tbuckley/cabot-search huggingface dataset:
Functional dissection of noncoding variants associated with rheumatoid arthritis
Authors: Ajay Jajodia, Arpit Mishra, Naresh Doni Jayavelu, Katharina Lambert, Nicholas Moss, Zongchen Yang, Karen Cerosaletti, Jane H Buckner, R David Hawkins
Journal: Annals of the Rheumatic Diseases (2025)

Noncoding variants are critical to our understanding of the genetic basis of diseases and disorders such as rheumatoid arthritis (RA). While genome-wide association studies have identified regions of the genome associated with disease, functional studies are still lagging that can identify potentially causative variants. In order to functionally fine-map RA-associated variants, we identified variants at enhancers marked in primary activated T helper cells and conducted massively parallel reporter assay in these cells. We found that combinations of functional variant genotypes are often exclusive to patients with RA. We leveraged 3-dimensional genome architecture and expression quantitative trait loci data to identify target genes of enhancers exhibiting allelic differences in activity. We confirmed enhancer activity and target gene interactions by Clustered Regularly Interpaced Short Palindromic Repeats Cas9 (CRISPR-Cas9) deletion in primary T cells. The identification of functional enhancer variants suggests possible causal variants, and their target genes reveal known and novel genes as likely drivers of RA, as well as a means for therapeutic intervention.
Re: Thomas van Doeveren, Sebastiaan Remmers, Egbert R. Boevé, et al. Intravesical Instillation of Chemotherapy Before Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: The REBACARE Trial. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2024.12.006
Authors: Jianjun Ye, Qiang Wei, Yige Bao
Journal: European Urology (2025)
Adalimumab serum concentration to choose a subsequent biological DMARD in patients with rheumatoid arthritis (ADDORA-switch): results of a blinded randomised test-treatment trial
Authors: Maike H M Wientjes, Sadaf Atiqi, Gerrit J Wolbink, Michael T Nurmohamed, Maarten Boers, Femke Hooijberg, Theo Rispens, Annick de Vries, Ronald F van Vollenhoven, Sofia Ramiro, Noortje van Herwaarden, Bart J F van den Bemt, Alfons A den Broeder
Journal: Annals of the Rheumatic Diseases (2025)

A substantial proportion of patients with rheumatoid arthritis (RA) discontinue adalimumab due to ineffectiveness. The next treatment step can be another tumour necrosis factor inhibitor (TNFi) or a biological/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). Therapeutic drug monitoring (TDM) of serum drug levels may help guide this choice. This study evaluated whether switching treatments based on adalimumab trough levels is more effective than random switching. In this 24-week, multicentre, triple-blinded, randomised controlled trial, patients with RA who stopped adalimumab due to inefficacy (disease activity score based on 28 joint count and C-reactive protein [DAS28-CRP] >2.9) were enrolled. Participants were randomly assigned (1:1) to a TDM-based or random switching (control) strategy. The primary outcome was the difference in mean time-weighted DAS28-CRP between groups at 24 weeks. From July 2020 to November 2023, 83 consecutive patients with RA were included, with 78 initiating a new b/tsDMARD (TDM-based group: n = 38; control: n = 40). The mean time-weighted DAS28-CRP was 3.15 in both groups (TDM: SD, 0.99; control: SD, 1.01; 95% CI of difference: -0.46 to 0.47). There were no significant differences between the groups in flare rates, escape medication use, disease activity, or adverse events. Receiver operating characteristic analyses in the control group found no predictive value of adalimumab levels for response to TNFi or non-TNFi. Switching treatments based on adalimumab trough levels was not more effective than random switching in patients with RA who failed adalimumab treatment. Therefore, serum drug level measurements to guide therapy choices in this context is not recommended.
Radiotherapy-Induced Neurocognitive Decline among Adult Intracranial Tumor Patients: A Voxel-Based approach
Authors: Charlotte Sleurs, Catharina M L Zegers, Marvin F Ribeiro, Wouter van Elmpt, Jeanette Dijkstra, Alida A Postma, Laurien De Roeck, Karin Gehring, Wouter De Baene, Margriet M Sitskoorn, Maarten Lambrecht, Daniëlle B P Eekers
Journal: Neuro-Oncology (2025)

