tbuckley/cabot-search huggingface dataset:
Cost–utility analysis of the DREAMS START intervention for people living with dementia and their carers: a within-trial economic evaluation
Authors: Lina Gonzalez, Penny Rapaport, Gill Livingston, Sarah Amador, Mariam O Adeleke, Julie A Barber, Sube Banerjee, Georgina Charlesworth, Chris Clarke, Colin A Espie, Simon D Kyle, Malgorzata Raczek, Zuzana Walker, Lucy Webster, Monica Manela, Rachael Maree Hunter
Journal: The Lancet Healthy Longevity (2025)
Effect of household air pollution on the gut microbiome and virome of adult women living in Uganda
Authors: Ching-Ying Huang, Edwin Nuwagira, Michael Tisza, Minsik Kim, Mellon Tayebwa, Jacob Vieira, Nicholas Lam, Eli Wallach, Matthew Wiens, Alexander C. Tsai, Linda Valeri, Jose Vallarino, Joseph G. Allen, Peggy S. Lai
Journal: Environmental Health Perspectives (2025)

Emerging observational studies suggest air pollution can influence the gut microbiome. However, this association is often highly confounded by factors such as diet and poverty. The gut virome may influence respiratory health independent of the gut microbiome. We recently demonstrated in a randomized waitlist-controlled trial (ClinicalTrials.gov NCT03351504) that a clean lighting intervention reduced personal exposure to air pollution among adult women in rural Uganda. To determine the effect of a solar lighting intervention on changes to the gut microbiome and virome and secondarily to determine association between these changes on lung health. Between 2018 and 2019, we collected stool samples and assessed respiratory symptoms and spirometry from 80 adult women living in rural Uganda at baseline, 12 and 18 months post-randomization. The intervention group received a solar lighting system after randomization, while the waitlist-controlled group received one at 12 months. Deep metagenomics sequencing of stool was performed and profiled for non-viral and viral taxonomic composition. The primary analysis focused on pre- vs. post-intervention changes due power considerations, adjusting for potential confounding by age, diet, antibiotic use, and season. A sensitivity analysis was conducted using intention-to-treat principles. When comparing pre- vs. post-intervention periods, we used sparse partial least squares models to identify non-viral and viral signatures of reduced air pollution exposure. Mixed effects models were used to evaluate changes in health outcomes as well as associations between microbial signatures of reduced air pollution exposure and health. The average age was 39.2 years. The solar lighting intervention led to larger changes in viral compared to non-viral microbial community structure and differential abundance of bacteria, eukaryotes, and viruses. Provision of solar lighting systems was associated with a reduction in the presence of respiratory symptoms from 57.1% to 36.1% (p = 0.002) while there was no impact on lung function. Microbiome and virome signatures had AUCs of 0.74 and 0.76 respectively, in predicting pre- vs. post-intervention stool samples. Microbiome signatures were associated with a lower risk of respiratory symptoms (OR 0.68 (0.49-0.94), p = 0.020). Among adult women living in rural Uganda, both non-viral and viral components of the gut microbial community changed after a clean lighting intervention. Microbiome signatures reflective of lower air pollution exposures were associated with improved respiratory symptoms. These observations suggest that air pollution may influence lung health through the gut-lung axis, warranting further exploration in future intervention studies. https://doi.org/10.1289/EHP16002.
Mechanism of Initial Favorable Response to Decitabine in <i>TP53</i>-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse
Authors: Nelson K.L. Ng, Stephen S.Y. Lam, Lichuan Zheng, Xingliang Liu, Mingxuan Liang, Lam Ng, Koon C. Chan, Chun X. Zhang, Rachel L.S. Tse, Arthur K.L. Cheung, Ho-Wan Ip, Chun H. Au, Edmond S.K. Ma, Chi T. Ng, Ying Ni, Run S. Li, Guang S. Ling, Suet Y. Leung, Asif Javed, Anskar Y.H. Leung
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Myelodysplastic syndrome and acute myeloid leukemia with complex and monosomy karyotypes show a high prevalence of TP53 mutations (TP53m), poor response to induction chemotherapy, and adverse outcomes. These diseases may respond to decitabine, but the mechanisms are presently unclear. Experimental Design: Patients with myelodysplastic syndrome and acute myeloid leukemia were treated with decitabine for 10 days in a phase II clinical study. In this study, we collected serial samples from patients before and at the completion of decitabine treatment, morphologic remission, and relapse. The samples were interrogated with targeted myeloid panel sequencing, nanopore DNA cytosine methylation sequencing, and single-cell transcriptomics to investigate potential interactions between leukemic and immune populations. Results: The integrative analysis allowed for the characterization of shifting dynamics within leukemic and immune cell populations in individual patients. Single-cell transcriptomic analyses confirmed immune activation in TP53m responders after decitabine treatment. At relapse, leukemic populations showed upregulation of MYC signaling and heat shock response, whereas T cells showed an exhaustion signature. Conclusions: Our work highlighted the complex interplay between leukemic and immune populations in TP53m patients upon decitabine treatment that might account for clinical responses and subsequent relapses.
