage phenotype and oncogenic protein are expressed is relevant to current therapeutic developments that leverage macrophage phagocytosis to remove leukemic cells in part due to irreparable DNA damage. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"386-395"},"PeriodicalIF":7.3,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154370","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":"PCDHGC3 hypermethylation as a potential biomarker of intestinal neuroendocrine carcinomas","authors":"Tamara Cubiella,&nbsp;Lucía Celada,&nbsp;Jaime San-Juan-Guardado,&nbsp;Raúl Rodríguez-Aguilar,&nbsp;Álvaro Suárez-Priede,&nbsp;María Poch,&nbsp;Francisco Dominguez,&nbsp;Iván Fernández-Vega,&nbsp;Pedro Montero-Pavón,&nbsp;Mario F Fraga,&nbsp;Yoichiro Nakatani,&nbsp;So Takata,&nbsp;Shinichi Yachida,&nbsp;Nuria Valdés,&nbsp;María-Dolores Chiara","doi":"10.1002/path.6291","DOIUrl":"10.1002/path.6291","url":null,"abstract":"<p>Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin <i>PCDHGC3</i> gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored <i>PCDHGC3</i> gene methylation within the context of GEP-NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of <i>PCDHGC3</i> in 29% of GEP-NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi-center GEP-NEN cohorts. Mechanistic analysis revealed that <i>PCDHGC3</i> hypermethylation was not associated with <i>SDH</i> mutations or protein loss, indicating an SDH-independent epigenetic mechanism. Clinically, <i>PCDHGC3</i> hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas <i>PCDHGC3</i> hypermethylation exhibited a strong correlation with <i>TP53</i> somatic mutations, a hallmark of NEC, its predictive value surpassed that of <i>TP53</i> mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83–1.0) for discriminating GI-NECs from GI-NETs, highlighting its superior predictive performance. In conclusion, our findings position <i>PCDHGC3</i> methylation status as a promising molecular biomarker for effectively stratifying patients with GI-NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. © 2024 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":"263 4-5","pages":"418-428"},"PeriodicalIF":5.6,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141097160","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":"Ductal carcinoma in situ develops within clonal fields of mutant cells in morphologically normal ducts","authors":"Stefan J Hutten,&nbsp;Hendrik A Messal,&nbsp;Esther H Lips,&nbsp;Michael Sheinman,&nbsp;Marta Ciwinska,&nbsp;Esmee Braams,&nbsp;Carolien van der Borden,&nbsp;Petra Kristel,&nbsp;Saskia Stoffers,&nbsp;Lodewyk FA Wessels,&nbsp;Grand Challenge PRECISION Consortium,&nbsp;Jos Jonkers,&nbsp;Jacco van Rheenen,&nbsp;Jelle Wesseling,&nbsp;Colinda LGJ Scheele","doi":"10.1002/path.6289","DOIUrl":"10.1002/path.6289","url":null,"abstract":"<p>Mutations are abundantly present in tissues of healthy individuals, including the breast epithelium. Yet it remains unknown whether mutant cells directly induce lesion formation or first spread, leading to a field of mutant cells that is predisposed towards lesion formation. To study the clonal and spatial relationships between morphologically normal breast epithelium adjacent to pre-cancerous lesions, we developed a three-dimensional (3D) imaging pipeline combined with spatially resolved genomics on archival, formalin-fixed breast tissue with the non-obligate breast cancer precursor ductal carcinoma <i>in situ</i> (DCIS). Using this 3D image-guided characterization method, we built high-resolution spatial maps of DNA copy number aberration (CNA) profiles within the DCIS lesion and the surrounding normal mammary ducts. We show that the local heterogeneity within a DCIS lesion is limited. However, by mapping the CNA profiles back onto the 3D reconstructed ductal subtree, we find that in eight out of 16 cases the healthy epithelium adjacent to the DCIS lesions has overlapping structural variations with the CNA profile of the DCIS. Together, our study indicates that pre-malignant breast transformations frequently develop within mutant clonal fields of morphologically normal-looking ducts. © 2024 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":"263 3","pages":"360-371"},"PeriodicalIF":7.3,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079901","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":"Clonal