tbuckley/cabot-search huggingface dataset:
Succinate-loaded tumor cell–derived microparticles reprogram tumor-associated macrophage metabolism
Authors: Shuya Lu, Jiexiao Li, Yonggang Li, Shichuan Liu, Yutong Liu, Yue Liang, Xifen Zheng, Yiyang Chen, Jinghui Deng, Huafeng Zhang, Jingwei Ma, Jiadi Lv, Yugang Wang, Bo Huang, Ke Tang
Journal: Science Translational Medicine (2025)

The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded with succinate (SMPs) can remodel the metabolic state of TAMs. SMPs promote classical M1-like polarization of macrophages by enhancing glycolysis and attenuating the tricarboxylic acid (TCA) cycle in a protein succinylation–dependent manner. Mechanistically, succinate is delivered into the mitochondria and nucleus by SMPs, leading to succinylation of isocitrate dehydrogenase 2 (IDH2) and histone H3K122 within the lactate dehydrogenase A ( Ldha ) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane–derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification–based tumor immunotherapy.
Association between generation of cephalosporins and surgical site infection in open fractures: a prospective cohort study
Authors: Zhenbang Yang, Hongyu Meng, Junyong Li, Pei Du, Hongzhi Lv, Kuo Zhao, Junzhe Zhang, Ming Li, Zhucheng Jin, Ziheng Peng, Dandan Ye, Kai Ding, Zhaohui Song, Juan Wang, Xin Xing, Yanbin Zhu, Yingze Zhang, Wei Chen
Journal: International Journal of Surgery (2025)

Background: The use of cephalosporins for surgical site infection (SSI) prevention has become a clinical routine, however, high-level evidence regarding the optimal generation for open fractures is currently limited. This study aims to investigate the association between the generation of cephalosporins and SSI risk in open fractures. Methods: This prospective cohort study used data from the Surgical Site Infection in Orthopedic Surgery (SSIOS), a prospectively maintained database, conducted at a tertiary orthopedic university hospital from October 2014 to December 2020. The primary outcome was occurrence of SSI within 1 year after operation, and its association with the generation of cephalosporins was examined using multivariable logistic regressions and generalized estimating equations. Generalized additive models were used to calculate the relative contribution of potential factors likely influencing SSI. Results: A total of 3582 eligible patients, 74.6% males, with a mean age of 43.7 ± 14.1 years, were included. First-, second-, and third-generation cephalosporins were used in 1957 (54.6%), 1219 (34.0%), and 406 (11.3%) patients. Compared to first-generation cephalosporins, the use of second-generation cephalosporins was significantly associated with a higher risk of SSI (absolute risk difference [ARD] = 3.70%; 95% CI, 1.90%–5.51%; adjusted OR [aOR] = 1.604; 95% CI, 1.212–2.124), whereas third-generation cephalosporins were not (ARD = 1.02%; 95% CI, −1.78% to 3.82%; aOR = 1.234; 95% CI, 0.790–1.880). Among the 28 potential factors considered, the generation of cephalosporins was ranked 9th in terms of its impact on the risk of SSI. Conclusion: Perioperative use of higher-generation cephalosporins was not associated with a reduction in postoperative surgical site infections in open fractures. Our study supports existing guidelines that recommend the use of first-generation cephalosporins as the preferred agents for preventing SSIs in open fractures.
Hepatitis B virus resistance to nucleos(t)ide analogue therapy: WHO consultation on questions, challenges, and a roadmap for the field
Authors: Sheila F Lumley, Jolynne Mokaya, Tongai G Maponga, Anna Kramvis, Geoffrey Dusheiko, William Irving, Marion Delphin, Khadija Said Mohammed, Louise O Downs, Elizabeth Waddilove, Motswedi Anderson, Collins Iwuji, Nokukhanya Msomi, Ponsiano Ocama, Saeed Hamid, Danjuma Adda, Rachel Halford, Kenneth Kabagambe, Kimberley S M Benschop, Seth Inzaule, Polin Chan, Margaret Alia Samson Paul, Kiyohiko Izumi, Tiara Nisa, Jean De Dieu Iragena, Amalia Girón-Callejas, Aboudou Raïmi Kpossou, Ganiyu Jamiyu, Omolara Emmanuel, Mahamadou Balkissa, Mamadou Keita, Nishi Prabdial-Sing, Alexander Martinez, Eleanor Namusoke Magongo, Yiming Shao, Omar Sued, Leandro Soares Sereno, Robert W Shafer, Olufunmilayo Lesi, Diana Faini, Philippa Easterbrook, Chris Duncombe, Michael R Jordan, Philippa C Matthews
Journal: The Lancet Microbe (2025)

