Research square最新文献

{"title":"Evaluating Vision and Pathology Foundation Models for Computational Pathology: A Comprehensive Benchmark Study.","authors":"Olivier Gevaert, Rohan Bareja, Francisco Carrillo-Perez, Yuanning Zheng, Marija Pizurica, Tarak Nandi, Jeanne Shen, Ravi Madduri","doi":"10.21203/rs.3.rs-6823810/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6823810/v1","url":null,"abstract":"<p><p>To advance precision medicine in pathology, robust AI-driven foundation models are increasingly needed to uncover complex patterns in large-scale pathology datasets, enabling more accurate disease detection, classification, and prognostic insights. However, despite substantial progress in deep learning and computer vision, the comparative performance and generalizability of these pathology foundation models across diverse histopathological datasets and tasks remain largely unexamined. In this study, we conduct a comprehensive benchmarking of 31 AI foundation models for computational pathology, including general vision models (VM), general vision-language models (VLM), pathology-specific vision models (Path-VM), and pathology-specific vision-language models (Path-VLM), evaluated over 41 tasks sourced from TCGA, CPTAC, external benchmarking datasets, and out-of-domain datasets. Our study demonstrates that Virchow2, a pathology foundation model, delivered the highest performance across TCGA, CPTAC, and external tasks, highlighting its effectiveness in diverse histopathological evaluations. We also show that Path-VM outperformed both Path-VLM and VM, securing top rankings across tasks despite lacking a statistically significant edge over vision models. Our findings reveal that model size and data size did not consistently correlate with improved performance in pathology foundation models, challenging assumptions about scaling in histopathological applications. Lastly, our study demonstrates that a fusion model, integrating top-performing foundation models, achieved superior generalization across external tasks and diverse tissues in histopathological analysis. These findings emphasize the need for further research to understand the underlying factors influencing model performance and to develop strategies that enhance the generalizability and robustness of pathology-specific vision foundation models across different tissue types and datasets. PathBench : https://pathbench.stanford.edu/.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Dichotomy of Tumor Control by Recruited and Resident Tumor-Associated Macrophages.","authors":"Claudia Jakubzick, Soubhik Ghosh, Xin Li, Kavita Rawat, Aishwarya Dighal, Stephanie Kalinowski, Fred Knolling Iv, Carol Ringelberg","doi":"10.21203/rs.3.rs-6977440/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6977440/v1","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) play dual roles in cancer, either promoting or suppressing tumor progression, complicating therapeutic approaches. TAMs include recruited macrophages (recMacs), derived from circulating monocytes, and tissue-resident interstitial macrophages (IMs). We recently identified a heterogeneous population of chemokine-expressing IMs, including subsets that support tertiary lymphoid structure (TLS) formation during lung inflammation. Here, we show that IMs can be either pro- or anti-tumorigenic, depending on the subset. Using Pf4ᶜʳᵉCx3cr1ᴰᵀᴿ mice to deplete CD206hi IMs expressing Cxcl13, Cxcl9, and Cxcl10, we demonstrate their essential role in TLS formation, lymphocyte recruitment, and tumor suppression in melanoma and lung adenocarcinoma. In contrast, Ccl2-expressing IMs promote tumor growth by recruiting pro-tumorigenic recMacs. Spatial transcriptomics confirmed the distinct localization and chemokine profiles of these subsets. Finally, CCR5 blockade with the FDA-approved inhibitor Maraviroc during neoantigen vaccination improved tumor control by preventing the migration of immunosuppressive, antigen-presenting recMacs (moDCs). These findings support the development of macrophage-targeted therapies by identifying pro-tumorigenic subsets and recMac trafficking as actionable targets, while preserving macrophage populations that sustain anti-tumor immunity.