Pub Date : 2025-08-13DOI: 10.1016/j.labinv.2025.104225
Jaekwon Seok , Hee Jeong Kwak , Chan-Koo Kang , Ah Ram Kim , Woo Suk Choi , Hyoung Keun Park , Sung Hyun Paick , Hyeong Gon Kim , Yeonjoo Kwak , Tak-Il Jeon , Kyung Min Lim , Baeckseung Lee , Aram Kim , Ssang-Goo Cho
{"title":"Corrigendum to ‘Development of a Technique for Diagnosis and Screening of Superficial Bladder Cancer by Cell-Pellet DNA From Urine Sample’ [Laboratory Investigation 105 (2025) 104124]","authors":"Jaekwon Seok , Hee Jeong Kwak , Chan-Koo Kang , Ah Ram Kim , Woo Suk Choi , Hyoung Keun Park , Sung Hyun Paick , Hyeong Gon Kim , Yeonjoo Kwak , Tak-Il Jeon , Kyung Min Lim , Baeckseung Lee , Aram Kim , Ssang-Goo Cho","doi":"10.1016/j.labinv.2025.104225","DOIUrl":"10.1016/j.labinv.2025.104225","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 9","pages":"Article 104225"},"PeriodicalIF":4.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-06DOI: 10.1016/j.labinv.2025.104227
Hao Lin , Jia-Jie Liang , Chen-Xi Zhang , Qi-Wen Man , Rui-Fang Li , Lin-Zhou Zhang , Bing Liu
Cellular senescence and its associated microenvironment play a pivotal role in tumor initiation and progression. Although ameloblastoma (AM) is classified as a benign tumor, it is characterized by local invasiveness and a high recurrence rate. In this study, we identified a distinct population of senescent epithelial cells using senescence-associated β-galactosidase staining and explored the role of this subpopulation in AM progression. The CellChat tool was utilized to map intercellular communication networks, revealing that this senescent cell cluster promotes stemness in neighboring cells and drives angiogenesis and osteoclastogenesis, which was subsequently confirmed by a series of in vitro experiments. Moreover, conditioned medium from these senescent cells significantly enhanced tumor growth in patient-derived organoids. Clinical data further demonstrated that elevated levels of cellular senescence were strongly associated with greater tumor invasiveness and poorer prognosis in AM patients. In conclusion, our findings suggest that targeting this specific subset of senescent epithelial cells may offer a novel therapeutic approach for AM management, potentially reducing tumor aggressiveness and recurrence.
{"title":"Senescent Epithelial Cells Serve as Invasive Growth Drivers in Ameloblastoma","authors":"Hao Lin , Jia-Jie Liang , Chen-Xi Zhang , Qi-Wen Man , Rui-Fang Li , Lin-Zhou Zhang , Bing Liu","doi":"10.1016/j.labinv.2025.104227","DOIUrl":"10.1016/j.labinv.2025.104227","url":null,"abstract":"<div><div>Cellular senescence and its associated microenvironment play a pivotal role in tumor initiation and progression. Although ameloblastoma (AM) is classified as a benign tumor, it is characterized by local invasiveness and a high recurrence rate. In this study, we identified a distinct population of senescent epithelial cells using senescence-associated β-galactosidase staining and explored the role of this subpopulation in AM progression. The CellChat tool was utilized to map intercellular communication networks, revealing that this senescent cell cluster promotes stemness in neighboring cells and drives angiogenesis and osteoclastogenesis, which was subsequently confirmed by a series of <em>in vitro</em> experiments. Moreover, conditioned medium from these senescent cells significantly enhanced tumor growth in patient-derived organoids. Clinical data further demonstrated that elevated levels of cellular senescence were strongly associated with greater tumor invasiveness and poorer prognosis in AM patients. In conclusion, our findings suggest that targeting this specific subset of senescent epithelial cells may offer a novel therapeutic approach for AM management, potentially reducing tumor aggressiveness and recurrence.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104227"},"PeriodicalIF":4.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804359","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}