In this Review, we summarise outputs from a multidisciplinary consultation convened by WHO between July 11 and 13, 2023, to discuss hepatitis B virus (HBV) drug resistance (HBVDR). Treatment of chronic HBV infection with highly effective nucleos(t)ide analogue agents, tenofovir and entecavir, is a crucial intervention that supports the global goal of elimination of HBV infection as a public health threat. The risk of HBVDR as a threat to treatment outcomes is currently considered low from a public health perspective; however, drug resistance can influence individual outcomes, particularly among those who are treatment-experienced. We highlight the need to develop appropriate prevention, monitoring, and surveillance approaches for HBVDR, to support investment in the global scale-up of HBV diagnosis and treatment. Recommendations for the HBVDR field will ultimately be incorporated into a WHO integrated Global Action Plan for drug-resistant HIV, viral hepatitis, and priority sexually transmitted infections.
Filtering cells with high mitochondrial content depletes viable metabolically altered malignant cell populations in cancer single-cell studies
Authors: Josephine Yates, Agnieszka Kraft, Valentina Boeva
Journal: Genome biology (2025)

Abstract Background Single-cell transcriptomics has transformed our understanding of cellular diversity, yet noise from technical artifacts and low-quality cells can obscure key biological signals. A common practice is filtering out cells with a high percentage of mitochondrial RNA counts (pctMT), typically indicative of cell death. However, commonly used filtering thresholds, primarily derived from studies on healthy tissues, may be overly stringent for malignant cells, which often naturally exhibit higher baseline mitochondrial gene expression. Results We examine nine public single-cell RNA-seq datasets from various cancers, including 441,445 cells from 134 patients, and public spatial transcriptomics data, assessing the viability of malignant cells with high pctMT. Our analysis reveals that malignant cells exhibit significantly higher pctMT than nonmalignant cells, without a notable increase in dissociation-induced stress scores. Malignant cells with high pctMT show metabolic dysregulation, including increased xenobiotic metabolism, relevant to therapeutic response. Analysis of pctMT in cancer cell lines further reveals links to drug resistance. We also observe associations between pctMT and malignant cell transcriptional heterogeneity, as well as patient clinical features. Conclusions This study provides insights into the functional characteristics of malignant cells with elevated pctMT, challenging current quality control practices in tumor single-cell RNA-seq analyses and offering potential improvements in data interpretation for future cancer studies.
Assessment of a Polygenic Risk Score in Screening for Prostate Cancer
Authors: Jana K. McHugh, Elizabeth K. Bancroft, Edward Saunders, Mark N. Brook, Eva McGrowder, Sarah Wakerell, Denzil James, Reshma Rageevakumar, Barbara Benton, Natalie Taylor, Kathryn Myhill, Matthew Hogben, Netty Kinsella, Aslam A. Sohaib, Declan Cahill, Stephen Hazell, Samuel J. Withey, Naami Mcaddy, Elizabeth C. Page, Andrea Osborne, Sarah Benafif, Ann-Britt Jones, Dhruv Patel, Dean Y. Huang, Kaljit Kaur, Bradley Russell, Ray Nicholson, Fionnuala Croft, Justyna Sobczak, Claire McNally, Fiona Mutch, Samantha Bennett, Lenita Kingston, Questa Karlsson, Tokhir Dadaev, Sibel Saya, Susan Merson, Angela Wood, Nening Dennis, Nafisa Hussain, Alison Thwaites, Syed Hussain, Imran Rafi, Michelle Ferris, Pardeep Kumar, Nicholas D. James, Nora Pashayan, Zsofia Kote-Jarai, Rosalind A. Eeles
Journal: New England Journal of Medicine (2025)

