tbuckley/cabot-search huggingface dataset:
Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients
Authors: Jianzhou Chen, Antonin Levy, Ai-Ling Tian, Xuehan Huang, Guoxin Cai, Marine Fidelle, Conrad Rauber, Pierre Ly, Eugénie Pizzato, Lisa Sitterle, Gianmarco Piccinno, Peng Liu, Sylvère Durand, Misha Mao, Liwei Zhao, Valerio Iebba, Hannah Felchle, Anne-Laure Mallard de La Varende, Julius Clemens Fischer, Simon Thomas, Tim F. Greten, Jennifer C. Jones, Cecilia Monge, Sandra Demaria, Silvia Formenti, Lorenzo Belluomini, Valeria Dionisi, Christophe Massard, Pierre Blanchard, Charlotte Robert, Clément Quevrin, Eloise Lopes, Céline Clémenson, Michele Mondini, Lydia Meziani, Yizhou Zhan, Chengbing Zeng, Qingxin Cai, Daphne Morel, Roger Sun, Pierre-Antoine Laurent, Monica Mangoni, Vanessa Di Cataldo, Chiara Arilli, Maike Trommer, Simone Wegen, Sebastian Neppl, Rachel P. Riechelmann, Marcos P. Camandaroba, Elson Santos Neto, Pierre-Edouard Fournier, Nicola Segata, Peter Holicek, Lorenzo Galluzzi, Aitziber Buqué, Carolina Alves Costa Silva, Lisa Derosa, Guido Kroemer, Chuangzhen Chen, Laurence Zitvogel, Eric Deutsch
Journal: Cancer Cell (2025)

Highlights•Off-target ILDR synergizes with anti-PD-L1 to eradicate non-irradiated tumors•The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and volume•Gut composition governs the abscopal effects of ILDR combined with anti-PD-L1•ILDR and Christensenellaceae influence the emigration of intestinal mregDC to TdLNSummaryThe mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.Graphical abstract
Multimodal integration of liquid biopsy and radiology for the noninvasive diagnosis of gallbladder cancer and benign disorders
Authors: Mao Yang, Yuhao Zhao, Chen Li, Xiaoling Weng, Zhizhen Li, Wu Guo, Wenning Jia, Feiling Feng, Jiaming Hu, Haonan Sun, Bo Wang, Huaifeng Li, Ming Li, Ting Wang, Wei Zhang, Xiaoqing Jiang, Zongli Zhang, Fubao Liu, Hai Hu, Xiangsong Wu, Jianfeng Gu, Guocai Yang, Guosong Li, Hui Zhang, Tong Zhang, Hong Zang, Yan Zhou, Min He, Linhua Yang, Hui Wang, Tao Chen, Junfeng Zhang, Wei Chen, Wenguang Wu, Maolan Li, Wei Gong, Xinhua Lin, Fatao Liu, Yun Liu, Yingbin Liu
Journal: Cancer Cell (2025)
Estradiol protects against pain-facilitated fentanyl use via suppression of opioid-evoked dopamine activity in males
Authors: Jessica A. Higginbotham, Julian G. Abt, Rachel H. Teich, Joanna J. Dearman, Tania Lintz, Jose A. Morón
Journal: Neuron (2025)

Highlights•Inflammatory pain increases fentanyl self-administration selectively in males•VTA dopamine neuron response magnitude drives the magnitude of fentanyl use•Estradiol's effects on fentanyl use and dopamine activity are pain-context dependent•Estradiol suppresses fentanyl-evoked VTA dopamine in intact rats via ERβSummaryPain relief is the most frequently reported motivation for opioid misuse, but it remains unclear how pain alters reward pathway function contributing to maladaptive opioid use and whether these neuroadaptations occur in a sex-specific manner. Here, we show that persistent inflammatory pain leads to augmented fentanyl self-administration in male, not female, rats. Wireless in vivo fiber photometry recordings and chemogenetic manipulations indicate that pain-facilitated fentanyl use is mediated by enhanced ventral tegmental area dopamine (VTADA) neuron responses during self-administration. In females, ovariectomy enhances fentanyl self-administration, but the protective effects of ovarian hormones are not solely mediated by estradiol per se. Instead, pain and high estradiol states—naturally occurring in intact females or artificially produced in males—suppress fentanyl self-administration and associated VTADA activity through VTA estrogen receptor beta signaling. These findings highlight the importance of assessing hormonal factors in opioid misuse liability in the context of pain.Graphical abstract
Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer
Authors: Xueliang Wang, Yi Fang, Wei Liang, Chi Chun Wong, Huanlong Qin, Yaohui Gao, Meinong Liang, Lei Song, Yongxin Zhang, Miao Fan, Chuanfa Liu, Harry Cheuk-Hay Lau, Lixia Xu, Xiaoxing Li, Wu Song, Junlin Wang, Na Wang, Tao Yang, Mengmiao Mo, Xiang Zhang, Jingyuan Fang, Bing Liao, Joseph J.Y. Sung, Jun Yu
Journal: Cancer Cell (2025)
CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety
Authors: Cynthia L. Palmer, Britton Boras, Bernadette Pascual, Na Li, Danan Li, Scott Garza, Nanni Huser, Jing Tang Yuan, Julie A. Cianfrogna, Tae Sung, Elizabeth McMillan, Na Wei, Jason Carmody, Aubrey Nayeon Kang, Seth Darensburg, Taran Dodd, James V. Oakley, James Solowiej, Lisa Nguyen, Suvi T.M. Orr, Ping Chen, Eric Johnson, Xiu Yu, Wade C. Diehl, Gary M. Gallego, Mehran Jalaie, Rose Ann Ferre, Sujin Cho-Schultz, Hong Shen, Judith G. Deal, Qin Zhang, Timothy R. Baffi, Meirong Xu, Whijae Roh, Jennifer Lapira-Miller, Jerome Goudeau, Yanke Yu, Rajat Gupta, Kimberly Kim, Stephen G. Dann, Zhengyan Kan, John C. Kath, Sajiv K. Nair, Nichol Miller, Brion W. Murray, Andrew R. Nager, Casey Quinlan, Matthew D. Petroski, Cathy Zhang, Aida Sacaan, Todd VanArsdale, Lars Anders
Journal: Cancer Cell (2025)

Highlights•Atirmociclib (PF-07220060) is a next-generation CDK4 selective inhibitor•Impact reduction on neutrophils was in proportion to increase in CDK4 selectivity•Greater CDK4 target coverage results in deeper anti-tumor responses•Combinatorial agents further increase atirmociclib anti-tumor efficacySummaryCDK4/6 inhibitors have revolutionized treatment of hormone receptor positive (HR+), HER2 non-amplified (HER2−) breast cancer. Yet, all "dual" CDK4/6 inhibitors show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges to provide these agents at concentrations necessary to extinguish cell cycling in tumors. HR+ breast cancer cells are highly dependent on CDK4 but not CDK6. By contrast, CDK4 is dispensable for human bone marrow derived cells, due to the primary and compensatory role of CDK6 in hematopoiesis. This prompted us to develop atirmociclib (PF-07220060), a next-generation CDK4 selective inhibitor. Atirmociclib's impact on circulating neutrophils was reduced, in proportion with its increase in CDK4 versus CDK6 selectivity. Realized dose intensification led to greater CDK4 inhibition and deeper anti-tumor responses, pointing to CDK4 target coverage as a limiting factor of CDK4/6 inhibitor efficacy. We also highlight combinatorial agents that may counter acquired resistance to CDK4 selective inhibition and widen its clinical application.Graphical abstract
Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy
Authors: Huan Song, Lin Chen, Xuanxuan Pan, Yuru Shen, Maolin Ye, Guohong Wang, Can Cui, Qi Zhou, Yujen Tseng, Zheng Gong, Bin Zhong, Haoshu Cui, Shaocong Mo, Jiayue Zheng, Bryan Jin, Wanwei Zheng, Feifei Luo, Jie Liu
Journal: Cancer Cell (2025)