Abstract Background Cranial irradiation is a key component of neuro-oncological treatment, but can result in cognitive side effects. Preserving cognition from radiotherapy-(RT)-induced toxicity remains an ongoing debate. To spatially map radiotoxic effects in patients who underwent cranial RT, this study applied a voxel-based approach. Methods Cognitive assessments (Controlled Word Association (COWA), Hopkins Verbal Learning (HVLT-R), and Trail Making Tests (TMT A,B)) were conducted prospectively before, 6months and 1year post-RT in 111 intracranial tumor patients (18-80years). Reliable change indices indicated cognitive changes across timepoints. CT and T1-weighted MRI scans acquired at diagnosis were co-registered, normalized to standard space, and smoothed. Voxel-wise permutation-based regression analyses examined the relationship between RT dose and cognitive decline (α&amp;lt;.05 at cluster level). Results Images of 111 patients (Mdn age = 55.39 years; 47% male; lesions were gliomas (61%), meningiomas (18%), other (21%); in frontal (33%), temporal (25%), other location (42%)) were analyzed. Reliable decline was most pronounced at 6months, particularly on the TMT A (25.77%), TMT B (24.21%), and HVLT immediate recall (21%). At 1year, 20% of patients continued to show decline in TMT B. Higher RT doses to frontal gyri, temporal, occipital, and para-central regions were associated with declines in verbal fluency, memory, processing speed, and flexibility at both peak- and cluster-level. Conclusion Differential voxel-wise RT dose effects at peak versus cluster level suggest local and network-based recruitment of diverse functional regions and vulnerability to cranial RT. These insights may help re-define key regions at risk from a network-based perspective, preserving cognition in future RT planning.
Synthetic medical education in dermatology leveraging generative artificial intelligence
Authors: Arya S Rao, John Kim, Andrew Mu, Cameron C Young, Ezra Kalmowitz, Michael Senter-Zapata, David C Whitehead, Lilit Garibyan, Adam B Landman, Marc D Succi
Journal: npj Digital Medicine (2025)

The advent of large language models (LLMs) represents an enormous opportunity to revolutionize medical education. Via "synthetic education," LLMs can be harnessed to generate novel content for medical education purposes, offering potentially unlimited resources for physicians in training. Utilizing OpenAI's GPT-4, we generated clinical vignettes and accompanying explanations for 20 skin and soft tissue diseases tested on the United States Medical Licensing Examination. Physician experts gave the vignettes high average scores on a Likert scale in scientific accuracy (4.45/5), comprehensiveness (4.3/5), and overall quality (4.28/5) and low scores for potential clinical harm (1.6/5) and demographic bias (1.52/5). A strong correlation (r = 0.83) was observed between comprehensiveness and overall quality. Vignettes did not incorporate significant demographic diversity. This study underscores the potential of LLMs in enhancing the scalability, accessibility, and customizability of dermatology education materials. Efforts to increase vignettes' demographic diversity should be incorporated to increase applicability to diverse populations.
Complex neural-immune interactions shape glioma immunotherapy
Authors: Kun-Wei Song, Michael Lim, Michelle Monje
Journal: Immunity (2025)

Rich neural-immune interactions in the central nervous system (CNS) shape its function and create a unique immunological microenvironment for immunotherapy in CNS malignancies. Far from the now-debunked concept of CNS "immune privilege," it is now understood that unique immunological niches and constant immune surveillance of the brain contribute in multifaceted ways to brain health and robustly influence immunotherapy approaches for CNS cancers. Challenges include immune-suppressive and neurotoxicity-promoting crosstalk between brain, immune, and tumor cells. Developing effective immunotherapies for cancers of the nervous system will require a deeper understanding of these neural-immune-malignant cell interactions. Here, we review progress and challenges in immunotherapy for gliomas of the brain and spinal cord in light of these unique neural-immune interactions and highlight future work needed to optimize promising immunotherapies for gliomas.
Niche-specific therapeutic targeting of myeloid cells in the central nervous system
Authors: Maximilian Frosch, Marco Prinz
Journal: Immunity (2025)

