Laboratory Investigation最新文献

{"title":"Corrigendum to “386 Targeted NGS for TP53 and BRCA1, BRCA2, Gene Mutations and Comparison with Immune Cell Profiling and Immune Checkpoint Inhibitor Expression in Ascitic Fluid with Metastases from High Grade Serous Ovarian Carcinoma” [Laboratory Investigation 105 (2025) 102613]","authors":"Radhika Srinivasan , Megha Sharma , Amit Sharma , Bhavneet Kaur , Bhavana Rai , Man Updesh Sachdeva , Parikshaa Gupta , Upasana Gautam , Rashmi Bagga","doi":"10.1016/j.labinv.2025.104173","DOIUrl":"10.1016/j.labinv.2025.104173","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 7","pages":"Article 104173"},"PeriodicalIF":5.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279357","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":"Multiscale-fusion models with genomic, topological and pathomic features to predict response to radiation therapy for non-small cell lung cancer patients.","authors":"Yu Jin, Hidetaka Arimura, Takeshi Iwasaki, Takumi Kodama, Noriaki Yamamoto, Yunhao Cui, Yoshinao Oda","doi":"10.1016/j.labinv.2025.104204","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104204","url":null,"abstract":"<p><p>Artificial intelligence models with biomarkers to predict treatment responses to radiation would be necessary to maximise the treatment outcomes of individual patients, especially with histopathology images routinely obtained before treatment. We hypothesised that multiscale features, like genomic, pathomic and topological features, could be associated with the radiation response. We investigated fusion models with multiscale features in histopathology images to predict response to radiation therapy for patients (responders) with non-small cell lung cancer. Ten radiosensitivity-related (radiosensitive and radioresistant) genes were deployed as genomic features. Pathomic features were extracted from histopathology images by conventional pathomic analyses. Topological features represent the intrinsic properties of tumour cells using Betti numbers, which are mathematical invariants. We analysed non-small cell lung cancer (NSCLC) patients from TCGA and CPTAC who received radiotherapy and established three base models with genomic, topological, and pathomic features, respectively, and three fusion models. The topological model showed a higher area under the receiver operating characteristic curve (AUC) of 0.707 (p-value=0.026, log-rank test in overall survival analysis) in the internal test dataset and 0.720 (p-value=0.136) in the external test dataset. The results indicated that the topological models achieved better classification and prognostic prediction powers than the other base models. The inner-cell topological structure may have the ability to reveal the cell radiosensitivity-related information. Furthermore, the best fusion model with genomic, topological, and pathomic features achieved the highest AUC of 0.846 (p-value=0.019) and 0.731 (p-value=0.043) in predicting the treatment response and prognoses in the internal and external test datasets, respectively. This study demonstrated the predictive power of the multiscale fusion model for histopathology images, which may assist clinical physicians in the selection of responders to radiation for personalised radiation therapy and would be substantially beneficial for cancer patients.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104204"},"PeriodicalIF":5.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293991","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":"Siglec ligand immunohistochemistry reveals association with immune exclusion and survival.","authors":"Authors Jeremy R Ellis, Elizabeth Will, Aleksandra Ogurtsova, Logan L Engle, Janis M Taube, Joel C Sunshine","doi":"10.1016/j.labinv.2025.104203","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104203","url":null,"abstract":"<p><p>Sialic acids are overexpressed in many cancers, and binding of sialic acid via sialic acid binding immunoglobulin-like lectins (Siglecs) may contribute significantly to immune evasion and cancer progression. This important resistance mechanism in the tumor immune microenvironment (TIME) has been understudied, partially due to a lack of useful reagents. Here, we developed and optimized an immunohistochemistry (IHC) staining protocol for novel reagents that detect three types of Siglec-engaging sialoglycans (HYDRA-3, -7, and -9, which detect sialoglycans recognized by Siglec-3, -7, and -9, respectively) in the TIME. We evaluated HYDRA staining across 10 different cancer types across whole slides, finding that HYDRA-9 exhibited the highest overall staining range, with HYDRA-3 and -7 showing lower to moderate staining across