tbuckley/cabot-search huggingface dataset:
The inhibitory receptor Siglec-E controls antigen-presenting cell activation and T cell–mediated transplant rejection
Authors: Thiago J. Borges, Karina Lima, Rodrigo B. Gassen, Kaifeng Liu, Yoshikazu Ganchiku, Guilherme T. Ribas, Minxue Liao, Joao I. B. Goncalves, Isadora T. Lape, Ivy A. Rosales, Yunlong Zhao, Enfu Hui, Robert L. Fairchild, Christian LeGuern, Cristina Bonorino, Stuart K. Calderwood, Joren C. Madsen, Leonardo V. Riella
Journal: Science Translational Medicine (2025)

After transplantation, inflammation and tissue injury release danger signals that activate myeloid cells, driving adaptive immune responses and acute rejection. Current immunosuppressants primarily target T cells but inadequately control innate immunity. Regulatory signals controlling innate responses in transplantation remain elusive. The sialic acid–binding immunoglobulin-like lectin-E (Siglec-E, or SigE) binds sialylated ligands to suppress inflammation. In mouse heart transplants, SigE is up-regulated in graft-infiltrating myeloid cells, including dendritic cells (DCs). SigE deficiency in recipients, but not donors, accelerates acute rejection by enhancing DC activation, nuclear factor κB (NF-κB) signaling, and tumor necrosis factor–α (TNF-α) production, thereby boosting alloreactive T cell responses. Conversely, SigE overexpression on DCs reduces activation by danger signals and their T cell allostimulatory capacity. The human homologs Siglecs-7 and -9 were up-regulated in rejecting allograft biopsies, and their higher expression correlated with improved allograft survival. Thus, SigE/7/9 is a crucial inhibitory receptor controlling antigen-presenting cell activation and T cell–mediated transplant rejection, offering therapeutic potential.
Mitigating T cell DNA damage during PARP inhibitor treatment enhances antitumor efficacy
Authors: Jiahao Liu, Xiaofei Jiao, Wei Mu, Huayi Li, Yu Xia, Yijie Wu, Li Zhu, Qing Zhong, Wen Pan, Xingzhe Liu, Minghua Xiang, Jiali Cheng, Haolong Lin, Xuejiao Zhao, Zhiyong Ding, Guang Hu, Gordon B. Mills, Ding Ma, Qinglei Gao, Yong Fang
Journal: Science Translational Medicine (2025)

Poly(ADP-ribose) polymerase inhibitors (PARPis) are a class of agents targeting DNA damage repair that have become standard therapy for epithelial ovarian cancer (EOC) and multiple other solid tumors. In addition to targeting DNA damage repair, PARPis actively modulate antitumor immune responses, with efficacy being partially dependent on T cell activity. Here, we found that patient T cells sustain DNA damage during PARPi treatment, which reduces treatment efficacy. Leveraging paired pre- and posttreatment tumor samples from a clinical trial of patients with EOC treated with neoadjuvant niraparib as monotherapy, we showed that the PARPi caused DNA damage, slowed proliferation, and increased apoptosis in T cells, which we validated both in vitro and in mouse models. A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) knockout screen in primary human T cells identified PARP1 as the principal mediator of PARPi-induced T cell death. T cell–specific deletion of PARP1 or mutating Parp1 at its binding sites in transgenic mice led to reduced T cell DNA damage during PARPi treatment, resulting in improved efficacy of PARPis, alone or in combination with immune checkpoint inhibition. We then engineered PARPi-tolerant CAR T cells using cytosine base editing, which decreased PARPi-induced PARP1 trapping and led to reduced PARPi-induced DNA damage, resulting in superior antitumor efficacy in xenograft models compared with parental CAR T cells. This study highlights the relevance of PARPi-induced DNA damage to T cells and suggests opportunities to improve the efficacy of PARPis as monotherapy or in combination with immunotherapy.
Splicing regulatory dynamics for precision analysis and treatment of heterogeneous leukemias
Authors: Meenakshi Venkatasubramanian, Leya Schwartz, Nandini Ramachandra, Joshua Bennett, Krithika R. Subramanian, Xiaoting Chen, Shanisha Gordon-Mitchell, Ariel Fromowitz, Kith Pradhan, David Shechter, Srabani Sahu, Diane Heiser, Peggy Scherle, Kashish Chetal, Aishwarya Kulkarni, Davy Lee, Jeff Zhou, Kasiani C. Myers, Elizabeth Tseng, Matthew T. Weirauch, H. Leighton Grimes, Daniel T. Starczynowski, Amit Verma, Nathan Salomonis
Journal: Science Translational Medicine (2025)