evolution and relapse in early-stage follicular lymphoma – a tree with many branches†","authors":"Falko Fend,&nbsp;Leticia Quintanilla-Martinez","doi":"10.1002/path.6294","DOIUrl":"10.1002/path.6294","url":null,"abstract":"<p>Follicular lymphoma (FL) is an indolent B-cell neoplasm characterised by multistep evolution from premalignant precursor cells carrying the hallmark t(14;18) translocation in the majority of cases. In a new article in <i>The Journal of Pathology</i>, samples of relapsed early-stage FL – primary manifestation and relapse with or without transformation – initially treated with radiotherapy only, were studied for clonal relationships and evolution. Using somatic mutations and the rearranged immunoglobulin sequences as markers, the majority of paired lymphoma samples showed so-called branched evolution from a common, possibly premalignant progenitor cell, with both shared and private mutations. In addition, clonally unrelated cases were identified. This and previous studies with similar findings clearly document that relapse or transformation of FL in many instances not necessarily represents a linear progression of disease due to acquisition of additional mutations and therapy resistance, but rather new outgrowths derived from a pool of clonally related, long-lived, and low proliferating precursor cells, or even unrelated second neoplasms. © 2024 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":"263 3","pages":"271-274"},"PeriodicalIF":7.3,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6294","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074483","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":"Characterization of discordance between mismatch repair deficiency and microsatellite instability testing may prevent inappropriate treatment with immunotherapy","authors":"Birgit S Geurts,&nbsp;Laurien J Zeverijn,&nbsp;Jade M van Berge Henegouwen,&nbsp;Hanneke van der Wijngaart,&nbsp;Louisa R Hoes,&nbsp;Gijs F de Wit,&nbsp;Ilse AC Spiekman,&nbsp;Thomas W Battaglia,&nbsp;Daphne M van Beek,&nbsp;Paul Roepman,&nbsp;Anne ML Jansen,&nbsp;Wendy WJ de Leng,&nbsp;Annegien Broeks,&nbsp;Mariette Labots,&nbsp;Carla ML van Herpen,&nbsp;Hans Gelderblom,&nbsp;Henk MW Verheul,&nbsp;Petur Snaebjornsson,&nbsp;Emile E Voest","doi":"10.1002/path.6279","DOIUrl":"10.1002/path.6279","url":null,"abstract":"<p>In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS. Therefore, we aimed to evaluate the discordance rate between routine dMMR/MSI diagnostics and WGS and to further characterize discordant cases. We assessed patients enrolled in DRUP with dMMR/MSI-positive tumors identified by routine diagnostics, who were treated with immune checkpoint blockade (ICB) and for whom WGS data were available. Patient and tumor characteristics, study treatment outcomes, and material from routine care were retrieved from the patient medical records and via Palga (the Dutch Pathology Registry), and were compared with WGS results. Initially, discordance between routine dMMR/MSI diagnostics and WGS was observed in 13 patients (13/121; 11%). The majority of these patients did not benefit from ICB (11/13; 85%). After further characterization, we found that in six patients (5%) discordance was caused by dMMR tumors that did not harbor an MSI molecular phenotype by WGS. In six patients (5%), discordance was false due to the presence of multiple primary tumors (<i>n</i> = 3, 2%) and misdiagnosis of dMMR status by immunohistochemistry (<i>n</i> = 3, 2%). In one patient (1%), the exact underlying cause of discordance could not be identified. Thus, in this group of patients limited to those initially diagnosed with dMMR/MSI tumors by current routine diagnostics, the true assay-based discordance rate between routine dMMR/MSI-positive diagnostics and WGS was 5%. To prevent inappropriate ICB treatment, clinicians and pathologists should be aware of the risk of multiple primary tumors and the limitations of different tests. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"288-299"},"PeriodicalIF":7.3,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920517","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":"ARAP3 protects from excessive formylated peptide-induced microvascular leakage by acting on endothelial cells and neutrophils","authors":"Julia Y Chu,&nbsp;Barry McCormick,&nbsp;Kruthika Sundaram,&nbsp;Gareth Hardisty,&nbsp;Utsa Karmakar,&nbsp;Caroline Pumpe,&nbsp;Elizabeth Krull,&nbsp;Christopher D Lucas,&nbsp;Joana Amado-Azevedo,&nbsp;Peter L Hordijk,&nbsp;Andrea Caporali,&nbsp;Harry Mellor,&nbsp;J Kenneth Baillie,&nbsp;Adriano G Rossi,&nbsp;Sonja Vermeren","doi":"10.1002/path.6288","DOIUrl":"10.1002/path.6288","url":null,"abstract":"<p>Vascular permeability is temporarily heightened during inflammation, but excessive inflammation-associated microvascular leakage can be detrimental, as evidenced in the inflamed lung. Formylated peptides regulate vascular leakage indirectly via formylated peptide receptor-1 (FPR1)-mediated recruitment and activation of neutrophils. Here we identify how the GTPase-activating protein ARAP3 protects against formylated peptide-induced microvascular permeability via endothelial cells and neutrophils. <i>In vitro</i>, <i>Arap3</i>^−/− endothelial monolayers were characterised by enhanced formylated peptide-induced permeability due to upregulated endothelial FPR1 and enhanced vascular endothelial cadherin internalisation. <i>In vivo</i>, enhanced inflammation-associated microvascular leakage was observed in <i>Arap3</i>^−/− mice. Leakage of plasma protein into the lungs of <i>Arap3</i>^−/− mice increased within hours of formylated peptide administration. Adoptive transfer experiments indicated this was dependent upon ARAP3 deficiency in both immune and non-immune cells. Bronchoalveolar lavages of formylated peptide-challenged <i>Arap3</i>^−/− mice contained neutrophil extracellular traps (NETs). Pharmacological inhibition of NET formation abrogated excessive microvascular leakage, indicating a critical function of NETs in this context. The observation that <i>Arap3</i>^−/− mice developed more severe influenza suggests these findings are pertinent to pathological situations characterised by abundant formylated peptides. © 2024 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":"263 3","pages":"347-359"},"PeriodicalIF":7.3,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907682","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":"Genetic and epigenetic alterations in precursor lesions of endometrial endometrioid carcinoma","authors":"Osamu Gotoh,&nbsp;Yuko Sugiyama,&nbsp;Akiko Tonooka,&nbsp;Mayuko Kosugi,&nbsp;Sunao Kitaura,&nbsp;Ryu Minegishi,&nbsp;Masatoshi Sano,&nbsp;Sayuri Amino,&nbsp;Rie Furuya,&nbsp;Norio Tanaka,&nbsp;Tomoko Kaneyasu,&nbsp;Kohei Kumegawa,&nbsp;Akiko Abe,&nbsp;Hidetaka Nomura,&nbsp;Yutaka Takazawa,&nbsp;Hiroyuki Kanao,&nbsp;Reo Maruyama,&nbsp;Tetsuo Noda,&nbsp;Seiichi Mori","doi":"10.1002/path.6278","DOIUrl":"10.1002/path.6278","url":null,"abstract":"<p>The hyperplasia–carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH–AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the <i>PTEN</i> mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 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":"263 3","pages":"275-287"},"PeriodicalIF":7.3,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6278","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907690","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":"Megalin-related mechanism of hemolysis-induced acute kidney injury and the therapeutic strategy","authors":"Sawako Goto,&nbsp;Michihiro Hosojima,&nbsp;Hideyuki Kabasawa,&nbsp;Kaho Arai,&nbsp;Kazuya Takemoto,&nbsp;Hiroyuki Aoki,&nbsp;Koichi Komochi,&nbsp;Ryota Kobayashi,&nbsp;Nanako Sugita,&nbsp;Taeko Endo,&nbsp;Ryohei Kaseda,&nbsp;Yutaka Yoshida,&nbsp;Ichiei Narita,&nbsp;Yoshiaki Hirayama,&nbsp;Akihiko Saito","doi":"10.1002/path.6284","DOIUrl":"10.1002/path.6284","url":null,"abstract":"<p>Hemolysis-induced acute kidney injury (AKI) is attributed to heme-mediated proximal tubule epithelial cell (PTEC) injury and tubular cast formation due to intratubular protein condensation. Megalin is a multiligand endocytic receptor for proteins, peptides, and drugs in PTECs and mediates the uptake of free hemoglobin and the heme-scavenging protein α₁-microglobulin. However, understanding of how megalin is involved in the development of hemolysis-induced AKI remains elusive. Here, we investigated the megalin-related pathogenesis of hemolysis-induced AKI and a therapeutic strategy using cilastatin, a megalin blocker. A phenylhydrazine-induced hemolysis model developed in kidney-specific mosaic megalin knockout (MegKO) mice confirmed megalin-dependent PTEC injury revealed by the co-expression of kidney injury molecule-1 (KIM-1). In the hemolysis model in kidney-specific conditional MegKO mice, the uptake of hemoglobin and α₁-microglobulin as well as KIM-1 expression in PTECs was suppressed, but tubular cast formation was augmented, likely due to the nonselective inhibition of protein reabsorption in PTECs. Quartz crystal microbalance analysis revealed that cilastatin suppressed the binding of megalin with hemoglobin and α₁-microglobulin. Cilastatin also inhibited the specific uptake of fluorescent hemoglobin by megalin-expressing rat yolk sac tumor-derived L2 cells. In a mouse model of hemolysis-induced AKI, repeated cilastatin administration suppressed PTEC injury by inhibiting the uptake of hemoglobin and α₁-microglobulin and also prevented cast formation. Hemopexin, another heme-scavenging protein, was also found to be a novel ligand of megalin, and its binding to megalin and uptake by PTECs in the hemolysis model were suppressed by cilastatin. Mass spectrometry-based semiquantitative analysis of urinary proteins in cilastatin-treated C57BL/6J mice indicated that cilastatin suppressed the reabsorption of a limited number of megalin ligands in PTECs, including α₁-microglobulin and hemopexin. Collectively, cilastatin-mediated selective megalin blockade is an effective therapeutic strategy to prevent both heme-mediated PTEC injury and cast formation in hemolysis-induced AKI. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"315-327"},"PeriodicalIF":7.3,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896619","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":"Multiomics sequencing and immune microenvironment characteristics define three subtypes of small cell neuroendocrine carcinoma of the cervix","authors":"Baoyue Pan,&nbsp;Shumei Yan,&nbsp;Linjing Yuan,&nbsp;Huiling Xiang,&nbsp;Mingxiu Ju,&nbsp;Shijie Xu,&nbsp;Weihua Jia,&nbsp;Jundong Li,&nbsp;Qi Zhao,&nbsp;Min Zheng","doi":"10.1002/path.6290","DOIUrl":"10.1002/path.6290","url":null,"abstract":"<p>Small cell cervical carcinoma (SCCC) is the most common neuroendocrine tumor in the female genital tract, with an unfavorable prognosis and lacking an evidence-based therapeutic approach. Until now, the distinct subtypes and immune characteristics of SCCC combined with genome and transcriptome have not been described. We performed genomic (<i>n</i> = 18), HPV integration (<i>n</i> = 18), and transcriptomic sequencing (<i>n</i> = 19) of SCCC samples. We assessed differences in immune characteristics between SCCC and conventional cervical cancer, and other small cell neuroendocrine carcinomas, through bioinformatics analysis and immunohistochemical assays. We stratified SCCC patients through non-negative matrix factorization and described the characteristics of these distinct types. We further validated it using multiplex immunofluorescence (<i>n</i> = 77) and investigated its clinical prognostic effect. We confirmed a high frequency of <i>PIK3CA</i> and <i>TP53</i> alterations and HPV18 integrations in SCCC. SCCC and other small cell carcinoma had similar expression signatures and immune cell infiltration patterns. Comparing patients with SCCC to those with conventional cervical cancer, the former presented immune excluded or ‘desert’ infiltration. The number of CD8+ cells in the invasion margin of SCCC patients predicted favorable clinical outcomes. We identified three transcriptome subtypes: an inflamed phenotype with high-level expression of genes related to the MHC-II complex (<i>CD74</i>) and IFN-α/β (SCCC-I), and two neuroendocrine subtypes with high-level expression of <i>ASCL1</i> or <i>NEUROD1</i>, respectively. Combined with multiple technologies, we found that the neuroendocrine groups had more <i>TP53</i> mutations and SCCC-I had more <i>PIK3CA</i> mutations. Multiplex immunofluorescence validated these subtypes and SCCC-I was an independent prognostic factor of overall survival. These results provide insights into SCCC tumor heterogeneity and potential therapies. © 2024 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":"263 3","pages":"372-385"},"PeriodicalIF":7.3,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6290","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896623","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}