tbuckley/cabot-search huggingface dataset:
Mutagenic impact and evolutionary influence of chemo-radiotherapy in hematologic malignancies
Authors: Benjamin Diamond, Dhanvantri Chahar, Michael D. Jain, Alexandra M. Poos, Michael A. Durante, Bachisio Ziccheddu, Marcella Kaddoura, Marios Papadimitriou, Kylee H. Maclachlan, Tomas Jelinek, Faith E. Davies, Nicholas B. Figura, Gareth J. Morgan, Elias K. Mai, Katja Weisel, Roland Fenk, Marc S. Raab, Saad Usmani, Ola Landgren, Frederick L. Locke, Hartmut Goldschmidt, Jonathan Harry. Schatz, Niels Weinhold, Francesco Maura
Journal: Blood Cancer Discovery (2025)

Abstract Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of indels, and their repair by non-homologous end-joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. Here, we interrogated 580 whole-genome sequence samples (WGS) from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet, ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode we demonstrate that a single RT-surviving cell may seed distant relapse.
Neoadjuvant PD-1 and PD-L1 Blockade With Chemotherapy for Borderline Resectable and Unresectable Stage III Non–Small Cell Lung Cancer
Authors: Biagio Ricciuti, Francesca Fusco, Alissa Cooper, Edoardo Garbo, Federica Pecci, Mihaela Aldea, Xinan Wang, Maria Mayoral Penalva, Michelle Ginsberg, Lynette M. Sholl, Mizuki Nishino, Alessandro Di Federico, Narek Shaverdian, Matthew Bott, Valentina Santo, Erino Rendina, Rocco Trisolini, Sara Ramella, Filippo Gallina, Enrico Melis, Simonetta Buglioni, Gabriele Minuti, Lorenza Landi, Paula A. Ugalde Figueroa, Alice T. Shaw, Jamie Chaft, Mark M. Awad, Federico Cappuzzo
Journal: JAMA Oncology (2025)

Importance Patients with borderline resectable or unresectable stage III non–small cell lung cancer (NSCLC) with T4 and/or N2-N3 involvement face limited treatment options and poor outcomes. Neoadjuvant chemoimmunotherapy has shown promise in improving resectability and pathological responses. Objective To evaluate the efficacy of neoadjuvant programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 (PD-L1) blockade combined with chemotherapy in enhancing surgical outcomes and pathological responses in patients with T4 and/or N2-N3 stage III NSCLC. Design, Setting, and Participants This multicenter cohort study analyzed data from patients treated between February 2018 and January 2024 with neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy at academic and tertiary care centers across the US and Italy. Pathological and survival outcomes were assessed. Patients with stage III NSCLC and T4 and/or N2-N3 involvement were included. Data were collected from February 2018 to January 2024. Exposures Neoadjuvant PD-1/PD-L1 blockade combined with platinum-based chemotherapy. Main Outcomes and Measures Pathological complete response (pCR), major pathological response, surgical resectability, and event-free survival (EFS). Results Of 112 patients, 58 (51.8%) were female, and the median (range) age was 66 (41-84) years. A total of 84(75.0%) underwent surgical resection, achieving a pCR rate of 29.0% (24 of 83 with available final pathology) and a major pathological response rate of 42.2% (35 of 83). Patients with both PD-L1 expression of 50% or more and high tumor mutational burden achieved the highest pCR rate (4 of 9 [44.4%]; P = .03). Conversely, covariants in KRAS / STK11 or KRAS / KEAP1 were associated with lack of pCR. Patients with single-station or multistation N2/N3 disease exhibited comparable pathological outcomes. The median EFS for all resected patients was 52.6 months (95% CI, 27.8 to not reached), and this was significantly longer in patients with pCR (not reached vs 27.8 months [95% CI, 19.5 to not reached]; P &amp;amp;lt; .001). Conclusions and Relevance In this study, neoadjuvant PD-1/PD-L1 blockade combined with chemotherapy resulted in high pathological response rates and surgical resectability in patients with T4 and/or N2-N3 stage III NSCLC. This approach offers a viable treatment option for patients with borderline resectable or unresectable NSCLC but requires further validation through prospective studies.
Breast Cancer Outcomes in Transgender and Gender-Diverse Patients in the National Cancer Database
Authors: Kelley Chan, Joseph H. Cotler, Alexandra C. Istl, Sailaja Kamaraju, Andrew E. Petroll, Melinda Stolley, Chandler S. Cortina
Journal: JAMA Oncology (2025)