The role of poly (adenosine diphosphate [ADP]-ribose) polymerase 1 binding protein (PARPBP) in hepatocellular carcinoma (HCC) prognosis remains unclear. This study investigated PARPBP expression in HCC clinical samples and evaluated its clinicopathological significance in relation to CD8-positive tumor-infiltrating lymphocytes (CD8+ TILs). PARPBP expression and CD8+ TIL density were assessed in surgical specimens from 96 patients with HCC. We performed immunohistochemical analysis to determine PARPBP protein levels, which were correlated with clinicopathological features and patient outcomes. Additionally, we performed experiments using a doxycycline-inducible short hairpin RNA system targeting PARPBP in Huh7 cells. Results indicated that moderately and poorly differentiated HCC had significantly higher PARPBP expression than well-differentiated tumors. Patients with high PARPBP expression exhibited shorter recurrence-free survival and overall survival than those with low expression (both P < .001). Multivariate analysis showed that high PARPBP expression (hazard ratio [HR], 2.806; P = .002), high CD8+ TIL density (HR, 0.148; P < .001), and α-fetoprotein ≥ 10 ng/mL (HR, 1.904; P = .047) were independent predictors of prognosis. Combined analysis revealed that patients with high PARPBP expression and low CD8+ TIL density had the worst recurrence-free survival and overall survival outcomes (both P < .001). In vitro experiments showed that the mRNA expression of PARPBP was higher in liver cancer cell lines than in normal liver cells and that PARPBP knockdown suppressed huh7 cell proliferation. In conclusion, elevated PARPBP expression was associated with poor differentiation and survival in patients with HCC. Furthermore, the combination of high PARPBP expression and low CD8+ TIL density improved prognostic accuracy.
{"title":"Prognostic Significance of Poly (ADP-Ribose) Polymerase 1 Binding Protein Expression and CD8+ Tumor-Infiltrating Lymphocytes in Hepatocellular Carcinoma","authors":"Masako Okada , Misako Sato-Matsubara , Masaru Enomoto , Truong Huu Hoang , Sawako Uchida-Kobayashi , Akihiro Tamori , Tsutomu Matsubara , Kenichi Kohashi , Takeaki Ishizawa , Norifumi Kawada","doi":"10.1016/j.labinv.2025.104226","DOIUrl":"10.1016/j.labinv.2025.104226","url":null,"abstract":"<div><div>The role of poly (adenosine diphosphate [ADP]-ribose) polymerase 1 binding protein (PARPBP) in hepatocellular carcinoma (HCC) prognosis remains unclear. This study investigated PARPBP expression in HCC clinical samples and evaluated its clinicopathological significance in relation to CD8-positive tumor-infiltrating lymphocytes (CD8<sup>+</sup> TILs). PARPBP expression and CD8<sup>+</sup> TIL density were assessed in surgical specimens from 96 patients with HCC. We performed immunohistochemical analysis to determine PARPBP protein levels, which were correlated with clinicopathological features and patient outcomes. Additionally, we performed experiments using a doxycycline-inducible short hairpin RNA system targeting PARPBP in Huh7 cells. Results indicated that moderately and poorly differentiated HCC had significantly higher PARPBP expression than well-differentiated tumors. Patients with high PARPBP expression exhibited shorter recurrence-free survival and overall survival than those with low expression (both <em>P</em> < .001). Multivariate analysis showed that high PARPBP expression (hazard ratio [HR], 2.806; <em>P</em> = .002), high CD8<sup>+</sup> TIL density (HR, 0.148; <em>P</em> < .001), and α-fetoprotein ≥ 10 ng/mL (HR, 1.904; <em>P</em> = .047) were independent predictors of prognosis. Combined analysis revealed that patients with high PARPBP expression and low CD8<sup>+</sup> TIL density had the worst recurrence-free survival and overall survival outcomes (both <em>P</em> < .001). In vitro experiments showed that the mRNA expression of <em>PARPBP</em> was higher in liver cancer cell lines than in normal liver cells and that <em>PARPBP</em> knockdown suppressed huh7 cell proliferation. In conclusion, elevated PARPBP expression was associated with poor differentiation and survival in patients with HCC. Furthermore, the combination of high PARPBP expression and low CD8<sup>+</sup> TIL density improved prognostic accuracy.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104226"},"PeriodicalIF":4.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-29DOI: 10.1016/j.labinv.2025.104220
Mohamed Omar , Giuseppe Nicolo’ Fanelli , Fabio Socciarelli , Varun Ullanat , Sreekar Reddy Puchala , James Wen , Alex Chowdhury , Itzel Valencia , Cristian Scatena , Luigi Marchionni , Renato Umeton , Massimo Loda