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating PI-RADS lesions and clinically significant prostate cancer in Black and Asian men: a PREVENT randomized clinical trial secondary analysis.","authors":"Conor Driscoll, Nicole Handa, Mitchell Huang, Adam Murphy, Jim Hu, Edward Schaeffer","doi":"10.21203/rs.3.rs-6905600/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6905600/v1","url":null,"abstract":"<p><p><b>Purpose</b> : Non-White patients are poorly represented in prostate cancer trials. MRI PI-RADS scoring was developed in primarily White populations, but prostate cancer differs in non-White men. We aimed to explore differences in PI-RADS calibration for Asian and Black men. <b>Materials and Methods:</b> This is a secondary analysis of PREVENT, a multi-institutional study of infection rates for transrectal vs. transperineal biopsy. We compared cancer detection for self-identifying Asian and Black men. We compared detection rates on a per-person basis, stratified by index PI-RADS lesion, to White men, using Fisher's exact and logistic regression. <b>Results:</b> Of 665/752 trial patients with PI-RADS 3-5 lesions, 88 (13%) were Black and 36 (6%) were Asian. Black men were younger at diagnosis with increased rates of overall (70% vs. 43%%, <i>P</i> =0.004) and clinically significant prostate cancer (60% vs. 27%, <i>P</i> =0.003) and Asian men had decreased rates of overall (0% vs. 47%, <i>P</i> =0.004) and clinically significant prostate cancer (0% vs. 27%, <i>P</i> =0.003) in PI-RADS 3 lesions compared to White men. On multivariable regression, Black men with PI-RADS 3/4 lesions had higher odds of overall (OR 1.17, <i>P</i> =0.009) and clinically significant prostate cancer (OR 1.20, <i>P</i> =0.004) and Asian men had lower odds of overall (OR 0.79, <i>P</i> =0.01) but not clinically significant prostate cancer (OR 0.94, <i>P</i> =0.5). <b>Conclusions:</b> Black men with PI-RADS 3/4 lesions had 20% higher odds of clinically significant prostate cancer than White men while all PI-RADS 3 lesions in Asian men were negative. These findings suggest PI-RADS may require differential interpretation when assessing prostate cancer risk in non-White men. <b>Source of Funding:</b> Supported by the NCI (5R01CA241758-05). <b>Trial Registration:</b> Registered at ClinicalTrials.gov (NCT04843566, https://clinicaltrials.gov/study/NCT04843566).</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid temporal processing in the olfactory bulb underlies concentration invariant odor identification and signal decorrelation.","authors":"Dmitry Rinberg, Shy Shoham, Mursel Karadas, Jonathan Gill, Sebastian Ceballo","doi":"10.21203/rs.3.rs-4415331/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4415331/v1","url":null,"abstract":"<p><p>In a dynamic environment, sensory systems must filter out irrelevant information to construct a stable percept. Animals who rely on smell need to identify and discriminate odors despite fluctuations in concentration, yet odor receptor activation is strongly concentration-dependent. Here, we explored how odor signals are transformed within the mouse olfactory bulb (OB) by developing an all-optical approach to identify the connectivity between odor receptor channels (glomeruli) and the mitral and tufted cells (MTCs), while monitoring their odor responses. We found that the glomeruli and MTCs activated earliest in a sniff robustly represented odor identity across concentrations, while MTCs connected to later-activated glomeruli were concentration-dependent. Furthermore, probing the responsiveness of MTCs to glomerular input found a short temporal window of excitability at a sniff's start, followed by prolonged odor-evoked inhibition. Our findings reveal a temporal filter implemented by the OB, responsible for stabilizing identity across concentrations while decorrelating responses between odors.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 vaccination unmasks distinct immune dysfunctions across lymphoma subtypes and therapies.","authors":"Yogambigai Velmurugu, Anna Halling Folkmar Rahimic, Ryan Curtin, Yuan Hao, Samantha Nyovanie, James Langton, Pamela Mishra, Iryna Voloshyna, Akiko Koide, Shohei Koide, Gregg J Silverman, Ramin Sedaghat Herati, Yury Patskovsky, Catherine Diefenbach, Michelle Krogsgaard","doi":"10.21203/rs.3.rs-7016519/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-7016519/v1","url":null,"abstract":"<p><p>Patients with lymphoma are at increased risk of severe infections, including SARS-CoV-2, due to immune suppression. Using multidimensional spectral flow cytometry and serology, we characterized in-depth immune responses in 50 SARS-CoV-2 vaccinated lymphoma patients across12 lymphoma subtypes, treated with anti-CD20 antibody (aCD20) ± chemotherapy (CT) or CT alone. Compared to healthy control, aCD20±CT-treated patients exhibited distinct immune alterations, including elevated late-stage effector memory (EM3) CD4+, and terminally differentiated (EMRA) CD8+ T cells, reduced circulating T follicular helper (cTfh) cells, and increased dysfunctional DN3 B cells. While B cell depletion was expected with aCD20 therapy, our data reveals broader immune dysregulation beyond B cell loss. Consistent with these phenotypic changes, aCD20±CT treated patients showed impaired vaccine-induced antibody and T-cell responses. In contrast, CT-only Hodgkin lymphoma patients maintained antibody responses comparable to healthy controls. Notably, SARS-CoV-2-specific T cells in aCD20±CT treated patients displayed fewer regulatory T cells, increased Th1 population, and more EMRA CD8+ T cells, suggesting a compensatory T-cell mediated immunity. Antibody response correlated positively with naïve T cell frequencies and transitional, classical memory, and DN2 B cell subsets. These findings inform the tailored development of vaccine strategies for immunocompromised patients to enhance protection against emerging SARS-CoV-2 variants and other viral pathogens.