This cohort study examines breast cancer outcomes in transgender and gender-diverse patients compared with cisgender patients, including overall survival and sociodemographic characteristics.
Neural Mechanisms in Cardiovascular Health and Disease
Authors: Karin A. Ziegler, Stefan Engelhardt, Daniela Carnevale, Cameron S. McAlpine, Tomasz J. Guzik, Stefanie Dimmeler, Filip K. Swirski
Journal: Circulation Research (2025)

Although the neurocardiac axis is central to cardiovascular homeostasis, its dysregulation drives heart failure and cardiometabolic diseases. This review examines the bidirectional interplay between the autonomic nervous system and the heart, highlighting the role of this interplay in disease progression and its therapeutic potential. The autonomic nervous system modulates cardiac function and vascular tone through its sympathetic and parasympathetic branches. However, in heart failure, chronic sympathetic overdrive and parasympathetic withdrawal exacerbate myocardial remodeling and metabolic dysfunction, both of which are exacerbated by cardiometabolic conditions such as obesity and diabetes. These conditions are increasingly recognized to impair neurocardiac regulation, thereby promoting inflammation and adverse outcomes. An important emerging area concerns neuroimmune control, in which the brain orchestrates systemic inflammation through circuits involving the bone marrow, spleen, and other organs, thereby amplifying cardiovascular damage. This neuroimmune axis integrates peripheral signals to influence immune responses that contribute to disease progression. Lifestyle factors, such as stress, sleep, exercise, and diet, affect autonomic and immune balance and, thus, cardiovascular disease. Therapeutically, targeting neurocardiac and neuroimmune pathways pharmacologically or via neuromodulation (eg, vagal or splenic nerve stimulation) offers promise although the clinical translation of the latter remains challenging. In this review, we synthesize preclinical and clinical data to highlight the neurocardiac axis as a critical nexus in heart failure and cardiometabolic disease. Harnessing neuroimmune and neurocardiac interactions may inform precision approaches to reduce the burden of these conditions.
Multiorgan Imaging for Interorgan Crosstalk in Cardiometabolic Diseases
Authors: Ana Devesa, Victoria Delgado, Ladislav Valkovic, Joao A.C. Lima, Eike Nagel, Borja Ibanez, Betty Raman
Journal: Circulation Research (2025)

Cardiometabolic diseases encompass a group of conditions characterized by metabolic and inflammatory abnormalities that increase the risk of diabetes and cardiovascular disease. These syndromes involve multiple organs, including the heart, arterial system, brain, skeletal muscle, adipose tissue, hematopoietic system, liver, kidneys, and pancreas. The crosstalk between these organs contributes to the development of disease. Advances in imaging techniques, such as magnetic resonance imaging, magnetic resonance spectroscopy, computed tomography, and positron emission tomography, have revolutionized the evaluation of these conditions. Hybrid imaging modalities, such as positron emission tomography/computed tomography and positron emission tomography/magnetic resonance imaging, provide unique insights into the anatomy and metabolic alterations occurring in response to cardiometabolic risk factors. These methods are particularly valuable for assessing multisystemic involvement and interorgan crosstalk, revealing critical interactions such as the brain-heart axis, the heart-liver axis, and the fat-muscle-heart dynamics. This review discusses the role of state-of-the-art imaging techniques in evaluating the pathophysiological mechanisms underlying these complex syndromes and the clinical applications of the different imaging techniques in the assessment of cardiometabolic diseases.
In Vitro Modeling of Interorgan Crosstalk: Multi-Organ-on-a-Chip for Studying Cardiovascular-Kidney-Metabolic Syndrome
Authors: Cody Juguilon, Ramak Khosravi, Milica Radisic, Joseph C. Wu
Journal: Circulation Research (2025)