all tested tumor types. To correlate HYDRA staining patterns and immune infiltration in melanoma, we stained melanoma tissue microarrays (TMAs) with the 3 HYDRA reagents and compared HYDRA staining profiles with a 6-plex multiplex immunofluorescence panel targeting CD8, CD163, FoxP3, PD1, PDL1, and Sox10/S100. Siglec-3 and -9 sialoglycan ligand expression negatively correlated with CD8 T cell infiltration (r=-0.28/p=0.002 and r=-0.29/p=0.001, respectively), particularly at the tumor-stromal interface (r =-0.37/p<0.001 and r=-0.44/p<0.001, respectively). Additionally, a high ratio of Siglec-3 and -9 ligand expression at the tumor-stromal interface versus the tumor core was associated with reduced overall survival (HR 2.60 and 2.11, respectively), whereas CD8 infiltration was not associated with survival outcomes in our cohort. Taken together, the expression levels and spatial distribution of Siglec-engaging sialoglycans may play a role in patient prognosis, potentially representing a biomarker of survival that is independent from conventional metrics of an inflamed tumor microenvironment. This study highlights the need for further investigation of Siglec ligand expression as a predictive and prognostic biomarker of treatment response and resistance.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104203"},"PeriodicalIF":5.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275277","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":"Cover","authors":"","doi":"10.1016/S0023-6837(25)00104-7","DOIUrl":"10.1016/S0023-6837(25)00104-7","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 6","pages":"Article 104194"},"PeriodicalIF":5.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298093","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":"Histopathological insights into metastatic breast cancer gained from rapid autopsies.","authors":"Gitte Zels, Anirudh Pabba, Maxim De Schepper, Tatjana Geukens, Karen Van Baelen, Marion Maetens, Amena Mahdami, Sophia Leduc, Edoardo Isnaldi, Ha-Linh Nguyen, Imane Bachir, Josephine Van Cauwenberge, Kristien Borremans, Birgit Weynand, Elia Biganzoli, Patrick Neven, Hans Wildiers, Wouter Van Den Bogaert, François Richard, Christine Desmedt, Giuseppe Floris","doi":"10.1016/j.labinv.2025.104202","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104202","url":null,"abstract":"<p><p>The biology of metastatic breast cancer is poorly understood, and its understanding is hampered by limited access to metastatic tissue. Post-mortem tissue donation programs may represent a step forward to circumvent this problem, allowing access to large volumes of samples that would often be inaccessible otherwise. In this context, we have set up the UZ/KU Leuven Post-mortem Tissue Donation Program to Enhance Research (UPTIDER, NCT04531696). In this study, we performed detailed histopathological examination of 662 unique metastases collected during autopsy from the first 20 patients in our UPTIDER program. Tissue procurement was guided by a patient-specific tissue donation plan based on available clinical and imaging data. Central pathology review included revision of the primary tumor and biomarker assessment (ER, PR, HER2 and KI67). Linear mixed quantile regression was used to assess relevant associations. Metastases in bones, liver, pleura and non-axillary lymph nodes were present in up to 17 patients. Our major findings include: a) an important clinical underestimation of disease burden in patients with invasive lobular carcinoma; b) a relatively modest disease burden associated with leptomeningeal metastases; c) a higher than anticipated loss of predictive biomarkers in metastases from primary ER+ and/or PR+ tumors (up to 84% and 100% of the patients having at least one ER-negative or PR-negative lesion, respectively), d) a high variability in KI67% between metastases with frequent zonation pattern, and, e) a high frequency of metastases with HER2-low or -ultralow status. Despite the challenging set-up of UPTIDER, we demonstrate here that the data and observations that emerge from this program have high potential for clinical translatability.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104202"},"PeriodicalIF":5.