The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations remains poorly understood. Prompted by the finding that splicing uniquely resolved genetic subtypes of cancer, we developed an unsupervised computational workflow called OncoSplice to comprehensively define tumor molecular landscapes. In adult and pediatric acute myeloid leukemia (AML), OncoSplice identified the spectrum of driver genetics from splicing profiles alone, defined more than a dozen previously unreported molecular subtypes recurrent across AML cohorts, and discovered a dominant splicing subtype that partially phenocopies U2AF1 -mutant splicing. Although pediatric leukemias lack splicing factor mutations, this U2AF1 -like subtype similarly spanned pediatric and adult AML genetics and consistently predicted poor prognosis. Using long-read single-cell RNA sequencing, we confirmed that discovered U2AF1 -like splicing was shared across cell states, co-opted a healthy circadian gene program, was stable through relapse, and induced a leukemic stem cell program. Pharmacological inhibition of an implicated U2AF1 -like splicing regulator, PRMT5, rescued leukemia missplicing and inhibited leukemic cell growth. Finally, genetic deletion of IRAK4 , a common target of U2AF1 -like and PRMT5 treatment, blocked leukemia development in xenograft models and induced differentiation. This work suggests that broad splicing dysregulation, in the absence of select mutations, is a therapeutic target in heterogeneous leukemias.
Outcomes of Radium-223 and Stereotactic Ablative Radiotherapy Versus Stereotactic Ablative Radiotherapy for Oligometastatic Prostate Cancers: The RAVENS Phase II Randomized Trial
Authors: Jarey H. Wang, Alexander D. Sherry, Soha Bazyar, Philip Sutera, Noura Radwan, Ryan M. Phillips, Matthew P. Deek, Jiayun Lu, Shirl Dipasquale, Curtiland Deville, Theodore L. DeWeese, Daniel Y. Song, Hao Wang, Robert F. Hobbs, Reem Malek, Sara A. Dudley, Stephen C. Greco, Emmanuel S. Antonarakis, Catherine H. Marshall, Samuel Denmeade, Channing J. Paller, Michael A. Carducci, Kenneth J. Pienta, Orhan K. Oz, Matthew Ramotar, James L. Leenstra, Sean S. Park, Matthew C. Abramowitz, Neil Desai, Alejandro Berlin, Bradley J. Stish, Chad Tang, Phuoc T. Tran, Ana P. Kiess
Journal: Journal of Clinical Oncology (2025)

PURPOSE Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression. METHODS This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS. RESULTS From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM , BRCA1/2 , RB1 , or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04). CONCLUSION Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.
Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure
Authors: Jakub Svoboda, Daniel J. Landsburg, James Gerson, Sunita D. Nasta, Stefan K. Barta, Elise A. Chong, Michael Cook, Noelle V. Frey, Joanne Shea, Amanda Cervini, Amy Marshall, Megan Four, Megan M. Davis, Julie K. Jadlowsky, Anne Chew, Edward Pequignot, Vanessa Gonzalez, Julia Han Noll, Luca Paruzzo, Juliana Rojas-Levine, Gabriela Plesa, John Scholler, Donald L. Siegel, Bruce L. Levine, David L. Porter, Saba Ghassemi, Marco Ruella, Andrew Rech, Rachel M. Leskowitz, Joseph A. Fraietta, Wei-Ting Hwang, Elizabeth Hexner, Stephen J. Schuster, Carl H. June
Journal: New England Journal of Medicine (2025)