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"To Turn Inward or Outward? Examining the Reciprocal Relationships Between Mindfulness, Interpersonal Emotion Regulation, and Aggression Over Time.","authors":"Erika Blair, David Chester","doi":"10.21203/rs.3.rs-6985856/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6985856/v1","url":null,"abstract":"<p><p>People frequently turn to others to help regulate their emotions in what is referred to as <i>inter</i> personal emotion regulation (IER). Mindfulness entails an <i>intra</i> personal strategy of turning inward to facilitate emotion regulation. Yet little research has examined the relationships between these distinct regulation strategies and their consequences for aggression. The current study aims to elucidate how dispositional tendencies towards mindfulness and IER interact to predict each other and aggression over time. To do so, a diverse sample of undergraduates ( <i>N</i> = 469) at a Minority Serving Institution completed a three-wave, longitudinal study with approximately 20 days between each wave. Against our predictions, between-participants estimates suggested that more mindful individuals engaged in less IER across time points. Paradoxically, within-participant analyses revealed that when participants were more mindful than usual, they subsequently engaged in <i>more</i> IER. IER and mindfulness did not consistently explain our measures of aggressive behavior. As both IER and mindfulness are effective regulatory approaches with salutary effects, the inverse relationship between the two raises important questions about the trade-offs between the costs and benefits associated with these approaches.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of Bulk RNA-seq Pipeline Metrics for Assessing Low-Quality Samples.","authors":"Samuel Hamilton, Gaurav Gadhvi, Tyler Therron, Deborah R Winter","doi":"10.21203/rs.3.rs-6976695/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6976695/v1","url":null,"abstract":"<p><p>Background With the rise of RNA-seq as an essential and ubiquitous tool for biomedical research, the need for guidelines on quality control (QC) is pressing. Specifically, there remains limited data as to which technical metrics are most informative in identifying low-quality samples. Results Here, we addressed this issue by developing the Quality Control Diagnostic Renderer (QC-DR), software designed to simultaneously visualize a comprehensive panel of QC metrics generated by an RNA-seq pipeline and flag samples with aberrant values when compared to a reference dataset. As an example, we applied QC-DR to the Successful Clinical Response in Pneumonia Therapy (SCRIPT) dataset, a large clinical RNA-seq dataset of sequenced alveolar macrophages (n = 252). Next, we used this dataset to assess relationships between a variety of QC metrics and sample quality. Among the most highly correlated pipeline QC metrics were <i>%</i> and <i># Uniquely Aligned Reads</i> , <i>% rRNA reads</i> , <i># Detected Genes</i> , and our newly developed metric of <i>Area Under the Gene Body Coverage Curve (AUC-GBC</i> ), while experimental QC metrics derived from the lab were not significantly correlated. We then trained a set of machine learning models on the SCRIPT dataset to evaluate the relative contribution of QC metrics to sample quality prediction. Our model performs well when tested on an independent dataset despite differences in the distribution of QC metrics. Conclusions Our results support the conclusion that any individual QC metric is limited in its predictive value and suggests approaches based on the integration of multiple metrics with QC thresholds. In summary, our work provides new insights, practical guidance, and novel QC software which can be used to improve the methodological rigor of RNA-seq studies.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vaccine Effectiveness Among 5- to 17-year-old Individuals with Prior SARS-CoV-2 Infection: An EHR-Based Target Trial Emulation Study from the RECOVER Project.","authors":"Yong Chen, Yuqing Lei, Jiajie Chen, Qiong Wu, Ting Zhou, Bingyu Zhang, Michael Becich, Yuriy Bisyuk, Saul Blecker, Elizabeth Chrischilles, Dimitri Christakis, Lindsay Cowell, Mollie Cummins, Soledad Fernandez, Daniel Fort, Sandy Gonzalez, Sharon Herring, Benjamin Horne, Carol Horowitz, Mei Liu, Susan Kim, Parsa Mirhaji, Abu Mosa, Jennifer Muszynski, Catharine Paules, Alice Sato, Hayden Schwenk, Soumitra Sengupta, Srinivasan Suresh, Bradley Taylor, David Williams, Yongqun He, Jeffrey Morris, Ravi Jhaveri, Christopher