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191945","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":"Integrative genetic and transcriptomic subtyping improves prognosis prediction in B-lineage acute lymphoblastic leukemia.","authors":"Mercilena Benjamin, Jay Singh, Avanish Kumar Pandey, Neha Thukral, Sarita Kumari, Jayanth Kumar, Sameer Bakhshi, Deepam Pushpam, Akash Kumar, Aditya Kumar Gupta, Jagdish Prasad Meena, Amitabh Singh, Pranay Tanwar, Amar Ranjan Singh, Sherry Bhalla, Anita Chopra","doi":"10.1016/j.labinv.2025.104201","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104201","url":null,"abstract":"<p><p>Whole-transcriptomic sequencing (WTS) has remarkably advanced our understanding of B-lineage acute lymphoblastic leukemia (B-ALL), allowing for detailed gene expression profiling and discovery of novel therapeutically-relevant subtypes. The aim of this study was to evaluate the diagnostic and prognostic relevance of combining WTS with traditional genetic methods in risk-stratifying B-ALL. In a cohort of 394 patients (301 children and 93 adults), conventional techniques such as FISH, cytogenetics, and RT-PCR identified sentinel chromosomal abnormalities like BCR::ABL1, TCF3::PBX1, ETV6::RUNX1, and KMT2A-R (rearranged), and ploidy status. WTS was performed on selected 257 patients to identify subtypes such as Ph-like, DUX4-R, PAX5-altered (PAX5-ALT), MEF2D-R, BCL2-R, UBTF-R, PAX5 P80R, NUTM1-R, ZNF384-R, ZNF384-like, ETV6::RUNX1-like, IKZF1 N159Y, and HLF-R. We used a multi-pronged strategy to identify the borderline subtypes such as Ph-like, PAX5-ALT, and CRLF2 (non-Ph-like), by integrating gene expression signatures using tSNE, subtype defining mutations, gene fusions, and copy number assessments. Our integrated approach not only identifies prognostically relevant sentinel molecular subtypes but also increases subtype assignment in upto ∼95% of B-ALL patients. The pro-B immunophenotype was found to be more frequent in UBTF-R and MEF2D-R ALL. Ph-like ALL was associated with poor remission rates and higher minimal residual disease positivity, while DUX4-R showed favorable prognosis. We further categorized pediatric patients into three risk groups: Favorable (hyperdiploid, ETV6::RUNX1, DUX4-R), Poor (BCR::ABL1, Ph-like, KMT2A-R, TCF3::PBX1, iAMP21, and hypodiploid), and Intermediate (PAX5-ALT, PAX5 P80R, NUTM1-R, MEF2D-R, CRLF2 (non-Ph-like), UBTF-R, ZNF384-R, ZNF384-like, BCL2-R, IKZF1 N159Y, ETV6::RUNX1-like, and B-rest). EFS and OS were significantly associated with this risk stratification. In adults, Ph-like ALL showed worse prognosis, particularly, in BCR::ABL1 negative ALL patients. Among the DUX4-R B-ALL, those with IKZF1 deletion had worse EFS and OS. We also identified several novel gene rearrangements in different subtypes of B-ALL. Our study demonstrated that integrating WTS with traditional methods provides a comprehensive, accurate, cost-effective strategy for risk-assessment and treatment planning for B-ALL.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104201"},"PeriodicalIF":5.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191955","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":"A validation workflow for novel oligonucleotide sequences to expand the multiplexing capacity of the CODEX platform.","authors":"Alexander Rochwarger, Louisa Kaufmann, Jing Zhao, Ahmad Makky, Nhat Anh Nguyen, Nastassja Lehmann, Nikolay Samusik, Christine Beschorner, Saumya S Manmadhan, Karen Greif, Christian M Schürch","doi":"10.1016/j.labinv.2025.104200","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104200","url":null,"abstract":"<p><p>Antibody-based multiplexed tissue imaging has the potential to provide critical advances in biological discoveries and their translation for clinical applications. With the increasing introduction of markers and modalities for spatial analysis, there is an according demand for the expansion of multiplexing capacities of such imaging platforms. CO-Detection by indEXing (CODEX) is a widely used multiplexed tissue imaging platform that utilizes DNA-conjugated antibodies for imaging. The multiplexing capacity of CODEX is limited by the availability of unique DNA oligonucleotide sequences for antibody barcoding. In this study, we demonstrate a workflow for the validation and the introduction of novel sets of candidate DNA oligonucleotide sequences for CODEX. Through cross-validation multicycle experiments with the already published library of DNA barcodes, we here present a set of 27 novel oligonucleotide sequences for CODEX, increasing the potential multiplexing capacity to 85+ markers. We confirmed the utility of the new barcodes by using a 74-plex antibody panel on a multi-tumor tissue microarray of paraffin-embedded tissues. The workflow presented here provides a reproducible method for extending the plexity of the CODEX platform, facilitating a deeper understanding of tissue microenvironments.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104200"},"PeriodicalIF":5.