tbuckley/cabot-search huggingface dataset:
Network Interactions of Circulating FGF23, HRG-HMGB1, and Cardiac Disease in CKD
Authors: Farzana Perwad, Elvis A. Akwo, Arushi Singhal, Nicholas Vartanian, Larry J. Suva, Peter A. Friedman, Cassianne Robinson-Cohen
Journal: Journal of the American Society of Nephrology (2025)

Background: Genome-wide association studies (GWAS) have identified numerous genetic loci associated with mineral metabolism markers but have exclusively focused on single-trait analysis. In this study, we performed a multi-trait analysis of GWAS (MTAG) of mineral metabolism, exploring overlapping genetic architecture between traits to identify novel genetic associations for fibroblast growth factor 23 (FGF23). Methods: We applied MTAG to variants common to GWAS of 5 genetically correlated mineral metabolism markers in European-ancestry participants. We integrated UK BioBank GWAS for blood levels for phosphate, 25-hydroxyvitamin D, and calcium (n=366,484) and CHARGE GWAS for parathyroid hormone (n=29,155) and FGF23 (n=13,716). We then used supervised and unsupervised deep machine learning to identify novel associations between genetic traits and FGF23. Results: MTAG increased the effective sample size for mineral metabolism markers to n=50,325 for FGF23. After clumping, MTAG identified independent genome-wide significant SNPs for all traits, including 62 loci for FGF23. Many of these loci have not been previously reported in single-trait analyses. Through a functional genomics approach, we identified Histidine-rich glycoprotein ( HRG ) and high-mobility-group-box 1 ( HMGB1 ) as master regulators of downstream canonical pathways associated with circulating FGF23, and both genes were highly enriched in hypertrophied cardiac tissue of deceased hemodialysis patients. In addition, we found DNMT3A was associated with uremic toxin, 8-Hydroxy-2-deoxyguanosine, a biomarker of DNA damage. In silico gene perturbation analysis revealed DNMT3A is protective in patients with heart failure caused by hypertrophied or dilated cardiomyopathy. Conclusions: Our findings highlight the importance of MTAG analysis of mineral metabolism markers to boost the number of genome-wide significant loci for FGF23 to identify novel genetic traits. Functional genomics revealed novel networks that inform unique cellular functions and identified HRG-HMGB1 as key master regulators of FGF23 and cardiovascular disease in CKD.
Cirrhosis and age are key determinants of HCC risk in individuals with primary sclerosing cholangitis: A multicenter longitudinal cohort study
Authors: Magnus Holmer, Michael Ingre, Martti Färkkilä, Cyriel Ponsioen, Bregje Mol, Christoph Schramm, Trine Folseraas, Kristine Wiencke, Nora Cazzagon, Elisa Catanzaro, Antonio Molinaro, Emma Nilsson, Johan Vessby, Stergios Kechagias, Nils Nyhlin, Mårten Werner, Annika Bergquist
Journal: Hepatology (2025)

Background &amp; Aims The risk of hepatocellular carcinoma (HCC) in primary sclerosing cholangitis (PSC) is unclear. Studies indicate a low risk for HCC questioning the rationale for current HCC surveillance guidelines. This study explores the risk of HCC in a longitudinal multicenter cohort with over 3.000 PSC-subjects. Approach &amp; results Subjects with well characterized PSC (n=3.071) were followed at 12 university hospitals within the International PSC registry (IPSCR) collaboration for a total of 38,387 person-years. Incident HCC was registered. Subjects were followed from PSC-diagnosis until death, liver transplantation, diagnosis of hepatobiliary malignancy, or February 2024. Poisson regression was used to calculate incidence rate ratios for HCC for the total population and for subgroups of different ages and cirrhosis status. Thirty-nine subjects developed HCC after a mean time of 16.4 years (SD ±10.7) from PSC diagnosis. In 26 (66.7%) of HCC cases, cirrhosis was diagnosed before HCC. The mean age at HCC diagnosis was 55.6 years (±SD13.1 years) and 28 (71.8%) were male. HCC was associated with cirrhosis (IRR 10.8;95%CI=5.7-20.5) and age (IRR 1.05;95%CI=1.03-1.08). At the age 50, the incidence rate was 0.81 and 0.47 for cirrhotic men and women respectively. For non-cirrhotic subjects, the risk was low for both men and women and all age groups. Conclusion Hepatocellular carcinoma is relatively rare in patients with primary sclerosing cholangitis who do not have cirrhosis, especially in those under the age of 50. Our findings indicate that HCC monitoring for patients with PSC can be tailored, based on their age and cirrhosis status.
Xenotransplantation
Authors: Vasishta S. Tatapudi, Aprajita Mattoo, Tamar Schiff, Sapna A. Mehta, Edward Y. Skolnik, Robert A. Montgomery
Journal: Journal of the American Society of Nephrology (2025)