Highlights•STING-induced PD-L1hi Tu.Mons dominate the resistance to STING agonist therapy•Cell-intrinsic PD-L1 induced by STING-IFN-I axis drives protumoral PD-L1hi Tu.Mons•TLR2 activation rewires STING signaling to reduce cell-intrinsic PD-L1•STING agonist combined with TLR2 pre-activation shows enhanced antitumor efficacySummarySTING is an important DNA sensing machinery in initiating immune response, yet therapies targeting STING have shown poor outcomes in clinical trials. Here, we reveal that STING signaling induces PD-L1hi tumor monocytes (Tu.Mons) that dominate the resistance against STING agonist therapy. Cell-intrinsic PD-L1, induced by the STING-IRF3-IFN-I axis, is identified as the driving factor for protumoral PD-L1hi Tu.Mons. Notably, TLR2-activated Tu.Mons resist STING-induced upregulation of cell-intrinsic PD-L1 and the associated protumoral functions. Mechanistically, TLR2 stimulation remodels STING signaling by facilitating STING and TRAF6 interaction, which suppresses the IRF3-IFN-I response and enhances NF-κB activation. Moreover, we demonstrate that combining STING agonists with TLR2 agonist pretreatment significantly improves antitumor efficacy in murine syngeneic and humanized models. Our findings uncover a protumoral aspect of STING activation mediated by cell-intrinsic PD-L1 and propose a promising strategy to boost antitumor immunity by fine-tuning STING signaling outputs.Graphical abstract
Sex hormones, the anticancer immune response, and therapeutic opportunities
Authors: Fabio Conforti, Laura Pala, Diletta Di Mitri, Chiara Catania, Emilia Cocorocchio, Daniele Laszlo, Giovanni Ceresoli, Marzia Locatelli, Flaminia Facella, Tommaso De Pas, Benedetta Rambaldi, Alessandro Rambaldi, Giuseppe Viale, Vincenzo Bagnardi, Giuseppe Giaccone, Alberto Mantovani
Journal: Cancer Cell (2025)

SummarySex-based differences have been observed in the incidence and prognosis of various cancers, as well as in the response to immune check point inhibitors (ICIs). These disparities are partially attributed to sex-based differences in the molecular characteristics of the anticancer immune response, which are largely influenced by sex hormones. Here, we provide a comprehensive overview on how sex hormones affect innate and adaptive immunity and contribute to shaping the features of tumor immune microenvironment and response to anticancer immunotherapy. We also discuss the promising potential and challenges of combining sex hormone manipulation with anticancer immunotherapy as new therapeutic strategy. We surmise that a sex-based perspective should be part of precision medicine approaches, and sex hormones manipulation provides opportunities for innovative immune therapeutic approaches.
Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia
Authors: Catherine Pham-Danis, Amanda J Novak, Etienne Danis, Samantha M McClellan, Lillie Leach, Michael C Yarnell, Christopher C Ebmeier, Sarah K Tasian, M Eric Kohler
Journal: Cancer Cell (2025)

Chimeric antigen receptor (CAR) T cells induce responses in patients with relapsed/refractory leukemia; however, long-term efficacy is frequently limited by relapse. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T cells and underlies most relapses following CD22BBz CAR T cell therapy. Here, we interrogate CD22BBz CAR signaling in response to low antigen and find inefficient phosphorylation of the linker for activation of T cells (LAT) limiting downstream signaling. To overcome this, we designed the adjunctive LAT-activating CAR T cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrate reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling, and AP-1 activity. ALA-CART cells show improved cytotoxicity, proliferation, persistence, and efficacy against antigen-low leukemias that were refractory to clinically active CD22BBz CAR T cells. Restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T cell failure.