The central nervous system (CNS) can be subdivided into distinct anatomical and functional compartments, including the parenchyma, perivascular space, leptomeninges, and dura mater, etc. Each compartment hosts distinct immune cell populations, such as monocytes and diverse macrophages, which play critical roles in local tissue homeostasis and regional disease pathogenesis. Advances in single-cell technologies have revealed complex immune cell compositions and functions in these anatomical regions. This review summarizes the latest approaches for modulating myeloid cell subsets in a compartment-specific manner, including cellular strategies such as stem cell therapy, ex vivo gene treatment, bone marrow transplantation, as well as non-cellular strategies like antibodies, small molecules, and viral gene delivery to augment CNS immune responses and improve disease outcomes. We also discuss the challenges and requirements of translating targeting strategies from mice to humans.
The sensory neuroimmune frontier
Authors: Brian S Kim, David Artis
Journal: Immunity (2025)

Sensing and recognition are key properties of both the immune and nervous systems. In the immune system, pattern recognition or antigen-specific receptors represent classic motifs in innate and adaptive immunity, respectively. In the nervous system, there is a major anatomic division between how we sense stimuli from within the body (vagal sensory nervous system) and the outside world (somatosensory nervous system). However, in the last 5 years, there has been an explosion of discoveries revealing interactions between the immune and the sensory nervous systems that govern an array of physiologic and pathologic processes including allergy, infection, autoimmunity, regeneration, cancer, and beyond. Herein, we highlight recent advances that demonstrate how peripheral sensory neuroimmunology has emerged as a powerful field that provides new insights into classic immunologic processes including immune hypersensitivity, inflammation, and tissue homeostasis.
Border-associated macrophages as gatekeepers of brain homeostasis and immunity
Authors: Mónica Vara-Pérez, Kiavash Movahedi
Journal: Immunity (2025)

The brain's border tissues serve as essential hubs for neuroimmune regulation and the trafficking of biomaterials to and from the brain. These complex tissues-including the meninges, perivascular spaces, choroid plexus, and circumventricular organs-balance the brain's need for immune privilege with immune surveillance and blood-brain communication. Macrophages are integral components of these tissues, taking up key strategic positions within the brain's circulatory system. These border-associated macrophages, or "BAMs," are therefore emerging as pivotal for brain homeostasis and disease. BAMs perform trophic functions that help to support border homeostasis but also act as immune sentinels essential for border defense. In this review, we integrate recent findings on BAM origins, cell states, and functions, aiming to provide global insights and perspectives on the complex relationship between these macrophages and their border niche.
Glymphatics and meningeal lymphatics unlock the brain-immune code
Authors: Min Woo Kim, Jonathan Kipnis
Journal: Immunity (2025)