Conventional histopathology has traditionally been the cornerstone of disease diagnosis, relying on qualitative or semiquantitative visual inspection of tissue sections to detect pathological changes. Singleplex immunohistochemistry (IHC), although effective in detecting specific biomarkers, is often limited by its single-marker focus, which constrains its ability to capture the complexity of the tissue environment. The introduction of multiplexed imaging technologies, such as multiplex IHC and multiplex immunofluorescence, has been transformative, enabling the simultaneous visualization of multiple biomarkers within a single tissue section. These approaches complement morphology with quantitative multimarker data and spatial context, providing a more comprehensive view of cellular interactions and disease mechanisms. However, the rich data from multiplex IHC/multiplex immunofluorescence experiments come with significant analytical challenges, as large multichannel images require comprehensive processing to transform raw imaging data into quantitative and meaningful information. This review focuses on the standard digital image analysis workflow for multiplex imaging in pathology, covering each step from image acquisition and preprocessing to cell segmentation and biomarker quantification. We discuss the common open-source tools that support each step to guide users in selecting appropriate solutions. By outlining an end-to-end pipeline with concrete examples, this review is intended for practicing pathologists and researchers with limited computational expertise. It provides practical guidance and best practices to help integrate multiplex image analysis into routine pathology workflows and translational research, bridging the gap between advanced imaging technology and day-to-day diagnostic practice.
{"title":"Antibody-Based Multiplex Image Analysis: Standard Analytical Workflows and Artificial Intelligence Tools for Pathologists","authors":"Mohamed Omar , Giuseppe Nicolo’ Fanelli , Fabio Socciarelli , Varun Ullanat , Sreekar Reddy Puchala , James Wen , Alex Chowdhury , Itzel Valencia , Cristian Scatena , Luigi Marchionni , Renato Umeton , Massimo Loda","doi":"10.1016/j.labinv.2025.104220","DOIUrl":"10.1016/j.labinv.2025.104220","url":null,"abstract":"<div><div>Conventional histopathology has traditionally been the cornerstone of disease diagnosis, relying on qualitative or semiquantitative visual inspection of tissue sections to detect pathological changes. Singleplex immunohistochemistry (IHC), although effective in detecting specific biomarkers, is often limited by its single-marker focus, which constrains its ability to capture the complexity of the tissue environment. The introduction of multiplexed imaging technologies, such as multiplex IHC and multiplex immunofluorescence, has been transformative, enabling the simultaneous visualization of multiple biomarkers within a single tissue section. These approaches complement morphology with quantitative multimarker data and spatial context, providing a more comprehensive view of cellular interactions and disease mechanisms. However, the rich data from multiplex IHC/multiplex immunofluorescence experiments come with significant analytical challenges, as large multichannel images require comprehensive processing to transform raw imaging data into quantitative and meaningful information. This review focuses on the standard digital image analysis workflow for multiplex imaging in pathology, covering each step from image acquisition and preprocessing to cell segmentation and biomarker quantification. We discuss the common open-source tools that support each step to guide users in selecting appropriate solutions. By outlining an end-to-end pipeline with concrete examples, this review is intended for practicing pathologists and researchers with limited computational expertise. It provides practical guidance and best practices to help integrate multiplex image analysis into routine pathology workflows and translational research, bridging the gap between advanced imaging technology and day-to-day diagnostic practice.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 10","pages":"Article 104220"},"PeriodicalIF":4.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-29DOI: 10.1016/j.labinv.2025.104221
