bioRxiv : the preprint server for biology最新文献

{"title":"In silico drug sensitivity predicts subgroup-specific therapeutics in medulloblastoma patients.","authors":"Anna M Jermakowicz, Luz Ruiz, Jonathan Chu, Nitish Jange, Robert K Suter, Nina S Kadan-Lottick, Derek Hanson, Nagi G Ayad","doi":"10.1101/2025.05.23.655845","DOIUrl":"https://doi.org/10.1101/2025.05.23.655845","url":null,"abstract":"<p><strong>Background: </strong>Medulloblastoma is the most common malignant pediatric brain tumor. Survival rates vary widely between subgroups, with an average overall survival of 70%. Recurrent medulloblastoma is highly aggressive, treatment-resistant, and usually fatal. In addition, current treatments are highly toxic to the developing brain and surviving patients suffer from lifelong side effects. Therefore, novel therapeutic options are urgently needed.</p><p><strong>Methods: </strong>To inform risk-based, personalized therapy, we developed a novel platform called DrugSeq, which allows predictions of drug sensitivities in patients across medulloblastoma subgroups. We used a perturbagen-response dataset to calculate transcriptional response signatures for each drug and compared this to patient medulloblastoma tumor gene expression. We then stratified patients by molecular subgroup and used an ANOVA analysis to identify drugs that selectively targeted each subgroup.</p><p><strong>Results: </strong>We found distinct differences in transcriptional profiles and predicted drug sensitivity for each medulloblastoma subgroup. We identified several kinase inhibitors, epigenetic inhibitors, and several drugs that have been investigated in drug repositioning studies for cancer.</p><p><strong>Conclusions: </strong>We posit that DrugSeq may identify novel therapies and facilitate patient stratification in clinical trials, leading to more successful targeted medulloblastoma therapies that improve tumor response while minimizing late toxicities. This computational tool can also be used for other cancers to stratify patients based on any clinical or molecular feature.</p><p><strong>Key points: </strong>DrugSeq calculates drug sensitivity for medulloblastoma tumors stratified by subgroup.DrugSeq platform may inform patient stratification strategies in clinical trials.</p><p><strong>Importance of the study: </strong>Medulloblastoma is the most common malignant pediatric brain tumor. Current standard-of-care typically includes surgical resection, multi-agent chemotherapy, and radiation. However, survival rates vary widely between subgroups, ranging from 45 to 90%, depending on age and molecular features. In addition, surviving children frequently suffer from debilitating late side effects of therapy including neurocognitive impairment, epilepsy, stroke, subsequent cancer, endocrinopathies, and early mortality. Therefore, novel therapeutic options are urgently needed. However, a one-size-fits-all approach for therapy is unlikely to be effective given the well-characterized intertumor heterogeneity of medulloblastoma.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236590","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":"DNA2 and FANCM function in two distinctive pathways in disrupting TERRA R-loops and suppressing replication stress at ALT telomeres.","authors":"Ashwin Ragupathi, Heba Z Abid, Yun Chen, Rongwei Zhao, Settapong T Kosiyatrakul, Derin I Yetil, Julia Neiswander, Rachel Feltman, Shannon Thomas, Benjamin Yusupov, Manrose Singh, Li Zheng, Binghui Shen, Huaiying Zhang, Hsueh-Ping C Chu, Carl L Schildkraut, Ming Xiao, Dong Zhang","doi":"10.1101/2025.05.22.655602","DOIUrl":"https://doi.org/10.1101/2025.05.22.655602","url":null,"abstract":"<p><p>Cancers maintain their telomeres through two main telomere maintenance mechanisms (TMMs): 85-90% of cancers rely on telomerase, while 10-15% of cancers adopt the Alternative Lengthening of Telomere (ALT) pathway. Previously, we and others reported that FANCM, one of the Fanconi Anemia proteins, plays a critical role in suppressing replication stress and DNA damage at ALT telomeres by actively disrupting TERRA R-loops [1-4]. Here, we showed that inactivation of DNA2 in ALT-positive (ALT+) cells, but not in telomerase-positive (TEL+) cells, induces a robust increase of replication stress and DNA damage at telomeres, which leads to a pronounced increase of many ALT properties, including telomere dysfunction-induced foci (TIFs), ALT-associated PML bodies (APBs), and C-circles. We further demonstrated that depletion of DNA2 induces a pronounced increase of TERRA R-loops and a decrease in replication efficiency at ALT telomeres. Most