The central nervous system (CNS) was once perceived as entirely shielded from the immune system, protected behind the blood-brain barrier and thought to lack lymphatic drainage. However, recent evidence has challenged many dogmas in neuroimmunology. Indeed, by means of glymphatics, brain-derived "waste" from deep within the CNS mobilizes toward immunologically active brain borders, where meningeal lymphatic vessels are appropriately positioned to drain antigens from the brain to the periphery. Accordingly, the presentation of brain-derived self-peptides emerges at the brain's borders and drives T cell responses with suppressive properties, critical in allowing active immunosurveillance while limiting aberrant immune reactivity. Taking into consideration these concepts, we further discuss how inflammation, aging, and neurodegenerative diseases potentially reshape the repertoire of self-antigens and immune cells, disrupting the healthy dialogue between the CNS and immune system. Collectively, this evolving perspective unveils new therapeutic avenues for CNS pathologies.
Using the experience sampling methodology to measure anhedonia and its correlates in mental health research: A systematic review
Authors: Joanne R Beames, Lotte Uyttebroek, Clementine J Edwards, Gudrun V Eisele, Nian D F Kemme, Olivia Collier, Eeske van Roekel, Thomas R Kwapil, Olivia J Kirtley, Inez Myin-Germeys
Journal: Clinical Psychology Review (2025)
Video thermography uncovers relationship between volume status and temperature in heart failure
Authors: Pawel Rubiś, Adam Piórkowski, Mateusz Winiarczyk, Karolina Nurzyńska, Ewa Dziewięcka, Sylwia Wiśniowska‐Śmiałek, Mariusz Marzec, Julia Lasek, John G.F. Cleland, Piotr Augustyniak
Journal: European Journal of Heart Failure (2025)
Mitochondrial targets in ischaemic heart disease and heart failure, and their potential for a more efficient clinical translation. A scientific statement of the <scp>ESC</scp> Working Group on Cellular Biology of the Heart and the <scp>ESC</scp> Working Group on Myocardial Function
Authors: Melanie Paillard, Mahmoud Abdellatif, Ioanna Andreadou, Christian Bär, Luc Bertrand, Bianca J.J.M. Brundel, Gemma Chiva‐Blanch, Sean M. Davidson, Dana Dawson, Fabio Di Lisa, Paul Evans, Zoltan Giricz, Derek J. Hausenloy, Petra Kleinbongard, Frank Lezoualc'h, Elisa Liehn, Christoph Maack, Ange Maguy, Elizabeth Murphy, Cinzia Perrino, Maurizio Pesce, Peter P. Rainer, Katrin Streckfuss‐Bömeke, Matthias Thielmann, Rong Tian, Carlo G. Tocchetti, Jolanda Van Der Velden, Sophie Van Linthout, Serena Zacchigna, Thomas Krieg
Journal: European Journal of Heart Failure (2025)

Abstract Acute myocardial infarction (MI) remains a major cause of death and disability worldwide. No adjuvant treatment has yet been fully validated in patients to limit the progression from the initial tissue damage due to acute MI, to the development of heart failure. However, mitochondria have long been demonstrated to be a key target for cardioprotective strategies to reduce cell death that leads to left ventricular dysfunction and ultimately heart failure. While pre‐clinical studies have investigated several mitoprotective strategies targeting different mitochondrial functions, such as oxidative stress or permeability transition pore opening, none have shown successful clinical translation so far. In this European Society of Cardiology scientific statement, we present recent research advances in the understanding of the mitochondrial alterations occurring in MI and in the discovery of key components of mitochondrial structure and function in order to improve drug development. We discuss the reasons for the failure of clinical translation and the remaining obstacles that need to be addressed, including timing of drug administration, tissue bioavailability and efficient mitochondrial targeting, together with the mitochondrial impact derived from risk factors, comorbidities and comedications. Taken together, this scientific statement aims to provides a consensus opinion from clinicians and basic scientists to translate some of the most promising mitoprotective targets into the clinical setting to protect against MI and heart failure.
Cancer-nervous system crosstalk: from biological mechanism to therapeutic opportunities
Authors: Sirui Huang, Jing Zhu, Linglu Yu, Yan Huang, Yue Hu
Journal: Molecular Cancer (2025)