Takeshi Iwasaki, Mari Masunaga, Takumi Tomonaga, Yosuke Masumoto, Yuri Akiyama, Yoshinao Oda
N6-methyladenosine (m6A), a widespread RNA modification, plays a vital role in various biological processes, including carcinogenesis, tumor progression, and immune regulation. We conducted this study to investigate the relationship between m6A regulators, such as METTL3, METTL14, WTAP, FTO, ALKBH5, and YTHDF1-3, and their association with c-Myc and programmed death ligand 1 (PD-L1) expression in leiomyosarcoma (LMS). The expression of these epitranscriptome regulator genes was evaluated using the next-generation sequencing data of 53 patients with LMS obtained from an online public database. We next determined the relationship between m6A regulators and c-Myc and CD274 (PD-L1) mRNA expression in an LMS cell line. We also performed immunohistochemical staining of 69 LMS cases. Immunohistochemical staining showed that cases with higher expression of METTL3, METTL14, ALKBH5, FTO, and WTAP exhibited higher c-Myc expression, and cases with higher expression of ALKBH5, YTHDF2, and WTAP exhibited higher mitotic activity. Gene set enrichment analysis revealed that METTL3, METTL14, and FTO knockdown significantly suppressed c-Myc target gene expression. Knockdown of METTL3, ALKBH5, YTHDF1, WTAP, and FTO in LMS cell lines reduced cell proliferation. These results suggest the relationship between m6A modifications and c-Myc-driven oncogenesis. Moreover, knockdown of YTHDF2 inhibited interferon gamma–induced PD-L1 expression, suggesting its role in immune evasion through PD-L1 regulation. Multivariate Cox proportional hazards analysis revealed that lower YTHDF2 expression and higher WTAP expression are unfavorable prognostic factors. These findings provide potential therapeutic targets for LMS, particularly in combination with immune checkpoint inhibitors. Further investigation into the molecular mechanisms of m6A-mediated regulation of PD-L1 and c-Myc expression is required to develop more effective treatments for LMS.
{"title":"Comprehensive Analysis of N6-Methyladenosine (m6A) RNA Methylation Regulators in Soft Tissue Leiomyosarcoma","authors":"Takeshi Iwasaki, Mari Masunaga, Takumi Tomonaga, Yosuke Masumoto, Yuri Akiyama, Yoshinao Oda","doi":"10.1016/j.labinv.2025.104221","DOIUrl":"10.1016/j.labinv.2025.104221","url":null,"abstract":"<div><div>N6-methyladenosine (m6A), a widespread RNA modification, plays a vital role in various biological processes, including carcinogenesis, tumor progression, and immune regulation. We conducted this study to investigate the relationship between m6A regulators, such as METTL3, METTL14, WTAP, FTO, ALKBH5, and YTHDF1-3, and their association with c-Myc and programmed death ligand 1 (PD-L1) expression in leiomyosarcoma (LMS). The expression of these epitranscriptome regulator genes was evaluated using the next-generation sequencing data of 53 patients with LMS obtained from an online public database. We next determined the relationship between m6A regulators and <em>c-Myc</em> and <em>CD274 (PD-L1)</em> mRNA expression in an LMS cell line. We also performed immunohistochemical staining of 69 LMS cases. Immunohistochemical staining showed that cases with higher expression of METTL3, METTL14, ALKBH5, FTO, and WTAP exhibited higher c-Myc expression, and cases with higher expression of ALKBH5, YTHDF2, and WTAP exhibited higher mitotic activity. Gene set enrichment analysis revealed that <em>METTL3</em>, <em>METTL14</em>, and <em>FTO</em> knockdown significantly suppressed c-Myc target gene expression. Knockdown of <em>METTL3</em>, <em>ALKBH5</em>, <em>YTHDF1</em>, <em>WTAP</em>, and <em>FTO</em> in LMS cell lines reduced cell proliferation. These results suggest the relationship between m6A modifications and c-Myc-driven oncogenesis. Moreover, knockdown of <em>YTHDF2</em> inhibited interferon gamma–induced <em>PD-L1</em> expression, suggesting its role in immune evasion through PD-L1 regulation. Multivariate Cox proportional hazards analysis revealed that lower YTHDF2 expression and higher WTAP expression are unfavorable prognostic factors. These findings provide potential therapeutic targets for LMS, particularly in combination with immune checkpoint inhibitors. Further investigation into the molecular mechanisms of m6A-mediated regulation of PD-L1 and c-Myc expression is required to develop more effective treatments for LMS.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104221"},"PeriodicalIF":4.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760449","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}