Chimeric antigen receptor (CAR) T cells targeting CD19 have transformed the treatment of B-cell cancers, but many patients do not have long-term remission. We designed an anti-CD19 enhanced (armored) CAR T-cell product (huCART19-IL18) that secretes interleukin-18 to enhance antitumor activity. In this study, we assessed the safety, feasibility, and preliminary efficacy of huCART19-IL18 in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy. Using a 3-day manufacturing process, we administered huCART19-IL18-positive cells in doses ranging from 3×106 to 3×108. A total of 21 patients received huCART19-IL18. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and immune effector-cell-associated neurotoxicity syndrome occurred in 14% (all grade 1 or 2). No unexpected adverse events were observed. Robust CAR T-cell expansion was detected across all dose levels. At 3 months after infusion, a complete or partial response was seen in 81% of the patients (90% confidence interval [CI], 62 to 93) and a complete response in 52% (90% CI, 33 to 71). With a median follow-up of 17.5 months (range, 3 to 34), the median duration of response was 9.6 months (90% CI, 5.5 to not reached). In this small study, huCART19-IL18 had a safety profile consistent with other CAR T-cell treatments and showed promising efficacy at low cell doses in patients with lymphoma after the failure of previous anti-CD19 CAR T-cell therapy. (ClinicalTrials.gov number, NCT04684563.).
Pegivirus-Associated Encephalomyelitis in Immunosuppressed Patients
Authors: Franziska Scheibe, Julia Melchert, Helena Radbruch, Eberhard Siebert, Till D. Best, Siegfried Kohler, Mira Fitzek, Alexander Kowski, Volker Siffrin, Jenny Meinhardt, Raphael Raspe, Viktor Horst, Bianca Zukunft, Klemens Budde, Frank K.H. van Landeghem, Christopher Power, Kai-Uwe Eckardt, Matthias Endres, Christian Drosten, Victor M. Corman, Klemens Ruprecht
Journal: New England Journal of Medicine (2025)
Augmented CD47 expression impairs alloreactive T-cell clearance after allo-HCT
Authors: Cindy Sheree Flamann, Haroon Shaikh, Carina Matos, Marina Kreutz, Hla Ali, Michael AG Kern, Maike Büttner-Herold, Benedikt Jacobs, Simon Völkl, Christopher Lischer, Christian Kellner, Johannes Berges, Katrin Bitterer, Domenica Saul, Manisha Goel, Cornelia Link-Rachner, Alma Zernecke, Daniela Andrea Weber, Dimitrios Mougiakakos, Andreas Mackensen, Andreas Beilhack, Heiko Bruns
Journal: Blood (2025)
A multiomic analysis of Waldenström macroglobulinemia defines distinct disease subtypes
Authors: Dylan C Gagler, Hussein Ghamlouch, Di Zhang, Patrick Blaney, Avital Tenenbaum, James Blake Langton, Marine Armand, Alexandre Eeckhoutte, Amina Joudat, Michaël Degaud, Michela Esposito, Gaurav Varma, Yubao Wang, Sanghoon Lee, Sanxiong Liu, Oscar B Lahoud, David Kaminetzky, Marc J. Braunstein, Louis Williams, Florence Nguyen-Khac, Brian A Walker, Damien Roos-Weil, Faith E Davies, Olivier A Bernard, Gareth J Morgan
Journal: Blood (2025)
BCG Revaccination for the Prevention of <i>Mycobacterium tuberculosis</i> Infection
Authors: Alexander C. Schmidt, Lee Fairlie, Elizabeth Hellström, Angelique Luabeya Kany Kany, Keren Middelkoop, Kogieleum Naidoo, Gonasagrie Nair, Anele Gela, Elisa Nemes, Thomas J. Scriba, Amy Cinar, Nicole Frahm, Robin Mogg, David Kaufman, Michael W. Dunne, Mark Hatherill
Journal: New England Journal of Medicine (2025)