Mind Care: The Moral Significance of the Dementia Caregiving Dyad
Authors: Andrew Peterson, Emily A. Largent, Jason Karlawish
Journal: The American Journal of Bioethics (2025)

Caregiving for persons living with dementia has long been conceived as a series of tasks that sustain the body. Tasks such as these describe the work of caregiving for a person living with dementia, but they do not adequately define the practice of caregiving. The central premise of this essay is that caregiving is body care, but it is also mind care. In this article, we describe how mind care occurs within the caregiving dyad. Utilizing the extended mind thesis developed in the philosophical literature, we characterize the dyad as a kind of mental extension. We then suggest that mental extension may also be related to the support of the self and the moral person. We conclude by highlighting how this theory informs dementia care and policy.
Associations of Concurrent Hypertension and Type 2 Diabetes With Mortality Outcomes: A Prospective Study of U.S. Adults
Authors: Ye Yuan, Carmen R. Isasi, Tala Al-Rousan, Arnab K. Ghosh, Pricila H. Mullachery, Priya Palta, Nour Makarem
Journal: Diabetes Care (2025)

OBJECTIVE To investigate associations of concurrent hypertension and type 2 diabetes (T2D) with mortality in U.S. adults and elucidate differences by sex, race, and ethnicity. RESEARCH DESIGN AND METHODS The study population included 48,727 adults from the 1999–2018 National Health and Nutrition Examination Surveys. Participants were categorized into four mutually exclusive categories: 1) no hypertension and no T2D, 2) hypertension only, 3) T2D only, and 4) coexisting hypertension and T2D. Outcomes were all-cause and cardiovascular mortality defined using ICD-10 codes. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to evaluate associations of hypertension and T2D status with mortality risk. RESULTS The burden of concurrent hypertension and T2D doubled between 1999 and 2018 from 6 to 12%. Overall, 50.5% of participants did not have T2D or hypertension, 38.4% had hypertension only, 2.4% had T2D only, and 8.7% had both. During a 9.2-year median follow-up, 7,734 deaths occurred. Concurrent hypertension and T2D versus no hypertension or T2D predicted higher all-cause (hazard ratio 2.46 [95% CI 2.45, 2.47]) and cardiovascular mortality risk (2.97 [2.94, 3.00]), with stronger associations in females versus males (P for interaction &amp;lt; 0.01). Compared with having hypertension or T2D only, concurrent hypertension and T2D predicted up to 66% and more than twofold higher all-cause and cardiovascular mortality risk, respectively, and associations varied by sex and race and ethnicity (P for interaction &amp;lt; 0.01), depending on the reference group (T2D only or hypertension only). Concurrent prediabetes and elevated blood pressure predicted up to 19% higher mortality risk compared with having neither or either condition. CONCLUSIONS Concurrent hypertension and T2D predict high mortality risk, underscoring the critical need for contextual interventions that extend healthspan in the U.S.