Cardiovascular-kidney-metabolic syndrome is a progressive disorder driven by perturbed interorgan crosstalk among adipose, liver, kidney, and heart, leading to multiorgan dysfunction. Capturing the complexity of human cardiovascular-kidney-metabolic syndrome pathophysiology using conventional models has been challenging. Multi-organ-on-a-chip platforms offer a versatile means to study underlying interorgan signaling at different stages of cardiovascular-kidney-metabolic syndrome and bolster clinical translation.
Metabolic and Immune Crosstalk in Cardiovascular Disease
Authors: Sarajo K. Mohanta, Coraline Heron, Alexandra Klaus-Bergmann, Hauke Horstmann, Ebba Brakenhielm, Chiara Giannarelli, Andreas J. R. Habenicht, Holger Gerhardt, Christian Weber
Journal: Circulation Research (2025)

Cardiovascular diseases including atherosclerosis and heart failure, arise from the intricate interplay of metabolic, immune, and neural dysregulation within vascular and cardiac tissues: This review focuses on integrating recent advances in metabolic and immune crosstalk of the cardiac vasculature that affects cardiometabolic health and disease progression. Coronary and lymphatic endothelial cells regulate cardiac metabolism, and their dysfunction is linked to cardiovascular diseases. Lymphatics maintain tissue homeostasis, including clearing metabolic waste, lipids, and immune cells, and their maladaptation in metabolic diseases worsens outcomes. Altered vascular endothelial metabolism in heart failure drives immune-mediated inflammation, fibrosis, and adverse cardiac remodeling. Concurrently, artery tertiary lymphoid organs formed in the adventitia of advanced atherosclerotic arteries, serve as pivotal neuroimmune hubs, coordinating local immunity through T and B cell activation and neurovascular signaling via artery-brain circuits. T cells within plaques and artery tertiary lymphoid organs undergo clonal expansion as a result of peripheral tolerance breakdown, with proinflammatory CD4 + and CD8 + subsets amplifying atherosclerosis, effects further shaped by systemic immune activation. Therapeutic strategies targeting endothelial cell metabolism, lymphatic dysfunction, neuroimmune crosstalk, and T cell plasticity hold promise for integrated cardiovascular disease management.
Renal-Cardiac Crosstalk in the Pathogenesis and Progression of Heart Failure
Authors: Heidi Noels, Emiel P.C. van der Vorst, Sébastien Rubin, Amber Emmett, Nikolaus Marx, Maciej Tomaszewski, Joachim Jankowski
Journal: Circulation Research (2025)

Chronic kidney disease (CKD) represents a global health issue with a high socioeconomic impact. Beyond a progressive decline of kidney function, patients with CKD are at increased risk of cardiovascular diseases, including heart failure (HF) and sudden cardiac death. HF in CKD can manifest both as HF with reduced ejection fraction and HF with preserved ejection fraction, with the latter further increasing in relative importance in the more advanced stages of CKD. Typical cardiac remodeling characteristics in uremic cardiomyopathy include left ventricular hypertrophy, myocardial fibrosis, cardiac electrical dysregulation, capillary rarefaction, and microvascular dysfunction, which are triggered by increased cardiac preload, cardiac afterload, and preload and afterload-independent factors. The pathophysiological mechanisms underlying cardiac remodeling in CKD are multifactorial and include neurohormonal activation (with increased activation of the renin-angiotensin-aldosterone system, the sympathetic nervous system, and mineralocorticoid receptor signaling), cardiac steroid activation, mitochondrial dysfunction, inflammation, innate immune activation, and oxidative stress. Furthermore, disturbances in cardiac metabolism and calcium homeostasis, macrovascular and microvascular dysfunction, increased cellular profibrotic responses, the accumulation of uremic retention solutes, and mineral and bone disorders also contribute to cardiovascular disease and HF in CKD. Here, we review the current knowledge of HF in CKD, including the clinical characteristics and pathophysiological mechanisms revealed in animal studies. We also elaborate on the detrimental impact of comorbidities of CKD on HF using hypertension as an example and discuss the clinical characteristics of hypertensive heart disease and the genetic predisposition. Overall, this review aims to increase the understanding of HF in CKD to support future research and clinical translational approaches for improved diagnosis and therapy of this vulnerable patient population.
Skeletal Muscle as a Mediator of Interorgan Crosstalk During Exercise: Implications for Aging and Obesity
Authors: Julia A. Shero, Maléne E. Lindholm, Marco Sandri, Kristin I. Stanford
Journal: Circulation Research (2025)