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187307","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":"Expression of Homo sapiens (Hsa)-miR-139-5p as a Clinically Feasible Prognostic Marker for Differentiated Thyroid Cancer (DTC).","authors":"Natalia Martínez-Puente, Ignacio Ruz-Caracuel, Luis Javier Leandro-García, Héctor Pian-Arias, Zaira Vega-Corral, Rocío Letón, Roberta Radu, Mariolga Berrizbeitia, Sara Mellid, Clara Reglero, Milton Eduardo Salazar-Hidalgo, Ester Arroba, Alberto Díaz-Talavera, Mónica Marazuela, Amparo Benito-Berlinches, Irene González-García, Sandra Campos-Mena, María Dolores Lozano-Escario, Sonsoles Guadalix, María Calatayud, Ana Pérez-Campos, Marcos Lahera, Alberto Cascón, Juan C Galofré, Maria Currás-Freixes, Eduardo J Caleiras, Pablo Valderrabano, Mercedes Robledo, Cristina Montero-Conde","doi":"10.1016/j.labinv.2025.104199","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104199","url":null,"abstract":"<p><p>Prognostic uncertainty often leads to overtreatment of differentiated thyroid cancer (DTC) or unspecific management of more aggressive entities. MiR-139-5p (miR139-5p) has emerged as a promising prognostic factor that may enhance current individual risk assessment systems. Therefore, we aimed to validate miR139-5p expression as a prognostic marker in DTC using a standardized method and to establish expression cut-off values for discriminating prognostic groups. Additionally, we explored an in situ approach to analyze this miRNA expression as a potential molecular tool for clinical practice. We collected a tissue series of 132 samples, including thyroid tumors, adjacent normal thyroid tissue, and lymph node metastases from a long-term follow-up retrospective cohort of 60 DTC patients with either progressive/persistent disease or an excellent response to primary treatment. We first identified recurrent tumor driver mutations and TERT promoter mutations using Next-Generation Sequencing. Through a standardized paired tumor/normal qPCR analysis, we confirmed a significant reduction in miR139-5p expression in progressive/persistent-DTCs compared to excellent response-DTCs (p-value = 0.002). Further analysis, including thyroid cancer TCGA tumor/normal pairs (n = 59), showed a strong association between reduced miR139-5p expression and TERT promoter mutations (p-value < 0.001), as well as advanced local or distant metastasis at diagnosis (p-value = 0.031). Next, we established miR139-5p^HIGH and miR139-5p^LOW tumor/normal cut-offs to discriminate prognostic groups, with high expression predicting excellent response and low expression predicting disease progression/persistence. Cut-offs were defined through logistic regression and ROC curve analysis and validated in an independent cohort (n = 38). Quantitative image analysis using QuPath software of an automatic chromogenic in situ hybridization assay for miR139 detection further supported the qPCR findings and revealed heterogeneous intratumor miR139 expression, which was lowest in the Ki-67 proliferation index positive foci. Overall, our data indicates that miR139 expression assessment is a feasible tool for clinical use, potentially reducing overtreatment during primary DTC interventions and supporting a risk-adjusted follow-up schedule.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104199"},"PeriodicalIF":5.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181725","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":"Decoding the Molecular Landscape of 262 Uterine Sarcomas: RNA-Seq Clustering of ESS, UTROSCT, and UUS with Prognostic Insights.","authors":"Jan Hojný, Jiří Dvořák, Romana Vránková, Michaela Kendall Bártů, Nikola Hájková, Eva Krkavcová, Miroslava Flídrová, Ivana Stružinská, Kristýna Němejcová, Jiří Bouda, Květoslava Michalová, David Cibula, Renata Poncová, Janusz Rys, Mariusz Ksiazek, Marcin Jędryka, Tymoteusz Poprawski, Alberto Berjon, Ignacio Zapardiel, Jan Laco, Munachiso Ndukwe, Jaroslav Klát, Vladimír Židlík, Zoard Krasznai, Robert Poka, Michal Zikán, Zuzana Špůrková, Magdalena Bizoń, Włodzimierz Sawicki, Nataliya Volodko, Iryna Yezhova, Francesca Ciccarone, Giulia Zinicola, Marcin Bobiński, Marta Ostrowska-Leśko, Ivan Franin, Mirela Kekić, Tetiana Piatnytska, Ihor Varchak, Radovan Pilka, Radim Marek, Jitka Hausnerová, Michaela Koblížková, Pavel Havelka, Vladimír Kalist, Maciej Stukan, Karolina Grabowska, Georgína Kolníková, Milan Krkoška, Michael Halaška, Jana Drozenová, Simona Stolnicu, Mihai Capilna, Archil Sharashenidze, Miranda Gudadze, Radoslav Matěj, Pavel Dundr","doi":"10.1016/j.labinv.2025.104198","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104198","url":null,"abstract":"<p><p>Low-grade endometrial stromal sarcomas (LG-ESS), high-grade endometrial stromal sarcomas (HG-ESS), undifferentiated uterine sarcomas (UUS), and uterine tumors resembling ovarian sex