Forrest","doi":"10.21203/rs.3.rs-6945998/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6945998/v1","url":null,"abstract":"<p><p>The effectiveness of COVID-19 vaccination in children and adolescents with prior SARS-CoV-2 infection remains unclear, particularly for Omicron subvariants. We evaluated vaccine effectiveness against reinfection with Omicron BA.1/2, BA.4/5, XBB, and later subvariants among 5- to 17-year-olds using data from the RECOVER initiative, a national electronic health record database covering 37 U.S. pediatric institutions. We emulated target trials by age group and variant period, comparing previously infected participants between January 2022 and August 2023. During the BA.1/2 period, vaccination reduced the risk of reinfection, with effectiveness rates of 62% in children and 65% in adolescents. During the BA.4/5 period, protection effectiveness in children was 57%, whereas no statistically significant protection was observed in adolescents. During the XBB or later period, no significant protection was observed in either group. In summary, COVID-19 vaccination provided protection against reinfection during early and mid-Omicron periods in previously infected pediatric populations, but effectiveness declined for later variants.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Natural Depsipeptide Antibiotic that Targets the E site of the Bacterial Ribosome.","authors":"Gerard Wright, Manpreet Kaur, Dmitrii Travin, Max Berger, Manoj Jangra, Martino Morici, Haaris Ahsan Safdari, Dorota Klepacki, Wenliang Wang, Michael Cook, Sommer Chou, Allison Guitor, Kalinka Koteva, Min Xu, Linda Ejim, Lesley Macneil, Nora Vázquez-Laslop, Alexander Mankin, Daniel Wilson","doi":"10.21203/rs.3.rs-6925047/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6925047/v1","url":null,"abstract":"<p><p>A significant challenge in addressing the antibiotic resistance crisis is identifying new antimicrobial compounds. Although natural products produced by fungi and bacteria, particularly actinomycetes, have been the source of most antibiotics discovered over the past 80 years, they have fallen out of favor due to the frequent rediscovery of known drug scaffolds. The current perception is that antibiotic-producing actinomycetes have been over-mined and possess little novelty left to yield. Here, we demonstrate that by using improved fractionation approaches that enrich previously overlooked minor products, even well-studied strains of antibiotic-producing actinomycetes can provide new chemical scaffolds with unique modes of action. By fractionating a library of natural product extracts from soil bacteria, we show that Streptomyces rimosus, the source of the well-known antibiotic oxytetracycline, produces a previously overlooked cyclic depsipeptide antibiotic that we called manikomycin. Manikomycin can kill multi-drug-resistant Enterobacteriaceae and is not susceptible to resistance associated with clinically used antibiotics. Biochemical, genetic, and structural analyses reveal that manikomycin binds in the 'exit' or E site of the large subunit of the bacterial ribosome preventing the entry of the 3' end of the tRNA into the E site and effectively hindering the translocation step of protein synthesis in a sequence context-specific manner. Manikomycin is the first antibacterial agent to target the critical but underexplored E site in the large ribosomal subunit, highlighting its value as a lead for developing new antibiotics.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FANCA Deficiency Induces Oncogenic R-Loop Dependent Synthetic Lethality with PARP1 Inhibitors.","authors":"Gaorav Gupta, Qinhong Wang, Simon Ellington, Paolo Guerra, Faeze Gharibpoor, Dennis Simpson, Min-Guk Cho, Adriana Beltran","doi":"10.21203/rs.3.rs-6080272/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6080272/v1","url":null,"abstract":"<p><p>Synthetic lethality (SL) underlies the success of PARP1 inhibitors (PARPi) in treating homologous recombination (HR) deficient cancers, but extending this paradigm to other DNA damage response (DDR) deficiencies has proven challenging. We performed an in vivo CRISPR screen to identify DDR gene mutations that both enhance tumorigenesis and confer sensitivity to PARPi. Our screen identified FANCA deficiency as a driver of PARPi SL that was validated across diverse human cancer models. FANCA deficiency does not impair HR but disrupts Okazaki fragment maturation (OFM), causing lagging strand gaps and RPA exhaustion upon PARPi treatment. These effects require FANCA interaction with FEN1, independently of its canonical role in interstrand crosslink repair. We find FANCA-mediated FEN1 recruitment is required for OFM at oncogene-associated R loops during PARPi treatment. These findings establish a novel and non-canonical function for FANCA in FEN1-mediated OFM that can be leveraged for PARPi synthetic lethality in FANCA-mutant cancers.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}