A disintegrin and metalloproteinase 28 (ADAM28), which comprises membrane-anchored form (ADAM28m) and short-secreted form (ADAM28s), is overexpressed by carcinoma cells and involved in cancer cell proliferation and metastasis in several cancers. However, little is known about the implications of ADAM28 in esophageal squamous cell carcinoma (ESCC). In this study, we investigated the expression and clinical implication of ADAM28 in ESCC and examined the molecular mechanism of ADAM28-mediated ESCC cell proliferation. Immunoblotting analysis demonstrated that ADAM28s is overexpressed in active forms of 42 and/or 40 kDa in ESCC tissues compared with nonneoplastic esophageal tissues. Immunohistochemistry and deep learning artificial intelligence showed that ADAM28s is expressed mainly by carcinoma cells in the ESCC tissue, and the 5-year overall survival and disease-specific survival rates in cases with extensive immunostaining are significantly worse than those in low immunostaining cases. Among several factors examined, interleukin 6 (IL-6) enhanced ADAM28s expression in ESCC cell lines (TE-1 and KYSE-140), which exhibited ADAM28 expression but not in a cell line without the expression (TE-8). Proliferation of TE-1 and KYSE-140 cells under IL-6 stimulation was effectively inhibited by treatment with anti-ADAM28 antibody or siRNA-mediated downregulation of ADAM28, whereas no such effect was observed in TE-8 cells. In mouse ESCC cell xenografts, tumor growth of KYSE-140ffLuc-cp156 cells was significantly reduced by treatment with the anti-ADAM28 antibody compared with the control immunoglobulin G–treated group. These results show that ADAM28s is overexpressed as active forms in ESCC cells and suggest that ADAM28s is involved in cell proliferation probably through the IL-6 signaling pathway.
{"title":"Increased Expression of Secreted Form A Disintegrin and Metalloproteinase 28 (ADAM28s) in Esophageal Squamous Cell Carcinoma: Implication for Carcinoma Cell Proliferation via Interleukin 6 Receptor Shedding","authors":"Keita Kouzu , Satsuki Mochizuki , Hironori Tsujimoto , Yusuke Ishibashi , Ines P. Nearchou , Kentaro Ohara , Seiichiro Fujishima , Yoji Kishi , Susumu Matsukuma , Yasunori Okada , Hideki Ueno","doi":"10.1016/j.labinv.2025.104222","DOIUrl":"10.1016/j.labinv.2025.104222","url":null,"abstract":"<div><div>A disintegrin and metalloproteinase 28 (ADAM28), which comprises membrane-anchored form (ADAM28m) and short-secreted form (ADAM28s), is overexpressed by carcinoma cells and involved in cancer cell proliferation and metastasis in several cancers. However, little is known about the implications of ADAM28 in esophageal squamous cell carcinoma (ESCC). In this study, we investigated the expression and clinical implication of ADAM28 in ESCC and examined the molecular mechanism of ADAM28-mediated ESCC cell proliferation. Immunoblotting analysis demonstrated that ADAM28s is overexpressed in active forms of 42 and/or 40 kDa in ESCC tissues compared with nonneoplastic esophageal tissues. Immunohistochemistry and deep learning artificial intelligence showed that ADAM28s is expressed mainly by carcinoma cells in the ESCC tissue, and the 5-year overall survival and disease-specific survival rates in cases with extensive immunostaining are significantly worse than those in low immunostaining cases. Among several factors examined, interleukin 6 (IL-6) enhanced ADAM28s expression in ESCC cell lines (TE-1 and KYSE-140), which exhibited ADAM28 expression but not in a cell line without the expression (TE-8). Proliferation of TE-1 and KYSE-140 cells under IL-6 stimulation was effectively inhibited by treatment with anti-ADAM28 antibody or siRNA-mediated downregulation of <em>ADAM28</em>, whereas no such effect was observed in TE-8 cells. In mouse ESCC cell xenografts, tumor growth of KYSE-140<sup>ffLuc-cp156</sup> cells was significantly reduced by treatment with the anti-ADAM28 antibody compared with the control immunoglobulin G–treated group. These results show that ADAM28s is overexpressed as active forms in ESCC cells and suggest that ADAM28s is involved in cell proliferation probably through the IL-6 signaling pathway.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104222"},"PeriodicalIF":4.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-29DOI: 10.1016/j.labinv.2025.104223