Physical exercise is critical for preventing and managing chronic conditions, such as cardiovascular disease, type 2 diabetes, hypertension, and sarcopenia. Regular physical activity significantly reduces cardiovascular and all-cause mortality. Exercise also enhances metabolic health by promoting muscle growth, mitochondrial biogenesis, and improved nutrient storage while preventing age-related muscle dysfunction. Key metabolic benefits include increased glucose uptake, enhanced fat oxidation, and the release of exercise-induced molecules called myokines, which mediate interorgan communication and improve overall metabolic function. These myokines and other exercise-induced signaling molecules hold promise as therapeutic targets for aging and obesity-related conditions.
Cardiovascular, Kidney, Liver, and Metabolic Interactions in Heart Failure: Breaking Down Silos
Authors: Chang Jie Mick Lee, Leah B. Kosyakovsky, Muhammad Shahzeb Khan, Feng Wu, Guo Chen, Joseph A. Hill, Jennifer E. Ho, Roger S.-Y. Foo, Faiez Zannad
Journal: Circulation Research (2025)

Over the past few decades, the rising burden of metabolic disease, including type 2 diabetes, prediabetes, obesity, and metabolic dysfunction–associated steatotic liver disease, has corresponded with fundamental shifts in the landscape of heart failure (HF) epidemiology, including the rising prevalence of HF with preserved ejection fraction. It has become increasingly important to understand the role of extracardiac contributors and interorgan communication in the pathophysiology and phenotypic heterogeneity of HF. Whereas traditional epidemiological strategies have separately examined individual contributions of specific comorbidities to HF risk, these approaches may not capture the shared mechanisms and more complex, bidirectional relationships between cardiac and noncardiac comorbidities. In this review, we highlight the cardiac, kidney, liver, and metabolism multiorgan interactions and pathways that complicate HF development and progression and propose research strategies to further understand HF in the context of multiple organ disease. This includes evolving epidemiological approaches such as multiomics and machine learning which may better capture common underlying mechanisms and interorgan crosstalk. We review existing preclinical models of HF and how they have enhanced our understanding of the role of multiorgan disease in the development of HF subtypes. We suggest recommendations as to how clinical practice across multiple specialties should screen for and manage multiorgan involvement in HF. Finally, recognizing the advent of novel combinatorial therapeutic agents that may have multiple indications across the cardiac-kidney-liver metabolism continuum, we review the current clinical trials landscape. We specifically highlight a pressing need for the design of more inclusive trials that examine the contributions of multimorbidity and incorporate multiorgan end points, which we propose may lead to outcomes that are evermore clinically relevant today.
Decoding the Liver-Heart Axis in Cardiometabolic Diseases
Authors: Federico Capone, Antonio Vacca, Guillaume Bidault, Dylan Sarver, Dorota Kaminska, Stefano Strocchi, Antonio Vidal-Puig, Carolina M. Greco, Aldons J. Lusis, Gabriele G. Schiattarella
Journal: Circulation Research (2025)

The liver and heart are closely interconnected organs, and their bidirectional interaction plays a central role in cardiometabolic disease. In this review, we summarize current evidence linking liver dysfunction—particularly metabolic dysfunction–associated steatotic liver disease, alcohol-associated liver disease, and cirrhosis—with an increased risk of heart failure and other cardiovascular diseases. We discuss how these liver conditions contribute to cardiac remodeling, systemic inflammation, and hemodynamic stress and how cardiac dysfunction in turn impairs liver perfusion and promotes hepatic injury. Particular attention is given to the molecular mediators of liver-heart communication, including hepatokines and cardiokines, as well as the emerging role of advanced research methodologies, including omics integration, proximity labeling, and organ-on-chip platforms, that are redefining our understanding of interorgan cross talk. By integrating mechanistic insights with translational tools, this review aims to support the development of multiorgan therapeutic strategies for cardiometabolic disease.
Aging at the Crossroads of Organ Interactions: Implications for the Heart
Authors: Ilke Sen, Natasha A. Trzaskalski, Yung-Ting Hsiao, Peter P. Liu, Ippei Shimizu, Geneviève A. Derumeaux
Journal: Circulation Research (2025)