The incidence of prostate cancer is increasing. Screening with an assay of prostate-specific antigen (PSA) has a high rate for false positive results. Genomewide association studies have identified common germline variants in persons with prostate cancer, which can be used to calculate a polygenic risk score associated with risk of prostate cancer. We recruited persons 55 to 69 years of age from primary care centers in the United Kingdom. Using germline DNA extracted from saliva, we derived polygenic risk scores from 130 variants known to be associated with an increased risk of prostate cancer. Participants with a polygenic risk score in the 90th percentile or higher were invited to undergo prostate cancer screening with multiparametric magnetic resonance imaging (MRI) and transperineal biopsy, irrespective of PSA level. Among 40,292 persons invited to participate, 8953 (22.2%) expressed interest in participating and 6393 had their polygenic risk score calculated; 745 (11.7%) had a polygenic risk score in the 90th percentile or higher and were invited to undergo screening. Of these 745 participants, 468 (62.8%) underwent MRI and prostate biopsy; prostate cancer was detected in 187 participants (40.0%). The median age at diagnosis was 64 years (range, 57 to 73). Of the 187 participants with cancer, 103 (55.1%) had prostate cancer classified as intermediate or higher risk according to the 2024 National Comprehensive Cancer Network (NCCN) criteria, so treatment was indicated; cancer would not have been detected in 74 (71.8%) of these participants according to the prostate cancer diagnostic pathway currently used in the United Kingdom (high PSA level and positive MRI results). In addition, 40 of the participants with cancer (21.4%) had disease classified as unfavorable intermediate risk or as high or very high risk according to NCCN criteria. In a prostate cancer screening program involving participants in the top decile of risk as determined by a polygenic risk score, the percentage found to have clinically significant disease was higher than the percentage that would have been identified with the use of PSA or MRI. (Funded by the European Research Council Seventh Framework Program and others; BARCODE1 ClinicalTrials.gov number, NCT03857477.).
Targetable Mutations in <i>BRAF</i> V600E–Negative Hairy-Cell Leukemia
Authors: Alessia Santi, Alessandra Venanzi, Alessandra Pucciarini, Gianluca Schiavoni, Marta Naccari, Elisa Albi, Lorenzo De Paoli, Tamara Intermesoli, Stefano Lazzi, Esmeralda Conte, Alessandro Mancini, Brunangelo Falini, Alessandro Gozzetti, Gianna M. D’Elia, Angelo Genua, Enrico Tiacci
Journal: New England Journal of Medicine (2025)
TF Profiler: a transcription factor inference method that broadly measures transcription factor activity and identifies mechanistically distinct networks
Authors: Taylor Jones, Rutendo F Sigauke, Lynn Sanford, Dylan J Taatjes, Mary A Allen, Robin D Dowell
Journal: Genome biology (2025)

TF Profiler is a method of inferring transcription factor (TF) regulatory activity, i.e., when a TF is present and actively participating in the regulation of transcription, directly from nascent sequencing assays such as PRO-seq and GRO-seq. While ChIP assays have measured DNA localization, they fall short of identifying when and where the effector domain of a transcription factor is active. Our method uses RNA polymerase activity to infer TF effector domain activity across hundreds of data sets and transcription factors. TF Profiler is broadly applicable, providing regulatory insights on any PRO-seq sample for any transcription factor with a known binding motif.
Integration of functional genomics and statistical fine-mapping systematically characterizes adult-onset and childhood-onset asthma genetic associations
Authors: Xiaoyuan Zhong, Robert Mitchell, Christine Billstrand, Emma E Thompson, Noboru J Sakabe, Ivy Aneas, Isabella M Salamone, Jing Gu, Anne I Sperling, Nathan Schoettler, Marcelo A Nóbrega, Xin He, Carole Ober
Journal: Genome Medicine (2025)