importantly, we uncovered a strong additive genetic interaction between DNA2 and FANCM in the ALT pathway. Furthermore, co-depletion of DNA2 and FANCM causes synthetic lethality in ALT+ cells, but not in TEL+ cells, suggesting that targeting DNA2 and FANCM could be a viable strategy to treat ALT+ cancers. Finally, utilizing the single-molecule telomere assay via optical mapping (SMTA-OM) technology, we thoroughly characterized genome-wide changes in DNA2 deficient cells and FANCM deficient cells and found that most chromosome arms manifested increased telomere length. Unexpectedly, we uncovered many chromosome arm-specific telomere changes in those cells, suggesting that telomeres at different chromosome arms may regulate and respond to replication stress differently. Collectively, our study not only shed new light on the molecular mechanisms of the ALT pathway, but also discovered a new strategy for targeting ALT+ cancer.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236511","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":"Human genetic variation shapes the antibody repertoire across B cell development.","authors":"Oscar L Rodriguez, Xiang Qiu, Kaitlyn Shields, Christopher Dunn, Amit Singh, Mary Kaileh, Corey T Watson, Ranjan Sen","doi":"10.1101/2025.05.19.654982","DOIUrl":"https://doi.org/10.1101/2025.05.19.654982","url":null,"abstract":"<p><p>The peripheral antibody repertoire is shaped by inherited genetic variation and selection during B cell development. However, how the repertoire changes across developmental stages and the relative impact of genetics and selection in establishing the antibody repertoire remain largely unknown. To dissect the individual and combined effects of these factors, we integrated antibody repertoire transcriptomics across pro-B, pre-B, immature, and naive B cells with single-molecule real-time long-read DNA sequencing of the immunoglobulin heavy (IGH), kappa (IGK), and lambda (IGL) chain loci. We find that IGH genetic variants establish gene usage biases at the pro-B stage that persist throughout development. In contrast, IGK and IGL repertoires are extensively remodeled during maturation, consistent with receptor editing. Surprisingly, IGH variants also exert trans effects on light chain gene usage, suggesting coordinated constraints on heavy-light chain pairing. Principal component and allele-specific analyses reveal that genetics primarily shapes the heavy chain repertoire, while selection more strongly influences light chain diversity. These findings define distinct dynamics of antibody repertoire development and underscore the importance of personal immunogenomics in understanding individual immune responses.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236582","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":"PIWIL2 downregulation in colon cancer promotes transposon activity and pro-tumorigenic phenotypes.","authors":"Alyssa Risner, Joyce Nair-Menon, Abhinav Cheedipudi, Joe R Delaney, Vamsi Gangaraju, Antonis Kourtidis","doi":"10.1101/2025.05.20.655197","DOIUrl":"https://doi.org/10.1101/2025.05.20.655197","url":null,"abstract":"<p><p>Reactivation of transposable elements (TEs) in somatic tissues, particularly of LINE-1, is associated with disease by causing gene mutations and DNA damage. Previous work has shown that the PIWI pathway is crucial for TE suppression in the germline. However, the status and function of this pathway has not been well characterized in differentiated somatic cells and there is lack of consensus on the role of the pathway in somatic tumorigenesis. To shed light on this conundrum, we examined the PIWI pathway in colon cancer through a combination of bioinformatic analyses and cell-based assays. Shifted Weighted Annotation Network (SWAN) analysis revealed that the pathway experiences significant allelic losses in colon cancer and that PIWIL2, the main catalytic component of the pathway responsible for TE silencing, experiences the highest percent deletions. PIWIL2 is downregulated in colon tumors of advanced stage, nodal metastasis, and in certain subtypes, correlating with poor survival, while it is even downregulated in ulcerative colitis, an inflammatory bowel disease that predisposes to colon cancer. Knockout studies in colon epithelial Caco2 cells show that PIWIL2 depletion leads to increased anchorage-independent growth, increased LINE-1 levels and activity, and in DNA damage, altogether highlighting a tumor-suppressing role of PIWIL2 in the colon.