Aging processes underlie common chronic cardiometabolic diseases such as heart failure and diabetes. Cross-organ/tissue interactions can accelerate aging through cellular senescence, tissue wasting, accelerated atherosclerosis, increased vascular stiffness, and reduction in blood flow, leading to organ remodeling and premature failure. This interorgan/tissue crosstalk can accelerate aging-related dysfunction through inflammation, senescence-associated secretome, and metabolic and mitochondrial changes resulting in increased oxidative stress, microvascular dysfunction, cellular reprogramming, and tissue fibrosis. This may also underscore the rising incidence and co-occurrence of multiorgan dysfunction in cardiometabolic aging in the population. Examples include interactions between the heart and the lungs, kidneys, liver, muscles, and brain, among others. However, this phenomenon can also present new translational opportunities for identifying diagnostic biomarkers to define early risks of multiorgan dysfunction, gain mechanistic insights, and help to design precision-directed therapeutic interventions. Indeed, this opens new opportunities for therapeutic development in targeting multiple organs simultaneously to disrupt the crosstalk-driven process of mutual disease acceleration. New therapeutic targets could provide synergistic benefits across multiple organ systems in the same at-risk patient. Ultimately, these approaches may together slow the aging process itself throughout the body. In the future, with patient-centered multisystem coordinated approaches, we can initiate a new paradigm of multiorgan early risk prediction and tailored intervention. With emerging tools including artificial intelligence–assisted risk profiling and novel preventive strategies (eg, RNA-based therapeutics), we may be able to mitigate multiorgan cardiometabolic dysfunction much earlier and, perhaps, even slow the aging process itself.
Gut-Heart Axis: The Role of Gut Microbiota and Metabolites in Heart Failure
Authors: Matthew Snelson, Rikeish R. Muralitharan, Chia-Feng Liu, Lajos Markó, Sofia K. Forslund, Francine Z. Marques, W.H. Wilson Tang
Journal: Circulation Research (2025)

Heart failure is a global health issue with significant mortality and morbidity. There is increasing evidence that alterations in the gastrointestinal microbiome, gut epithelial permeability, and gastrointestinal disorders contribute to heart failure progression through various pathways, including systemic inflammation, metabolic dysregulation, and modulation of cardiac function. Moreover, several medications used to treat heart failure directly impact the microbiome. The relationship between the gastrointestinal tract and the heart is bidirectional, termed the gut-heart axis. It is increasingly understood that diet-derived microbial metabolites are key mechanistic drivers of the gut-heart axis. This includes, for example, trimethylamine N -oxide and short-chain fatty acids. This review discusses current insights into the interplay between heart failure, its associated risk factors, and the gut microbiome, focusing on key metabolic pathways, the role of dietary interventions, and the potential for gut-targeted therapies. Understanding these complex interactions could pave the way for novel strategies to mitigate heart failure progression and improve patient outcomes.
Insights Into Heart-Tumor Interactions in Heart Failure
Authors: Tal Caller, Kathryn J. Moore, Lorenz H. Lehmann, Sean M. Wu, Jonathan Leor
Journal: Circulation Research (2025)

Heart failure (HF) often coexists with cancer. Beyond the known cardiotoxicity of some cancer treatments, HF itself has been associated with increased cancer incidence. The 2 conditions share common risk factors, mechanisms, and interactions that can worsen patient outcomes. The bidirectional relationship between HF and cancer presents a complex interplay of factors that are not fully understood. Recent preclinical evidence suggests that HF may promote tumor growth via the release of protumorigenic factors from the injured heart, revealing HF as a potentially protumorigenic condition. Our review discusses the biological crosstalk between HF and cancer, emphasizing the impact of HF on tumor growth, with inflammation, and modulating the immune system as central mechanisms. We further explore the clinical implications of this connection and propose future research directions. Understanding the mechanistic overlap and interactions between HF and cancer could lead to new biomarkers and therapies, addressing the growing prevalence of both conditions and enhancing approaches to diagnosis, prevention, and treatment.