Abstract Background Genome-wide association studies (GWAS) have identified hundreds of loci underlying adult-onset asthma (AOA) and childhood-onset asthma (COA). However, the causal variants, regulatory elements, and effector genes at these loci are largely unknown. Methods We performed heritability enrichment analysis to determine relevant cell types for AOA and COA, respectively. Next, we fine-mapped putative causal variants at AOA and COA loci. To improve the resolution of fine-mapping, we integrated ATAC-seq data in blood and lung cell types to annotate variants in candidate cis -regulatory elements (CREs). We then computationally prioritized candidate CREs underlying asthma risk, experimentally assessed their enhancer activity by massively parallel reporter assay (MPRA) in bronchial epithelial cells (BECs) and further validated a subset by luciferase assays. Combining chromatin interaction data and expression quantitative trait loci, we nominated genes targeted by candidate CREs and prioritized effector genes for AOA and COA. Results Heritability enrichment analysis suggested a shared role of immune cells in the development of both AOA and COA while highlighting the distinct contribution of lung structural cells in COA. Functional fine-mapping uncovered 21 and 67 credible sets for AOA and COA, respectively, with only 16% shared between the two. Notably, one-third of the loci contained multiple credible sets. Our CRE prioritization strategy nominated 62 and 169 candidate CREs for AOA and COA, respectively. Over 60% of these candidate CREs showed open chromatin in multiple cell lineages, suggesting their potential pleiotropic effects in different cell types. Furthermore, COA candidate CREs were enriched for enhancers experimentally validated by MPRA in BECs. The prioritized effector genes included many genes involved in immune and inflammatory responses. Notably, multiple genes, including TNFSF4 , a drug target undergoing clinical trials, were supported by two independent GWAS signals, indicating widespread allelic heterogeneity. Four out of six selected candidate CREs demonstrated allele-specific regulatory properties in luciferase assays in BECs. Conclusions We present a comprehensive characterization of causal variants, regulatory elements, and effector genes underlying AOA and COA genetics. Our results supported a distinct genetic basis between AOA and COA and highlighted regulatory complexity at many GWAS loci marked by both extensive pleiotropy and allelic heterogeneity.
Impact of quasi-elimination of Wuchereria bancrofti on HIV incidence in southwest Tanzania: a 12-year prospective cohort study
Authors: Inge Kroidl, Thomas F Marandu, Lucas Maganga, Sacha Horn, Agatha Urio, Antelmo Haule, Jacklina Mhidze, Jonathan Mnkai, Maureen Mosoba, Elizabeth Ntapara, Nhamo Chiwarengo, Petra Clowes, Bettina Pitter, Friedrich Riess, Basel Habboub, Elmar Saathoff, Manuel Ritter, Achim Hoerauf, Leonard Maboko, Christof Geldmacher, Nyanda E Ntinginya, Michael Hoelscher, Mkunde Chachage
Journal: The Lancet HIV (2025)
Trends in population exposure to compound extreme-risk temperature and air pollution across 35 European countries: a modelling study
Authors: Zhao-Yue Chen, Hicham Achebak, Hervé Petetin, Raúl Fernando Méndez Turrubiates, Yuming Guo, Carlos Pérez García-Pando, Joan Ballester
Journal: The Lancet Planetary Health (2025)
Bortezomib, melphalan, and prednisone with or without daratumumab in transplant-ineligible patients with newly diagnosed multiple myeloma (ALCYONE): final analysis of an open-label, randomised, multicentre, phase 3 trial
Authors: Maria-Victoria Mateos, Jesus San-Miguel, Michele Cavo, Kenshi Suzuki, Andrzej Jakubowiak, Stefan Knop, Chantal Doyen, Paulo Lucio, Zsolt Nagy, Ludek Pour, Sebastian Grosicki, Andre Crepaldi, Anna Marina Liberati, Philip Campbell, Sung-Soo Yoon, Genadi Iosava, Tomoaki Fujisaki, Mamta Garg, Mai Ngo, Eva G Katz, Maria Krevvata, Kasey Bolyard, Robin Carson, Fredrik Borgsten, Meletios A Dimopoulos
Journal: The Lancet Oncology (2025)
A rare clinical case of a gastric adenocarcinoma of fundic gland-type associated with a second independent gastric signet-ring cell carcinoma
Authors: Mamadou Diakite, Aïmène Khiari, Eukene Rojo, Pierre Lafeuille, Jérôme Rivory, Tanguy Fenouil, Mathieu Pioche
Journal: Endoscopy (2025)
Guiding clinical management of patients with CNS lymphomas by minimal-invasive detection of ctDNA in cerebrospinal fluid
Authors: S Weinschenk, U Philipp, J C Kuehn, K Mueller, J Fauser, D Boeckle, I Gebhard, M Hinz, N Neidert, S Bleul, E M Lauer, J A Mutter, S K Alig, D M Kurtz, J Finke, R Marks, M Diehn, A A Alizadeh, P C Reinacher, J Wehrle, U Keller, D Wolf, F Kocher, B Chapuy, J Beck, M Prinz, L von Baumgarten, E Schorb, J Duyster, F Scherer
Journal: Leukemia (2025)
Curriculum for training in peroral endoscopic myotomy (POEM) in Europe (Part I): European Society of Gastrointestinal Endoscopy (ESGE) Position Statement
Authors: Enrique Rodríguez de Santiago, David J. Tate, Ian M. Gralnek, Tony C. Tham, João Santos-Antunes, Sandra Nagl, Zuzana Vacková, Marcel Tantau, Isis K. Araujo, Eduardo Guimarães Hourneaux de Moura, Pietro Familiari, Helmut Messmann, Alanna Ebigbo, Paul Fockens, Raf Bisschops, Henriette Heinrich, Eduardo Albéniz, Amrita Sethi, Oleksandr Kiosov, Jan Martinek, Roy Soetikno
Journal: Endoscopy (2025)