Aihua Guo , Yilin Yu , Qinpeng Guo , Enhuan Zhang , Huaqin Lin , Mei Feng , Peilin Zhong , Jie Lin , Linghua Wang , Xiurong Lin , Haixia Wu , Yang Sun
This study aimed to identify and characterize novel macrophage–related molecular mechanisms underlying immunosuppression and tumor progression in cervical cancer. Through a systematic integrative analysis guided by immune-related gene signatures and robust regression modeling, we identified PARVB as a novel macrophage–associated prognostic gene with strong predictive value across multiple data sets. Further validation using large-scale transcriptomic data and single-cell RNA-sequencing profiles revealed that PARVB likely activates the SMAD signaling axis, leading to the upregulation of TNFSF13, a key driver of M2 macrophage polarization. This PARVB-SMAD3-TNFSF13 axis enhances interactions between M2 macrophages and TNFSF13+ subsets, promoting regulatory T-cell induction and fostering an immunosuppressive tumor microenvironment. Functional assays and multiplex immunohistochemistry further confirmed that this axis drives tumor proliferation and immune evasion. Collectively, our findings uncover a critical PARVB-driven signaling cascade that reprograms macrophages into an immunosuppressive M2 phenotype, facilitating immune escape and cervical cancer progression. Targeting this axis presents a promising therapeutic strategy to reshape the tumor microenvironment and improve immunotherapeutic outcomes.
{"title":"Potential Role of PARVB in Macrophage-Mediated Immunosuppression and Cervical Cancer Progression","authors":"Aihua Guo , Yilin Yu , Qinpeng Guo , Enhuan Zhang , Huaqin Lin , Mei Feng , Peilin Zhong , Jie Lin , Linghua Wang , Xiurong Lin , Haixia Wu , Yang Sun","doi":"10.1016/j.labinv.2025.104223","DOIUrl":"10.1016/j.labinv.2025.104223","url":null,"abstract":"<div><div>This study aimed to identify and characterize novel macrophage–related molecular mechanisms underlying immunosuppression and tumor progression in cervical cancer. Through a systematic integrative analysis guided by immune-related gene signatures and robust regression modeling, we identified PARVB as a novel macrophage–associated prognostic gene with strong predictive value across multiple data sets. Further validation using large-scale transcriptomic data and single-cell RNA-sequencing profiles revealed that PARVB likely activates the SMAD signaling axis, leading to the upregulation of TNFSF13, a key driver of M2 macrophage polarization. This PARVB-SMAD3-TNFSF13 axis enhances interactions between M2 macrophages and TNFSF13<sup>+</sup> subsets, promoting regulatory T-cell induction and fostering an immunosuppressive tumor microenvironment. Functional assays and multiplex immunohistochemistry further confirmed that this axis drives tumor proliferation and immune evasion. Collectively, our findings uncover a critical PARVB-driven signaling cascade that reprograms macrophages into an immunosuppressive M2 phenotype, facilitating immune escape and cervical cancer progression. Targeting this axis presents a promising therapeutic strategy to reshape the tumor microenvironment and improve immunotherapeutic outcomes.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104223"},"PeriodicalIF":4.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-17DOI: 10.1016/j.labinv.2025.104215
Yehan Zhou , Jiayu Li , Chengmin Zhou , Jun Hou , Jieyu Wang , Ting Lan , Dan Wan , Yuan Tu , Yungchang Chen , Qiao Yang , Jincheng Luo , Dan Luo , Lin Shi , Yang Liu