</p><p><strong>Summary statement: </strong>This study investigates the PIWI-piRNA pathway in colon cancer using a nuanced bioinformatic and cell-based approach, linking the downregulation of PIWIL2 to disease progression, transposable element activation and DNA damage.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236616","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":"Repurposing Romidepsin for Osteosarcoma: Screening FDA-Approved Oncology Drugs with Three-Dimensional Osteosarcoma Spheroids.","authors":"Emily E Seiden, Spencer M Richardson, Leah A Everitt, Gabrielle J Knafler, Gavin P Kinsella, Alyssa L Walker, Venetia A Whiteside, James D Buschbach, Deep A Gandhi, M Reza Saadatzadeh, L Daniel Wurtz, Patrick J Getty, Sheldon L Padgett, Rance M Gamblin, Michael O Childress, Christopher M Fulkerson, Karen E Pollok, Christopher D Collier, Edward M Greenfield","doi":"10.1101/2025.05.22.654354","DOIUrl":"https://doi.org/10.1101/2025.05.22.654354","url":null,"abstract":"<p><p>Osteosarcoma is the most common primary malignant bone tumor and predominantly affects children, adolescents, and young adults. It is the third most common cause of cancer-related deaths among 9-24-year-olds. Despite aggressive chemotherapeutic and surgical therapies, the survival rate is only 25% for patients with detectable lung metastases at diagnosis and only 70% in patients that present without detectable lung metastases. The poor prognosis is due to growth of metastases irrespective of whether they are initially large enough to detect clinically. It is therefore necessary to develop new methods to target the growth of lung micrometastases. An NCI panel of FDA-approved oncology drugs was therefore screened using three highly metastatic human osteosarcoma cell lines. To more closely approximate <i>in vivo</i> micro-metastases, the screen used a 3D multicellular <i>in vitro</i> osteosarcoma spheroid (sarcosphere) model. Among 13 hits from the initial screen, we identified the histone deacetylase inhibitor (HDI) romidepsin as the most promising inhibitor in secondary screens based on sarcosphere viability. Romidepsin potency was evident with and without standard-of-care chemotherapeutics (MAP: Methotrexate, Adriamycin, Cisplatin) at drug concentrations that are clinically achievable and did not affect non-transformed cells. By those criteria, romidepsin also substantially outperformed the other three FDA-approved HDIs and eight HDIs in clinical trials. Importantly, sarcospheres derived from 30-50% of human and canine patient samples were also sensitive to romidepsin with ED50s 10- to 700-fold less than the Cmax in human patients. Based on these 3-D screening approaches, romidepsin is a promising drug to repurpose for osteosarcoma.</p><p><strong>Significance statement: </strong>Our unbiased sarcosphere-based drug screen identified romidepsin as a promising candidate to repurpose for canine and human patients with metastatic osteosarcoma. This screening strategy allowed us to identify romidepsin-sensitive and -resistant patients. Sarcosphere-based screening may therefore be useful to stratify patients most likely to respond clinically to romidepsin or other drugs.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236640","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":"Contrastive Representation Learning for Single Cell Phenotyping in Whole Slide Imaging of Enrichment-free Liquid Biopsy.","authors":"Amin Naghdloo, Dean Tessone, Rajiv M Nagaraju, Brian Zhang, Jeffrey Kang, Shouyi Li, Assad Oberai, James B Hicks, Peter Kuhn","doi":"10.1101/2025.05.21.655334","DOIUrl":"https://doi.org/10.1101/2025.05.21.655334","url":null,"abstract":"<p><p>Tumor-associated cells derived from a liquid biopsy are promising biomarkers for cancer detection, diagnosis, prognosis, and monitoring. However, their rarity, heterogeneity and plasticity make precise identification and biological characterization challenging for clinical utility. Enrichment-free approaches using whole slide imaging of all circulating cells offer a comprehensive and unbiased strategy for capturing the full spectrum of tumor-associated cell phenotypes. However, current analysis methods often depend on engineered features and manual expert review, making them sensitive to technical variations and subjective biases. These limitations highlight the need for a better feature representation to improve performance and reproducibility of applications in large-scale patient cohort analyses. In this study, we present a deep contrastive learning framework for learning features of all circulating cells, enabling robust identification and stratification of single cells in whole slide immunofluorescence microscopy images. We demonstrate performance of