Main Recommendations Peroral endoscopic myotomy (POEM) is an advanced endoscopic procedure that has become a first-line treatment for esophageal achalasia and other esophageal spastic disorders. Structured training is essential to optimize the outcomes of this technique. The European Society of Gastrointestinal Endoscopy (ESGE) has recognized the need to formalize and enhance training in POEM. This Position Statement presents the results of a systematic review of the literature and a formal Delphi process, providing recommendations for an optimal training program in POEM that aims to produce endoscopists competent in this procedure. In a separate document (POEM curriculum Part II), we provide technical guidance on how to perform the POEM procedure based on the best available evidence. 1 POEM trainees should acquire a comprehensive theoretical knowledge of achalasia and other esophageal motility disorders that encompasses pathophysiology, diagnostic tool proficiency, clinical outcome assessment, potential adverse events, and periprocedural management. 2 Experience in advanced endoscopic procedures (endoscopic mucosal resection and/or endoscopic submucosal dissection [ESD]) is encouraged as a beneficial prerequisite for POEM training. 3 ESGE suggests that POEM trainees without ESD experience should perform an indicative minimum number of 20 cases on ex vivo or animal models before advancing to human POEM cases with an experienced trainer. 4 ESGE recommends that the trainee should observe an indicative minimum number of 20 live cases at expert centers before starting to perform POEM in humans. 5 The trainee should undertake an indicative minimum number of 10 cases under expert supervision for the initial human POEM procedures, ensuring that trainees can complete all POEM steps independently. 6 ESGE recommends avoiding complex POEM cases during the early training phase. 7 POEM competence should reflect the technical success rate, both the short- and long-term clinical success rates, and the rate of true adverse events. 8 A POEM center should maintain a prospective registry of all procedures performed, including patient work-up and outcomes, procedural techniques, and adverse events.
Asciminib monotherapy in patients with chronic myeloid leukemia in chronic phase without BCR::ABL1T315I treated with at least 2 prior TKIs: Phase 1 final results
Authors: Andreas Hochhaus, Dong-Wook Kim, Jorge E Cortes, Koji Sasaki, Michael J Mauro, Timothy P Hughes, Massimo Breccia, Moshe Talpaz, Hironobu Minami, Yeow Tee Goh, Daniel J DeAngelo, Fabian Lang, Oliver Ottmann, Michael C Heinrich, Valle Gomez Garcia de Soria, Philipp le Coutre, Gessami Sanchez-Olle, Meng Cao, Nathalie Pognan, Shruti Kapoor, Matthias Hoch, Delphine Rea
Journal: Leukemia (2025)

Abstract Asciminib is the first approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP). The present final analysis of the phase 1, open-label, nonrandomized trial (NCT02081378) assessed the long-term safety, tolerability, and antileukemic activity of asciminib in 115 patients with chronic myeloid leukemia in chronic phase without the BCR::ABL1 T315I mutation who received asciminib 10–200 mg twice daily (BID) or 80–200 mg once daily (cutoff: March 14, 2023). Median exposure duration was 5.9 (range, 0–8.4) years; 60.9% of patients continued receiving asciminib through post-trial access. Grade ≥3 adverse events (AEs) occurred in 88 patients (76.5%). AEs led to treatment discontinuation, dose adjustment/interruption, or additional therapy in 15 (13.0%), 74 (64.3%), and 106 (92.2%) patients, respectively. Most first-ever AEs, particularly hematologic AEs, presented within the first year and no new safety signals emerged. Of 56 patients who achieved major molecular response, 50 maintained the response by cutoff; the Kaplan-Meier-estimated probability of maintaining this response for ≥432 weeks ( ≈ 8.3 years) was 88% (95% confidence interval, 78.2–97.0%). The recommended dose for expansion was determined at 40 mg BID. With up to 8.4 years of treatment, asciminib continued to demonstrate long-term safety and efficacy in this population.
DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes
Authors: Fadimana Kaya, Findlay Bewicke-Copley, Juho J Miettinen, Pedro Casado, Eve Leddy, Özgen Deniz, Vincent-Philippe Lavallée, Celine Philippe, Jiexin Zheng, Florian Grebien, Naeem Khan, Szilvia Krizsán, Joseph Saad, Alexis Nolin-Lapalme, Josée Hébert, Sébastien Lemieux, Eric Audemard, Janet Matthews, Marianne Grantham, Doriana Di Bella, Krister Wennerberg, Alun Parsons, John Gribben, James D Cavenagh, Sylvie D Freeman, Csaba Bödör, Guy Sauvageau, Jun Wang, Pilar Llamas-Sillero, Jean-Baptiste Cazier, David C Taussig, Dominique Bonnet, Pedro R Cutillas, Caroline A Heckman, Jude Fitzgibbon, Kevin Rouault-Pierre, Ana Rio-Machin
Journal: Leukemia (2025)

Abstract The t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics, and drug screening with &gt;500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor &amp; Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of FOXC1 and HOX genes that are key leukemia mediators. CUT&amp;RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of FOXC1 and HOXA/B clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population.