Accurate detection of BRAF V600E mutation is critical for guiding therapeutic strategies. Unlike other solid tumors, colorectal cancer (CRC) lacks reliable immunohistochemical (IHC) interpretation criteria. This study aimed to establish CRC-specific IHC criteria through quantitative analysis. A cohort of 250 CRC cases with paired IHC and genetic testing (qPCR and next-generation sequencing) results was analyzed. Cross-platform generalization capability of 3 BRAF V600E antibodies was validated. Previously reported IHC criteria were applied and discordant cases were analyzed. A deep learning–based digital pathology platform quantified IHC parameters (H-score, staining intensity, and percentage). Receiver-operating characteristic analysis identified optimal thresholds, which were translated into practical criteria. External validation was performed to confirm generalizability. Cross-platform validation revealed consistent antibody performance across platforms, with absorbance optical density (2.0-2.3) and H-scores (145-160) showing no significant intergroup differences (P > .05). Initial comparison of existing criteria demonstrated 80.4% to 84.8% concordance with molecular testing. Discordant cases exhibited 5 distinct abnormal staining patterns. Artificial intelligence–driven quantification identified H-score 52.675 as the optimal upper cutoff (area under the curve [AUC], 0.938), translated into a positive criterion of >25% 2+ or >15% 3+ stained cells. A negative criterion of <20% 1+ cells was established. Cases with atypical staining patterns required molecular confirmation. The optimized criteria achieved superior concordance in internal (AUC, 0.932) and external validation (AUC, 0.977). This study established refined BRAF V600E IHC criteria for colorectal cancer using precision quantitative analysis. The optimized protocol significantly improves accuracy and standardization in complex real-world scenarios, demonstrating strong potential for broad clinical adoption.
{"title":"Deep Learning–Guided Quantitative Analysis Establishes Optimized BRAF V600E Immunohistochemical Criteria for Colorectal Cancer: A Multiplatform Validation Study","authors":"Yehan Zhou , Jiayu Li , Chengmin Zhou , Jun Hou , Jieyu Wang , Ting Lan , Dan Wan , Yuan Tu , Yungchang Chen , Qiao Yang , Jincheng Luo , Dan Luo , Lin Shi , Yang Liu","doi":"10.1016/j.labinv.2025.104215","DOIUrl":"10.1016/j.labinv.2025.104215","url":null,"abstract":"<div><div>Accurate detection of BRAF V600E mutation is critical for guiding therapeutic strategies. Unlike other solid tumors, colorectal cancer (CRC) lacks reliable immunohistochemical (IHC) interpretation criteria. This study aimed to establish CRC-specific IHC criteria through quantitative analysis. A cohort of 250 CRC cases with paired IHC and genetic testing (qPCR and next-generation sequencing) results was analyzed. Cross-platform generalization capability of 3 BRAF V600E antibodies was validated. Previously reported IHC criteria were applied and discordant cases were analyzed. A deep learning–based digital pathology platform quantified IHC parameters (H-score, staining intensity, and percentage). Receiver-operating characteristic analysis identified optimal thresholds, which were translated into practical criteria. External validation was performed to confirm generalizability. Cross-platform validation revealed consistent antibody performance across platforms, with absorbance optical density (2.0-2.3) and H-scores (145-160) showing no significant intergroup differences (<em>P</em> > .05). Initial comparison of existing criteria demonstrated 80.4% to 84.8% concordance with molecular testing. Discordant cases exhibited 5 distinct abnormal staining patterns. Artificial intelligence–driven quantification identified H-score 52.675 as the optimal upper cutoff (area under the curve [AUC], 0.938), translated into a positive criterion of >25% 2+ or >15% 3+ stained cells. A negative criterion of <20% 1+ cells was established. Cases with atypical staining patterns required molecular confirmation. The optimized criteria achieved superior concordance in internal (AUC, 0.932) and external validation (AUC, 0.977). This study established refined BRAF V600E IHC criteria for colorectal cancer using precision quantitative analysis. The optimized protocol significantly improves accuracy and standardization in complex real-world scenarios, demonstrating strong potential for broad clinical adoption.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104215"},"PeriodicalIF":4.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667951","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}
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