learned features in classification of diverse cell phenotypes in the liquid biopsy, achieving an accuracy of 92.64%. We further demonstrate that learned features improve performance in downstream applications such as outlier detection and clustering. Lastly, our feature representation enables automated identification and enumeration of distinct rare cell phenotypes, achieving average F1-score of 0.93 across cell lines mimicking circulating tumor cells and endothelial cells in contrived samples and average F1-score of 0.858 across CTC phenotypes in clinical samples. This workflow has significant implications for scalable analysis of tumor-associated cellular biomarkers in clinical prognosis and personalized treatment strategies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236494","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":"Determining preclinical safety of Aclarubicin in pediatric malignancies.","authors":"Darleen S Tu, Aaron K Olson, Kimberly S Waggie, Nicolas M Garcia, Virginia J Hoglund, Stephanie Walter, Jenna R Rosinski, Harini Sadeeshkumar, Radhika Patel, Erolcan Sayar, Michael C Haffner, Lisa Maves, Jacques Neefjes, Jay F Sarthy, Elizabeth R Lawlor, Shireen S Ganapathi","doi":"10.1101/2025.05.20.654130","DOIUrl":"https://doi.org/10.1101/2025.05.20.654130","url":null,"abstract":"<p><strong>Background: </strong>Anthracyclines are among the most effective chemotherapeutic agents used to treat pediatric malignancies. However, their clinical use is limited by dose-dependent toxicities, particularly cardiotoxicity and secondary malignancies. Aclarubicin (Acla) is an anthracycline derivative that induces chromatin damage while sparing DNA, offering potential therapeutic benefit with reduced longterm toxicity.</p><p><strong>Methods: </strong>We evaluated the anti-tumor efficacy and safety profile of Acla in multiple <i>in vitro</i> pediatric cancer models and <i>in vivo</i> mouse models designed to mimic anthracycline re-treatment following prior doxorubicin (Doxo) exposure. Tumor growth, genotoxic stress, survival, and organ toxicity were assessed.</p><p><strong>Results: </strong>Acla demonstrated robust anti-tumor activity comparable to Doxo across diverse pediatric <i>in vitro</i> models. Unlike Doxo, Acla treatment did not induce significant genotoxic stress. <i>In vivo</i> , mice receiving Acla after Doxo exposure showed no evidence of cumulative cardiotoxicity or end-organ damage. In contrast, a second course of Doxo led to significant toxic mortality, but was surprisingly not attributable to classic cardiac injury.</p><p><strong>Conclusion: </strong>Our study highlights Acla as a promising anthracycline derivative for pediatric cancers, with potent anti-tumor efficacy and a superior safety profile, even following prior anthracycline exposure. These results support continued investigation of chromatin-damaging anthracyclines that can kill pediatric cancer cells without inducing genotoxic stress. In addition, our studies underscore the need to refine preclinical models to better understand both acute and chronic anthracycline toxicities in pediatric and adolescent populations.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236503","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":"Integrating Single-Cell Biophysical and Transcriptomic Features to Resolve Functional Heterogeneity in Mantle Cell Lymphoma.","authors":"Ye Zhang, Lydie Debaize, Adam Langenbucher, Jenalyn Weekes, Ioulia Vogiatzi, Teemu P Miettinen, Mingzeng Zhang, Emily Sumpena, Huiyun Liu, Sarah M Duquette, Liam Hackett, Jeremy Zhang, Sona Baghiyan, Robert A Redd, Martin Aryee, Matthew S Davids, Austin I Kim, Christine E Ryan, David M Weinstock, Scott R Manalis, Mark A Murakami","doi":"10.1101/2025.05.20.655210","DOIUrl":"https://doi.org/10.1101/2025.05.20.655210","url":null,"abstract":"<p><p>Intra-tumor heterogeneity impacts disease progression and therapeutic resistance but remains poorly characterized by conventional histologic, immunophenotypic, and molecular approaches. Single-cell biophysical properties distinguish functional phenotypes complementary to these approaches, providing additional insight into cellular diversity. Here we link both buoyant mass and stiffness to gene expression to identify clinically relevant phenotypes within primary mantle cell lymphoma (MCL) cells, employing MCL as a model of biological and clinical diversity in human cancer. Linked measurements reveal that buoyant mass and stiffness characterize B-cell development states from naïve to plasma cell and correlate with expression of oncogenic B-cell receptor signaling genes such as <i>BLK</i> and <i>CD79A</i> . Additionally, changes in cell buoyant mass within primary patient specimens <i>ex vivo</i> correlate with sensitivity to Bruton's Tyrosine Kinase inhibitors <i>in vivo</i> in MCL and chronic lymphocytic leukemia, another B-cell malignancy. These findings highlight the value of biophysical properties as biomarkers of response in pursuit of future precision therapeutic strategies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236594","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":"Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2.","authors":"Mark J Althoff, Mohd Minhajuddin, Brett M Stevens, Austin E Gillen, Stephanie Gipson, Sweta B Patel, Ian T Shelton, Regan Miller, Ana Vujovic, Anna Krug, Tracy Young, William M Showers, Monika Dzieciatkowska, Daniel Stephenson, Anit Tyagi, Jana M Ellegast, Tristen Wright, Kimberly Stegmaier, Joseph T Opferman, Angelo D'Alessandro, Clayton A Smith, Craig T Jordan","doi":"10.1101/2025.05.22.655396","DOIUrl":"https://doi.org/10.1101/2025.05.22.655396","url":null,"abstract":"<p><p>While the development of venetoclax with azacitidine (ven/aza) has improved AML therapy, drug resistance remains a major challenge. Notably, primary ven/aza-resistant AML are frequently reliant on MCL1, however, the underlying mechanisms remain unclear. Co-immunoprecipitation of MCL1 from ven/aza-resistant AML samples coupled with mass spectrometry analysis identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) as an MCL1 binding partner. This interaction results in cytoplasmic IRF2BP2 localization and loss of transcriptional repression within ven/aza-resistant leukemic stem cells (LSC). Consequently, ven/aza-resistant LSC have increased IRF2BP2 target gene expression, including acyl-CoA synthetase long-chain family member 1 ( <i>ACSL1</i> ), an essential rate-limiting enzyme for fatty acid oxidation (FAO). Inhibition of ACSL1 functionally impaired ven/aza-resistant LSC through a depletion of long-chain acyl-carnitine metabolites and FAO. Collectively, these data provide evidence for a previously undescribed mechanism by which MCL1 mediates IRF2BP2 cytoplasmic sequestration and consequent de-repression of <i>ACSL1</i> , thereby promoting ven/aza-resistance in AML.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236653","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":"Aperiodic neural dynamics define a novel signature of glioma-induced excitation-inhibition dysregulation.","authors":"Youssef E Sibih, Abraham O Dada, Emily E Cunningham, Niels Olshausen, Jasleen Kaur, Velmurugan Jayabal, Sena Oten, Sanjeev Herr, Cesar N Gonzales, Andy Daniel, Saritha Krishna, Vardhaan S Ambati, Alexander A Aabedi, Gray Umbach, Kanish Mirchia, Poortata Lalwani, Edward F Chang, David R Raleigh, Srikantan Nagarajan, David Brang, Shawn L Hervey-Jumper","doi":"10.1101/2025.05.23.655626","DOIUrl":"https://doi.org/10.1101/2025.05.23.655626","url":null,"abstract":"<p><p>Diffuse gliomas remodel neuronal circuits with prognostic and therapeutic significance for patients. Electrophysiologic measures of cortical excitability hold promise for monitoring disease progression and evaluating therapeutic responses. The power law exponent (aperiodic slope) reflects the balance between excitatory and inhibitory activity within neuronal networks, a critical aspect of normal brain function often disrupted in neurological conditions. Despite its potential, the significance of the aperiodic slope in glioma-infiltrated tissue and its underlying cellular processes has not been fully investigated. Here, we integrate multi-modal electrophysiological analysis with transcriptomic profiling to analyze the aperiodic slope in both normal and glioma-infiltrated cortex. We determine that glioma infiltration induces a flattening of the aperiodic slope, indicating a shift toward excitation dominance that varies according to tumor subtype and correlates with impairments in semantic naming. Single-nucleus RNA sequencing revealed that cortical regions with flat aperiodic slope exhibit transcriptional programs enriched in glutamatergic signaling, membrane depolarization, and excitatory synaptic transmission. The aperiodic slope responds to pharmacologically induced changes in cortical inhibition during propofol administration, a GABAA agonist. Our results establish the aperiodic slope as a robust biomarker of glioma-associated excitation-inhibition imbalance, with potential applications in tumor classification and treatment monitoring.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236418","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}