In a previous phase 2 trial, bacille Calmette-Guérin (BCG) revaccination was not shown to provide protection from primary Mycobacterium tuberculosis infection but prevented sustained M. tuberculosis infection, defined by an initial conversion on a QuantiFERON-TB (QFT) test (an interferon-γ release assay) from negative to positive, followed by two additional positive QFT tests at 3 and 6 months after the initial conversion (a secondary end point). A vaccine efficacy of 45% (95% confidence interval [CI], 6 to 68) was observed. We performed a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of BCG revaccination, as compared with placebo, for the prevention of sustained QFT test conversion (primary end point) in QFT test-negative, human immunodeficiency virus (HIV)-negative adolescents. Adverse events were assessed in a secondary analysis, and immunogenicity was assessed in an exploratory analysis. Vaccine efficacy was evaluated in the modified intention-to-treat population, which included all the participants who had undergone randomization, received the BCG vaccine or placebo, and had a negative QFT test 10 weeks after receipt of BCG vaccine or placebo; the last criterion was added to exclude participants with M. tuberculosis infection around the time that the vaccine or placebo was administered. Hazard ratios and 95% confidence intervals were estimated from a stratified Cox proportional-hazards model. A total of 1836 participants underwent randomization; 918 received the BCG vaccine, and 917 received placebo. After a median 30 months of follow-up, a sustained QFT test conversion was observed in 62 of 871 participants in the BCG-vaccine group and 59 of 849 participants in the placebo group. The hazard ratio for a sustained QFT test conversion (BCG vaccine vs. placebo) was 1.04 (95% CI, 0.73 to 1.48), for a vaccine efficacy point estimate of -3.8% (95% CI, -48.3 to 27.4). Adverse events occurred more frequently in the BCG-vaccine group than in the placebo group, and most were due to injection-site reactions (pain, redness, swelling, and ulceration). BCG revaccination induced cytokine-positive type 1 helper CD4 T cells. BCG revaccination in QFT-test negative, HIV-negative adolescents did not provide protection from sustained M. tuberculosis infection. (Funded by the Gates Foundation; ClinicalTrials.gov number NCT04152161.).
BLAST: A Globally Applicable and Molecularly Versatile Survival Model for Chronic Myelomonocytic Leukemia
Authors: Ayalew Tefferi, Saubia Fathima, Maymona Abdelmagid, Ali Alsugair, Fnu Aperna, Mahsa Rezasoltani, Muhammad Yousuf, Anuya Natu, Clifford M Csizmar, Mark Gurney, Terra L Lasho, Christy M. Finke, Rashmi Kanagal-Shamanna, Danielle Hammond, Kelly Sharon Chien, Alexandre Bazinet, Courtney D. DiNardo, Tapan M. Kadia, Abhishek A. Mangaonkar, Naval G. Daver, Animesh D Pardanani, Gautam Borthakur, Cinthya J Zepeda-Mendoza, Kaaren K Reichard, Rong He, Sanam Loghavi, Francesco Passamonti, Farhad Ravandi, Koji Sasaki, Dirk Larson, Guillermo Garcia-Manero, Francesco Onida, Naseema Gangat, Guillermo Montalban-Bravo, Mrinal M. Patnaik
Journal: Blood (2025)
Long-read sequencing reveals novel isoform-specific eQTLs and regulatory mechanisms of isoform expression in human B cells
Authors: Yuya Nagura, Mihoko Shimada, Ryoji Kuribayashi, Ko Ikemoto, Hiroki Kiyose, Arisa Igarashi, Tadashi Kaname, Motoko Unoki, Akihiro Fujimoto
Journal: Genome biology (2025)

Genetic variations linked to changes in gene expression are known as expression quantitative loci (eQTLs). The identification of eQTLs helps to understand the mechanisms governing gene expression. However, prior studies have primarily utilized short-read sequencing techniques, and the analysis of eQTLs on isoforms has been relatively limited. In this study, we employ long-read sequencing technology (Oxford Nanopore) on B cells from 67 healthy Japanese individuals to explore genetic variations associated with isoform expression levels, referred to as isoform eQTLs (ieQTLs). Our analysis reveals 17,119 ieQTLs, with 70.6% remaining undetected by a gene-level analysis. Additionally, we identify ieQTLs that have significantly different effects on isoform expression levels within a gene. A functional feature analysis demonstrates a significant enrichment of ieQTLs at splice sites and specific histone marks, such as H3K36me3, H3K4me1, H3K4me3, and H3K79me2. Through an experimental validation using genome editing, we observe that a distant genomic region can modulate isoform-specific expression. Moreover, an ieQTL analysis and minigene splicing assays unveils functionally crucial variants in splicing that splicing prediction software did not assign a high prediction score. A comparison with GWAS data reveals a higher number of colocalizations between ieQTLs and GWAS findings compared to gene eQTLs. These findings highlight the substantial contribution of ieQTLs identified through long-read analysis in our understanding of the functional implications of genetic variations and the regulatory mechanisms governing isoforms.
Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function through the gut-brain axis
Authors: Virginia Mela, Violeta Heras, Monika Iesmantaite, María Luisa García-Martín, Manuel Bernal, Joel D Posligua-García, Alba Subiri-Verdugo, José Ignacio Martínez-Montoro, Ana María Gómez-Pérez, Borja Banderas, Isabel Moreno Indias, Francisco J Tinahones
Journal: Gut (2025)