Good FFRCT Test-Retest Reproducibility
Authors: Nadia Iraqi, Martin Bødtker Mortensen, Niels Peter Rønnow Sand, Martin Busk, Kristian Tækker Madsen, Erik Lerkevang Grove, Kamilla Bech Pedersen, Helle Kanstrup, Timothy A. Fairbairn, Erik Parner, Jesper Møller Jensen, Bjarne Linde Nørgaard
Journal: JACC. Cardiovascular imaging (2025)
Severe Aortic Stenosis With High Noncalcific Aortic Valve Volume
Authors: Davide Margonato, Hideki Koike, Miho Fukui, Takahiro Nishihara, Felipe Kazmirczak, Victor Cheng, John Lesser, Marc R. Dweck, Maurice Enriquez-Sarano, João L. Cavalcante
Journal: JACC. Cardiovascular imaging (2025)
Smart biomimetic “nano-med-fireman” blocking inflammation and lactate metabolism crosstalk for normalized spatiotemporal photo-immunotherapy
Authors: Honglin Huang, Ningxi Li, Li Zeng, Qianyi Zeng, Ziman Yang, Jinyang Shen, Xiaodan Wei, Hong Yang, Dengfeng Wang, Yiyao Liu, Chunhui Wu
Journal: Bioactive Materials (2025)
Autophagy is an upstream mediator of chromatin dynamics in normal and autoimmune germinal centre B cells
Authors: Marta C Sallan, Filip Filipsky, Christina H Shi, Elena Pontarini, Manuela Terranova-Barberio, Gordon Beattie, Andrew Clear, Michele Bombardieri, Kevin Y Yip, Dinis Parente Calado, Mark S Cragg, Sonya James, Matthew J Carter, Jessica Okosun, John G Gribben, Tanya Klymenko, Andrejs Braun
Journal: Journal of Clinical Investigation (2025)

Germinal centre (GC) B cells are pivotal in establishing a robust humoral immune response and long-term serological immunity while maintaining antibody self-tolerance. GC B cells rely on autophagy for antigen presentation and homeostatic maintenance. However, these functions, primarily associated with the light zone, cannot explain the spatiotemporal autophagy upregulation in the dark zone of GCs. Here, we define a functional mechanism controlling chromatin accessibility in GC B cells during their dark zone transition. This mechanism links autophagy and nuclear Lamin B1 dynamics with their downstream effects, including somatic hypermutation and antibody affinity maturation. Moreover, the autophagy-Lamin B1 axis is highly active in the aberrant ectopic germinal centres in the salivary glands of Sjogren's disease, defining its role in autoimmunity.
Hepatoblastoma
Authors: Luca Pio, Allison F O'Neill, Helen Woodley, Andrew J Murphy, Gregory Tiao, Stefanie Franchi-Abella, Brice Fresneau, Kenichiro Watanabe, Rita Alaggio, Dolores Lopez-Terrada, Eiso Hiyama, Sophie Branchereau
Journal: Nature Reviews Disease Primers (2025)
Targeting lipid metabolism in acute myeloid leukemia: biological insights and therapeutic opportunities
Authors: Vilma Dembitz, Sophie C James, Paolo Gallipoli
Journal: Leukemia (2025)

Abstract Metabolic rewiring is a hallmark of malignant transformation in leukemic cells and the potential offered by its therapeutic targeting has garnered significant attention. The development of clinically relevant metabolic targeted therapies in acute myeloid leukemia (AML) has mostly focused on targeting mitochondrial energy production, but progress has been hampered by generalized toxicities. An alternative strategy is to shift the focus from targeting energy production to targeting more specialized metabolic functions, such as energy storage, the regulation of oxidative stress and availability of cofactors needed for the function of specific metabolic reactions. Lipid metabolism plays a role in many of these metabolic functions and its importance in AML maintenance and response to therapy is being increasingly recognized but needs to be adequately interpreted in the context of its interaction with the microenvironment, particularly the adipose niche. In this review, we provide an overview of our current understanding of AML cellular metabolic dependencies on fatty acid and lipid metabolism and discuss their relevance in the context of functional interactions with adipocytes. We highlight unresolved questions about how to best target lipid metabolism and suggest approaches needed to fully understand the interplay between malignant cells and their niche in the context of metabolic dependencies.