Clinical Effect of Genetic Testing in Inherited Cardiovascular Diseases
Authors: Steffany Grondin, Benjamin Neveu, Iness Soltani, Ahmed Amine Alaoui, Alexander Messina, Laurence Gaumond, Fabrice Demonière, Ken Sin Lo, Amélie Jeuken, Catherine Barahona-Dussault, Guillaume Sylvain-Drolet, Laura Robb, Johannie Gagnon, Evelyne Naas, Valérie-Anne Codina-Fauteux, Diana Margarita Victoria Moron, Sandra Therrien-Laperrière, Valérie Hay, Guillaume Lettre, Marie-A Chaix, Léna Rivard, Geneviève Giraldeau, Philippe L L'Allier, Patrick Garceau, Maxime Tremblay-Gravel, Julia Cadrin-Tourigny, Mario Talajic, Julie Amyot, Rafik Tadros
Journal: Journal of the American College of Cardiology (2025)
Best Practices for Imaging of Transcatheter Valve Failure
Authors: Omar K Khalique, Syed Zaid, Gilbert H L Tang, Mohamed Abdel-Wahab, Miriama Akodad, Vinayak N Bapat, Jeroen J Bax, Daniel J Blackman, Philipp Blanke, Sabine Bleiziffer, Davide Capodanno, Joao L Cavalcante, Lakshmi P Dasi, Ole De Backer, Matthiew De Beuel, Alison Duncan, Marc R Dweck, Miho Fukui, Aakriti Gupta, Kentaro Hayashida, Howard C Herrmann, Tsuyoshi Kaneko, Nicole Karam, Jaffar M Khan, Jan Kovac, Uri Landes, Jonathon A Leipsic, Martin B Leon, Michael J Mack, Mahesh V Madhavan, Moody M Makar, Raj R Makkar, Mouaz Al Mallah, David Meier, Thomas Modine, Atsushi Okada, Roosha K Parikh, Radoslaw Parma, Dhairya Patel, Philippe Pibarot, Bernard Prendergast, Nishath Quader, Michael J Reardon, Toby Rogers, Lucy M Safi, Stephanie L Sellers, Sabah Skaf, Giuseppe Tarantini, Didier Tchetche, Nicolas van Mieghem, Dee Dee Wang, John G Webb, Stephan Windecker, Steven J Yakubov, Victoria Delgado, Rebecca T Hahn, Hasan Jilaihawi
Journal: Journal of the American College of Cardiology (2025)
Evolution of temporomandibular joint reconstruction: from autologous tissue transplantation to alloplastic joint replacement
Authors: Hanghang Liu, Liwei Huang, Shibo Liu, Linyi Liu, Bolun Li, Zizhuo Zheng, Yao Liu, Xian Liu, En Luo
Journal: International Journal of Oral Science (2025)

Abstract The reconstruction of the temporomandibular joint presents a multifaceted clinical challenge in the realm of head and neck surgery, underscored by its relatively infrequent occurrence and the lack of comprehensive clinical guidelines. This review aims to elucidate the available approaches for TMJ reconstruction, with a particular emphasis on recent groundbreaking advancements. The current spectrum of TMJ reconstruction integrates diverse surgical techniques, such as costochondral grafting, coronoid process grafting, revascularized fibula transfer, transport distraction osteogenesis, and alloplastic TMJ replacement. Despite the available options, a singular, universally accepted ‘gold standard’ for reconstructive techniques or materials remains elusive in this field. Our review comprehensively summarizes the current available methods of TMJ reconstruction, focusing on both autologous and alloplastic prostheses. It delves into the differences of each surgical technique and outlines the implications of recent technological advances, such as 3D printing, which hold the promise of enhancing surgical precision and patient outcomes. This evolutionary progress aims not only to improve the immediate results of reconstruction but also to ensure the long-term health and functionality of the TMJ, thereby improving the quality of life for patients with end-stage TMJ disorders.