Abstract Background Obesity-related cognitive decline is linked to gut microbiota dysbiosis, with emerging evidence suggesting that dietary interventions may ameliorate cognitive impairment via gut-brain axis modulation. The role of microglial cells in this process remains underexplored. Objective To investigate how diet-induced changes in gut microbiota influence cognitive function in individuals with obesity and their microglial activity, and to determine the impact of specific dietary interventions. Design This study included 96 participants with obesity who were randomised into three dietary intervention groups: Mediterranean diet (Med), alternate-day fasting (ADF) and ketogenic diet (Keto). Cognitive performance and microbiota composition were assessed pre-intervention and post-intervention. The effects of microbiota-related changes on microglial function were further evaluated in mice models through faecal transplantation and in vitro model with microbiota exosome treatment. Results Both the Keto and ADF groups demonstrated significant weight loss, but cognitive performance improved most notably in the ADF group, in association with reduced inflammation. Diet-related microbiota composition was correlated with the cognitive outcomes in the human study. Mice models confirmed that the cognitive benefits of ADF were microbiota-dependent and linked to enhanced microglial phagocytic capacity and reduced inflammation, accompanied by changes in microglia morphology. Conclusion Fasting-induced modifications in gut microbiota contribute to cognitive improvement in individuals with obesity, with microglial cells playing a crucial mediatory role. Among the interventions, ADF most effectively enhanced microglial function and cognitive performance, suggesting its potential as a therapeutic strategy for obesity-related cognitive decline. Further studies are required to fully elucidate the underlying mechanisms. Trial registration number NCT04453150 .
High rates of post-tuberculosis lung disease among persons successfully treated for drug-susceptible and resistant tuberculosis
Authors: Russell R Kempker, Argita D Salindri, Teona Avaliani, Hardy Kornfeld, Sara C Auld, Nino Jakobia, Cheryl L Day, Arijita Subuddhi, Krista N Krish, Sergo Vashakidze, Zaza Avaliani, Leila Goginashvili, Cassandra Bryan, Adam Bernheim, Maia Kipiani, Matthew J Magee
Journal: Thorax (2025)

Introduction Tuberculosis (TB) remains a critical global public health challenge, and there is an urgent need to improve the diagnosis and management of post-TB lung disease (PTLD). We aimed to compare end of treatment prevalence of PTLD among participants with and without drug-resistant TB and to evaluate the association between plasma cytokines and matrix metalloproteinases with lung damage. Methods We conducted a prospective cohort study among individuals with microbial cure status for drug-susceptible or multidrug-resistant pulmonary TB in Tbilisi, Georgia during 2020–2021. Eligible participants were ≥16 years without prior TB treatment history, microbiologically confirmed disease at baseline and who had a favourable treatment outcome (cured or completed treatment). The study outcome was the presence of PTLD defined as abnormalities on either chest CT, spirometry or Saint George’s Respiratory Questionnaire. Results Among 123 participants, the prevalence of PTLD was 74% (n=91) with 53 participants meeting one criteria, 27 two criteria and 11 all three criteria. The prevalence of impaired respiratory health (47%) and lung damage on imaging (46%) was higher than abnormal lung function (21%). PTLD was not associated with drug resistance (adjusted OR 0.91, 95% CI 0.42 to 1.99). Persistent cavitary disease at the end of treatment was associated with higher matrix metalloproteinase 8 and lower matrix metalloproteinase 2, interleukin-17A and interleukin-1ß. Conclusion Using comprehensive criteria, we found nearly three in four individuals with microbial cure status for TB disease had prevalent PTLD regardless of drug resistance status. Persistent cavitary disease was associated with serum markers of inflammation and lung tissue remodelling.