Localised rectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Authors: R-D Hofheinz, E Fokas, L Benhaim, T J Price, D Arnold, R Beets-Tan, M G Guren, G A P Hospers, S Lonardi, I D Nagtegaal, R O Perez, A Cervantes, E Martinelli
Journal: Annals of Oncology (2025)
Blockade of CLEVER-1 restrains immune evasion and enhances anti-PD-1 immunotherapy in gastric cancer
Authors: Kuan Yu, Yifan Cao, Zihao Zhang, Leihao Wang, Yichao Gu, Tianwei Xu, Xiaolei Zhang, Xinxin Guo, Zhenbin Shen, Jing Qin
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Gastric cancer (GC) remains a major global health burden. Despite the advancements in immunotherapy for patients with GC, the heterogeneity of GC limits response rates, especially in immune “cold” subtypes, including genomically stable and epithelial-mesenchymal transition GC. Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1), a newly recognized immune checkpoint molecule predominantly expressed on tumor-associated macrophages (TAMs), remains poorly understood in GC. This study aims to explore the clinical significance of CLEVER-1 + TAM infiltration, elucidate its role in modulating the tumor immune landscape, and investigate the therapeutic potential of CLEVER-1 blockade in enhancing immunotherapy. Methods This study analyzed two independent GC cohorts and single-cell RNA sequencing data (GSE183904). CLEVER-1 expression in TAMs was assessed via multiplex immunofluorescence, flow cytometry, and RNA sequencing. The clinical relevance of CLEVER-1 + TAM infiltration was evaluated in relation to tumor, node, metastases staging, molecular subtypes, prognosis, and immunochemotherapy response. Transcriptomic and pathway analyses characterized the immunophenotype of CLEVER-1 + TAMs. Functional assays examined their suppression on CD8 + T cells, while interventional experiments assessed the impact of CLEVER-1 blockade alone or with programmed cell death protein-1 (PD-1) inhibition. Results CLEVER-1 was predominantly expressed on TAMs in GC and was associated with worse clinical outcomes. Transcriptomic and phenotypic analyses revealed that CLEVER-1 + TAMs display a dynamic immunophenotype and critically suppress T-cell function, fostering an immunosuppressive microenvironment. High CLEVER-1 + TAM infiltration was linked to poor response or adaptive resistance to PD-1 blockade therapy. CLEVER-1 blockade reprogrammed TAMs toward a pro-inflammatory phenotype, resulting in enhanced CD8 + T cell cytotoxicity and proliferation. Co-targeting CLEVER-1 and PD-1 synergistically enhanced antitumor responses. Conclusions High infiltration of CLEVER-1 + TAMs indicates immune suppression and poor prognosis in GC. The combination of CLEVER-1 and PD-1 blockade emerges as a dual-pronged strategy to boost immune-mediated tumor control and prevent treatment relapse in GC.
Equity in research: a global consensus statement on the urgency of including children in long COVID clinical trials
Authors: Lael M Yonker, Binita Kane, Etheresia Pretorius, David Putrino, Sammie McFarland, Petter Brodin, Kanecia O Zimmerman, Daniel Munblit, Peter C Rowe, Theo Vos, David Warburton, Terence Stephenson, Danilo Buonsenso
Journal: European Respiratory Journal (2025)
Single-cell RNA sequencing of baseline PBMCs predicts ICI efficacy and irAE severity in patients with NSCLC
Authors: Gyeong Dae Kim, So-I Shin, Pureum Sun, Jeong Eun Lee, Chaeuk Chung, Yea Eun Kang, Da Hyun Kang, Jihwan Park
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immune checkpoint inhibitors (ICIs) have transformed treatment and have provided significant clinical benefits and durable responses for patients with advanced non-small cell lung cancer (NSCLC). However, only a small percentage of patients respond to ICI treatment, and immune-related adverse events (irAEs) leading to treatment discontinuation remain challenging. Despite the recognized need for biomarkers to predict both the efficacy of ICIs and the risk of irAEs, such biomarkers are yet to be clearly identified. Methods In this study, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from 33 patients with NSCLC before ICIs treatment. To validate our findings, we reanalyzed public scRNA-seq data, conducted a cytometric bead array (CBA), and supported our findings with T-cell receptor sequencing. Results While the immune response was more pronounced in patients with a favorable prognosis, the hypoxic pathway was more prominent in patients with primary resistance. Lymphocytes such as CD8 T cells, CD4 T cells, and natural killer cells were primarily involved in these pathways, with PRF1 and GZMB expression showing strong associations with favorable prognosis. In contrast, irAEs were mainly linked to myeloid cells, such as monocytes and macrophages. As irAE severity increased, inflammation and the TNF-NFKB1 pathway were more prominent. Specifically, increased expression of IL1B , CXCL8 , and CXCL2 in monocytes and TNF in macrophages was closely associated with severe irAE through involvement in these pathways. Notably, the increase of PRF1 and GZMB expression showed a close association with both a favorable prognosis and a reduced severity of irAE, which was validated through CBA analysis. Moreover, the expression of these key markers varied according to prognosis and irAE severity regardless of patient background, such as programmed death-ligand 1 expression levels, tumor histology, or prior treatment regimens. Conclusions This study identified biological pathways and key biomarkers associated with ICI prognosis and irAE severity using PBMC samples before treatment. These findings provide a foundation for improved therapeutic strategies that enhance clinical outcomes while minimizing ICI treatment-associated risks.