A growing body of research suggests a bidirectional interaction between cancer and the nervous system. Neural cells exert their effects on tumors by secreting neurotransmitters and cell adhesion molecules, which interact with specific receptors on tumor cells to modulate their behavior. Conversely, tumor-secreted factors, particularly including inflammatory factors, can alter neural activity and increase neuronal excitability, potentially contributing to neurological manifestations such as epilepsy. The immune system also serves as a crucial intermediary in the indirect communication between cancer and the nervous system. These insights have opened promising avenues for novel therapeutic strategies targeting both tumors and their associated neurological complications. In this review, we have synthesized the key biological mechanisms underlying cancer-nervous system interactions that have emerged over the past decade. We outline the molecular and cellular pathways mediating this cross-talk and explore the clinical implications of targeting the nervous system to suppress tumor growth and metastasis, mitigate neurological complications arising from cancer progression, and modulate the immune response through neural regulation in the context of cancer therapy.
Pathophysiology and clinical use of agents with vasodilator properties in acute heart failure. A scientific statement of the <scp>Heart Failure Association</scp> (<scp>HFA</scp>) of the <scp>European Society of Cardiology</scp> (<scp>ESC</scp>)
Authors: Ovidiu Chioncel, Alexandre Mebazaa, Dimitrios Farmakis, Magdy Abdelhamid, Lars H. Lund, Veli‐Pekka Harjola, Stefan Anker, Gerasimos Filippatos, Tuvia Ben‐Gal, Kevin Damman, Hadi Skouri, Laura Antohi, Sean P. Collins, Marianna Adamo, Oscar Miro, Loreena Hill, John Parissis, Brenda Moura, Christian Mueller, Ewa Jankowska, Yury Lopatin, Mark Dunlap, Maurizio Volterrani, Marat Fudim, Andreas J. Flammer, Wilfried Mullens, Peter S. Pang, Otilia Tica, Piotr Ponikowski, Arsen Ristic, Javed Butler, Gianluigi Savarese, Mariantonietta Cicoira, Thomas Thum, Antoni Bayes Genis, Effie Polyzogopoulou, Petar Seferovic, Mehmet Birhan Yilmaz, Giuseppe Rosano, Andrew J.S. Coats, Marco Metra
Journal: European Journal of Heart Failure (2025)
The anti-diabetic PPARγ agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer
Authors: Emine Atas, Kerstin Berchtold, Michaela Schlederer, Sophie Prodinger, Felix Sternberg, Perla Pucci, Christopher Steel, Jamie D Matthews, Emily R James, Cécile Philippe, Karolína Trachtová, Ali A Moazzami, Nastasiia Artamonova, Felix Melchior, Torben Redmer, Gerald Timelthaler, Elena E Pohl, Suzanne D Turner, Isabel Heidegger, Marcus Krueger, Ulrike Resch, Lukas Kenner
Journal: Molecular Cancer (2025)

Abstract Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPARγ agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPARγ protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells' metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo , Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPKα and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy. Graphical Abstract
Multiomic profiling of glioblastoma metabolic lesions reveals complex intratumoral genomic evolution and dipeptidase-1-driven vascular proliferation
Authors: Atul Anand, Jeanette Krogh Petersen, Lars van Brakel Andersen, Mark Burton, Clara Rosa Levina Oudenaarden, Martin Jakob Larsen, Philip Ahle Erichsen, Christian Bonde Pedersen, Frantz Rom Poulsen, Peter Grupe, Torben A Kruse, Mads Thomassen, Bjarne Winther Kristensen
Journal: Neuro-Oncology (2025)

Abstract Background Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through clinical positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution. Methods In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome, exome, transcriptome, and imaging analyses. Results Our findings unveil that hypermetabolic lesions, originating from hypometabolic lesions, exhibit strategic focal amplifications and deletions, and heightened APOBEC3 activity. Furthermore, we identify dipeptidase 1 as a novel vascular endothelial tip marker for hypermetabolic lesions in glioblastoma, facilitating angiogenesis and tumor metabolism by regulating transporter activities. Conclusions Hypermetabolic lesions are associated with a higher frequency of genomic abnormalities and dipeptidase 1 emerges as a novel diagnostic and prognostic vascular marker for hypermetabolic lesions. This study underscores a spatial genomic evolution with diagnostic implications and elucidates challenges and opportunities crucial for the development of novel therapeutic strategies.
Standard versus reduced-dose chemoradiotherapy in anal cancer (PLATO-ACT4): short-term results of a phase 2 randomised controlled trial
Authors: Alexandra Gilbert, Richard Adams, Joanne Webster, Duncan C Gilbert, Natalie L Abbott, Lindy Berkman, Daniel Bottomley, Sarah R Brown, Natalie Casanova, Joanne Copeland, Stephen Falk, Rob Glynne-Jones, Vicky Goh, Maria A Hawkins, Shaharyar Khan, Rebecca Muirhead, Sheela Rao, Andrew G Renehan, Susan D Richman, Sharon Ruddock, Alexandra Smith, Alexandra J Stewart, Max Whibley, Henry M Wood, David Sebag-Montefiore, Mark Harrison
Journal: The Lancet Oncology (2025)