cord tumors (UTROSCT) are distinct non-smooth muscle cell neoplasms with varying clinical outcomes often exhibiting overlapping characteristics. Diagnosis can be supported by identifying characteristic recurrent translocations, which may be absent in some cases, complicating the distinction of equivocal cases. Additionally, cases with overlapping features of LG and HG characteristics are recognized. To address these challenges, we analyzed RNA-Seq profiles of 262 cases. Our results revealed that LG-ESS, with and without recurrent fusions, clustered into two partially overlapping expression profiles associated with distinct overall and relapse-free survival outcomes, with the cluster containing a majority of fusion-negative tumors demonstrating better prognoses. UTROSCT expression profiles closely resembled those of both LG-ESS subgroups, with NCOA3 fusion-positive cases clustering in groups with better survival outcomes. Furthermore, a distinct cluster for HG-ESS with BCOR and YWHAE fusions was identified, differentiating these tumors from HG-ESS without fusions. ONECUT3 emerged as a potential specific marker for this HG-ESS-fusion entity. A significant expression overlap was observed between monomorphic HG-ESS without fusions and pleomorphic UUS. These samples separated further into two mixed clusters distinguished by differences in immune activity, which significantly influenced overall survival and relapse-free survival outcomes. Unsupervised clustering of UUS revealed subgroups resembling either HG-ESS or muscle-cell differentiated tumors, suggesting that UUS may include poorly differentiated distinct entities, such as leiomyosarcoma, and that the distinction from HG-ESS may, in some cases, be arbitrary. Our transcriptome analysis highlights several entities with distinct survival characteristics, providing a foundation for further characterization of these rare, often difficult-to-classify, tumors.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104198"},"PeriodicalIF":5.1,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150971","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":"Aryl Hydrocarbon Receptor Deficiency Upregulates Intercellular Adhesion Molecule 1 in Retinal Pigment Epithelial Cells and Contributes to Retinal Inflammation","authors":"Tsung-Min Yang ,&nbsp;Te-Chao Fang ,&nbsp;Yu-Cheng Lee ,&nbsp;Chen-Chen Lee ,&nbsp;Yen-Ju Chan ,&nbsp;Ida Fitriana ,&nbsp;Yu-Wen Cheng ,&nbsp;Ching-Hao Li","doi":"10.1016/j.labinv.2025.104197","DOIUrl":"10.1016/j.labinv.2025.104197","url":null,"abstract":"<div><div>Retinal pigment epithelium (RPE) cells, located between the photoreceptors and choroid, play a crucial role in maintaining retinal health and function. They act as immunosuppressive barriers, preventing immune cell infiltration from the choroid. Retinal inflammation contributes to the development of various ocular diseases. The aryl hydrocarbon receptor (AHR) is a well-established ligand-dependent transcription factor that mediates potent anti-inflammatory signals following ligand binding. AHR expression is notably reduced under several conditions that negatively affect the retina. We hypothesized that AHR protein loss may impair RPE cell function, shifting them toward a proinflammatory phenotype. In this study, we investigated the proinflammatory pathways activated by AHR knockout (AHR-KO) and examined associated retinal phenotypic changes in AHR-KO mice. Our findings suggest that AHR deficiency may enhance the activity of αvβ3-integrin, extracellular signal–regulated kinase 1/2, and p65 subunit of nuclear factor kappa B, leading to an upregulation of intercellular adhesion molecule 1 (ICAM1) and promoting monocyte adhesion in vitro. Introducing an AHR-green fluorescent protein into AHR-KO RPE cells or pretreating the cells with pharmacologic inhibitors targeting αvβ3 (cyclo[RGDfk]), focal adhesion kinase (PF573228), phospholipase C (U73122), extracellular signal–regulated kinase 1/2 (U0126), and nuclear factor kappa B (Bay11-7082) prevented ICAM1 induction in AHR-KO RPE cells. These results suggest that the proinflammatory pathway is driven by AHR deficiency. In AHR-KO mice, retinal tissues showed ICAM1 accumulation, microglial activation, and migration, indicating chronic retinal inflammation because of AHR deficiency. These mice also displayed early-onset electroretinogram degeneration. Collectively, our data support the protective role of AHR in maintaining RPE cell physiology and retinal health.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 9","pages":"Article 104197"},"PeriodicalIF":5.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132492","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}