Small-diameter artery grafts engineered from pluripotent stem cells maintain 100% patency in an allogeneic rhesus macaque model
Authors: Jue Zhang, Diana Marcela Tabima, David Vereide, Weifeng Zeng, Nicholas J. Albano, Sarah Lyon, Peter J. Nicksic, Ellen C. Shaffrey, Robert E. George, Mitchell D. Probasco, Elizabeth S. Perrin, Yiyang Xu, Matthew E. Brown, Ron Stewart, Naomi C. Chesler, Lih-Sheng Turng, Samuel O. Poore, Igor I. Slukvin, James A. Thomson, John P. Maufort
Journal: Cell Reports Medicine (2025)

Highlights•A 3-mm-diameter graft is developed using PSC-derived arterial endothelial cells•MHC-WT grafts maintain 100% patency for 6 months in an allogeneic rhesus model•The graft endothelium is repopulated with host cells, ensuring the long-term patencySummaryAutologous vascular grafts, the only clinically approved option for small-diameter (<6 mm) revascularizations, require invasive harvesting and have limited availability and variable quality. To address these challenges, we develop a 3-mm-diameter artery graft by using arterial endothelial cells (AECs) derived from pluripotent stem cells (PSCs). After establishing technologies for pure AEC generation and expanded polytetrafluoroethylene (ePTFE) graft coating, we engineer artery grafts by seeding the inner lumen of ePTFE vascular grafts with either major histocompatibility complex (MHC) mismatched unmodified-wild-type (MHC-WT) AECs or MHC class I/II double knockout (MHC-DKO) AECs. Their function is evaluated in a rhesus arterial interposition grafting model. MHC-WT grafts maintained 100% patency for 6 months, significantly better than naked and MHC-DKO grafts. Additionally, the endothelium of MHC-WT grafts is repopulated with host cells, supporting long-term patency. Collectively, our study demonstrates that PSC-derived MHC-WT artery grafts provide an unlimited homogenous resource for allogeneic arterial revascularization.Graphical abstract
Efficacy of Acoramidis on All-Cause Mortality and Cardiovascular Hospitalization in Transthyretin Amyloid Cardiomyopathy
Authors: Daniel P Judge, Kevin M Alexander, Francesco Cappelli, Marianna Fontana, Pablo Garcia-Pavia, Simon D J Gibbs, Martha Grogan, Mazen Hanna, Ahmad Masri, Mathew S Maurer, Laura Obici, Prem Soman, Xiaofan Cao, Ted Lystig, Jean-François Tamby, Suresh Siddhanti, Adam Castaño, Leonid Katz, Jonathan C Fox, Kenneth W Mahaffey, Julian D Gillmore
Journal: Journal of the American College of Cardiology (2025)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed chronic disease associated with progressive heart failure that results in impaired quality of life, repeated hospitalizations, and premature death. Acoramidis is a selective, oral transthyretin stabilizer recently approved by the U.S. Food and Drug Administration for the treatment of ATTR-CM. In a phase 3, randomized, double-blind study (ATTRibute-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]), acoramidis was well tolerated and showed clinical efficacy in improving the primary endpoint, a hierarchical combination of all-cause mortality (ACM), cardiovascular-related hospitalization (CVH), N-terminal pro-B-type natriuretic peptide level, and 6-minute walk distance. The goal of this study was to characterize the efficacy of acoramidis on ACM and CVH. In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to receive acoramidis hydrochloride (800 mg twice daily) or placebo for 30 months. Efficacy analyses were conducted in the modified intention-to-treat population (participants with a baseline estimated glomerular filtration rate ≥30 mL/min/1.73 m2). CVH and the composite of ACM or first CVH were plotted by using