Decoding resistance to immune checkpoint inhibitors in non-small cell lung cancer: a comprehensive analysis of plasma proteomics and therapeutic implications
Authors: Michal Harel, Nili Dahan, Coren Lahav, Eyal Jacob, Yehonatan Elon, Igor Puzanov, Ronan J Kelly, Yuval Shaked, Raya Leibowitz, David P Carbone, David R Gandara, Adam P Dicker
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immune checkpoint inhibitors (ICIs) have shown substantial benefit for patients with advanced non-small cell lung cancer (NSCLC). However, resistance to ICIs remains a major clinical challenge. Here, we perform a comprehensive bioinformatic analysis of plasma proteomic profiles to explore the underlying biology of treatment resistance in NSCLC. Methods The analysis was performed on 388 “resistance-associated proteins” (RAPs) that were previously described as pretreatment plasma proteomic predictors within the PROphet computational model designed to predict ICI clinical benefit in NSCLC. Putative tissue origins of the RAPs were explored using publicly available datasets. Enrichment analyses were performed to investigate RAP-related biological processes. Plasma proteomic data from 50 healthy subjects and 272 patients with NSCLC were compared, where patients were classified as displaying clinical benefit (CB; n=76) or no CB (NCB; n=196). Therapeutic agents targeting RAPs were identified in drug and clinical trial databases. Results The RAP set was significantly enriched with proteins associated with lung cancer, liver tissue, cell proliferation, extracellular matrix, invasion, and metastasis. Comparison of RAP expression in healthy subjects and patients with NSCLC revealed five distinct RAP subsets that provide mechanistic insights. The RAP subset displaying a pattern of high expression in the healthy population relative to the NSCLC population included multiple proteins associated with antitumor activities, while the subset displaying a pattern of highest expression in the NCB population included proteins associated with various hallmarks of treatment resistance. Analysis of patient-specific RAP profiles revealed inter-patient diversity of potential resistance mechanisms, suggesting that RAPs may aid in developing personalized therapeutic strategies. Furthermore, examination of drug and clinical trial databases revealed that 17.5% of the RAPs are drug targets, highlighting the RAP set as a valuable resource for drug development. Conclusions The study provides insight into the underlying biology of ICI resistance in NSCLC and highlights the potential clinical value of RAP profiles for developing personalized therapies.
Common origin and somatic mutation patterns of composite lymphomas and leukemias
Authors: Victoria Berg, Anna Lollies, Markus Schneider, Patricia Johansson, Marc A Weniger, Emma Albertini, Fabio Facchetti, Stefano Ascani, Abubakar Moawia, Susanne Bens, Anja Fischer, Reiner Siebert, Wolfram Klapper, Luisa Lorenzi, Enrico Tiacci, Sylvia Hartmann, Bettina Budeus, Martin-Leo Hansmann, Ralf Küppers
Journal: Leukemia (2025)

Abstract When two lymphomas occur concurrently or sequentially in a patient, it is a major question whether they derive from the same lymphocyte or hematopoietic precursor cell or developed independently. We studied four composite classic Hodgkin lymphomas (HL) and other mature B-cell lymphomas, and two composite mature B- and T-cell neoplasias by whole exome sequencing (WES). Analysis of their IGV genes revealed that three composite B-cell lymphomas originated from common germinal center-experienced B cells. WES identified shared somatic mutations in the lymphomas of these clonally related composite lymphomas, indicating their derivation from a common, pre-malignant precursor. Most mutations were restricted to one or the other of these lymphomas, likely explaining how distinct lymphomas developed from a common ancestral B cell. In the two B-cell/T-cell lymphoma cases, and a composite clonally unrelated HL/chronic lymphocytic leukemia, the lymphoma partners did not share any somatic mutations. In three cases, we identified potentially oncogenic variants also in cells serving as constitutional controls. These variants may have contributed to development of a composite lymphoma/leukemia. We provide additional evidence of frequent clonal relation in composite lymphomas, highlight the multistep transformation process of related lymphomas with a likely pre-malignant intermediate common precursor, and support the importance of constitutional variants in lymphomagenesis.