Kaplan-Meier curves and summarized with a stratified Cox proportional hazards model. The annualized frequency of CVH was analyzed by using a negative binomial regression model. Subgroup analyses were conducted for the composite of ACM or first CVH. Of the 632 participants randomized to treatment, 611 (97%) were included in efficacy analyses (acoramidis, n = 409; placebo, n = 202). Compared with placebo, acoramidis reduced the occurrence of the composite of ACM or first CVH (acoramidis, 35.9%; placebo, 50.5%; HR: 0.64; 95% CI: 0.50-0.83; P = 0.0008) and of first CVH (acoramidis, 26.7%; placebo, 42.6%; HR: 0.60; 95% CI: 0.45-0.80; P = 0.0005), with Kaplan-Meier curves separating at month 3 and continuing to diverge through month 30. Annualized frequency of CVH was reduced with acoramidis compared with placebo (acoramidis, 0.22; placebo, 0.45; relative risk ratio: 50%; 95% CI: 0.36-0.70; P < 0.0001). The efficacy of acoramidis on the composite of ACM or first CVH was consistent across subgroups. Acoramidis was well tolerated, with no safety signals of potential clinical concern identified. In participants with ATTR-CM, acoramidis reduced the composite of ACM or first CVH vs placebo, with an early effect driven by a reduction in CVH. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).
Estimating the effects of hypothetical ambient PM <sub>2.5</sub> interventions on the risk of dementia using the parametric g-formula in the UK Biobank cohort
Authors: Chengyi Lin, Riyang Liu, Caroline Sutton, Andrew Thomas DeWan, Laura Forastiere, Kai Chen
Journal: Environmental Health Perspectives (2025)

Emerging evidence identifies ambient particulate matter with an aerodynamic diameter ≤ 2.5μm (PM2.5) as a modifiable risk factor for dementia, but the potential health benefits gained by enacting regulations that reduce PM2.5 remain unclear.
Spatial-Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and Tumor-Immune Microenvironment
Authors: Wei Lv, Yuchen Zeng, Conghui Li, Yuan Liang, Huiying Tao, Yanfen Zhu, Xiaolong Sui, Yue Li, Shiqi Jiang, Qingqing Gao, Elias Rodriguez-Fos, Gino Prasad, Yuanmei Wang, Run Zhou, Zhe Xu, Xiaoguang Pan, Linlin Chen, Xi Xiang, Huajing Teng, Chaoyang Sun, Tianyu Qin, Wei Dong, Yongwei Li, Xun Lan, Xuesong Li, Lin Lin, Lars Bolund, Huanming Yang, Roel G.W. Verhaak, Bishoy M. Faltas, Jacob B. Hansen, Sihan Wu, Paul S. Mischel, Anton G. Henssen, Vineet Bafna, Jens Luebeck, Birgitte Regenberg, Yonglun Luo, Chunhua Lin, Peng Han
Journal: Cancer Discovery (2025)

Extrachromosomal DNA (ecDNA) presents a promising target for cancer therapy; however, its spatial-temporal diversity and influence on tumor evolution and the immune microenvironment remain largely unclear. We apply computational methods to analyze ecDNA from whole-genome sequencing data of 595 urothelial carcinoma (UC) patients. We demonstrate that ecDNA drives clonal evolution through structural rearrangements during malignant transformation and recurrence of UC. This supports a model wherein tumors evolve via the selective expansion of ecDNA-bearing cells. Through multi-regional sampling of tumors, we demonstrate that ecDNA contributes to the evolution of multifocality and increased intratumoral heterogeneity. EcDNA is present in 36% of UC tumors and correlates with an immunosuppressive phenotype and poor prognosis. Single-cell RNA sequencing analyses reveal that ecDNA+ malignant cells exhibit diminished expression of major histocompatibility complex class I molecules, enabling them to evade T-cell immunity. Finally, we show that sequencing of urinary sediment-derived DNA has excellent specificity in detecting ecDNA.