The scarcity of transplantable organs represents a worldwide public health crisis, and as a result, thousands of people with end-stage kidney disease (ESKD) die waiting for a transplant each year. Xenotransplantation involves transplanting organs from an animal source into humans, offering a potential solution to this significant unmet need. Indeed, if there is a limitless supply of organs, many more patients who do not meet the current criteria for transplant eligibility could also be considered candidates. While there are examples of attempts to transplant animal tissues or organs into humans dating back over 300 years, none were successful due to cross-species immunologic incompatibility. Even so, significant advances in genetic engineering and the emergence of novel immunosuppressive agents have spurred impressive improvements in xenograft survival in preclinical studies involving nonhuman primates. Furthermore, recent reports of genetically modified pig kidney and heart xenotransplants in human decedents and living recipients on a compassionate use basis have provided impetus to advancing the field towards first-in-human trials. However, studies in nonhuman primates and humans thus far have described adaptive as well as innate immune-mediated xenograft injury. Understanding the mechanistic aspects of these responses at the cellular and molecular levels is critical to the development of targeted genetic modifications and innovative therapeutic strategies aimed at preventing rejection and inducing tolerance. Moreover, the physiological components of the bidirectional communication between the human host and pig xenograft must also be understood and manipulated. Here, we review the breakthroughs in renal xenotransplantation in the past few decades and highlight the immunologic hurdles that have yet to be overcome.
The role of epicardial adipose tissue remodelling in heart failure with preserved ejection fraction
Authors: Carolina Janssen-Telders, Etto C Eringa, Joris R de Groot, Frances S de Man, M Louis Handoko
Journal: Cardiovascular Research (2025)

Abstract Heart failure with preserved ejection fraction (HFpEF) is a growing global health problem characterized by high morbidity and mortality, with limited effective therapies available. Obesity significantly influences haemodynamic and structural changes in the myocardium and vasculature, primarily through the accumulation and action of visceral adipose tissue. Particularly, epicardial adipose tissue (EAT) contributes to HFpEF through inflammation and lipotoxic infiltration of the myocardium. However, the precise signalling pathways leading to diastolic stiffness in HFpEF require further elucidation. This review explores the dynamic role of EAT in health and disease. Drawing upon insights from studies in other conditions, we discuss potential EAT-mediated inflammatory pathways in HFpEF and how they may contribute to functional and structural myocardial and endothelial derangements, including intramyocardial lipid infiltration, fibrosis, endothelial dysfunction, cardiomyocyte stiffening, and left ventricular hypertrophy. Lastly, we propose potential targets for novel therapeutic avenues.
Genotype-specific immune responses at the intestinal barrier predispose to colitis in chronic granulomatous disease in mice
Authors: Emma Darbinian, Kodjovi D. Mlaga, Prabha Chandrasekaran, Yu Han, Agnes Donkó, Aléhandra Desjardins, Thomas L. Leto, Steven M. Holland, Johanne Poudrier, Emilia Liana Falcone
Journal: Blood (2025)

Chronic granulomatous disease (CGD) is an inborn error of immunity caused by defects in any one of the 6 subunits (gp91phox, p47phox, p22phox, p67phox, p40phox or chaperone EROS) forming the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2) and resulting in defective phagocyte-derived reactive oxygen species (ROS) production. Almost 50% of patients with CGD have inflammatory bowel disease (IBD) associated with dysbiosis and age of IBD onset may vary according to CGD genotype. While we previously demonstrated that the intestinal microbiota determines colitis susceptibility in CGD mice, underlying mechanisms remain unknown. We hypothesized that NOX2 defects are associated with distinct intestinal microbiome signatures and immune responses, which impact colitis severity. Chemical colitis susceptibility was evaluated in 2 strains of CGD mice (gp91phox-/- and p47phox-/-) with distinct microbiota, from 2 different animal facilities, while also evaluating the impact of microbiota standardization and colitogenic microbiota transfer on mucosal immune responses at the intestinal barrier. While p47phox-/- and gp91phox-/-mice harbouring colitogenic microbiota had increased colitis severity, the intestinal epithelial cells from p47phox-/- mice produced more ROS which was associated with increased NOX isoform gene expression. In contrast, gp91phox-/- mice had decreased mucin production and a mucosal immune response profile suggestive of increased inflammasome activation at the intestinal barrier compared to control and p47phox-/- mice. Our findings suggest that the microbiota impacts colitis susceptibility in a CGD genotype-specific manner, thereby potentially explaining differences in the timing of IBD onset in patients with different CGD genotypes while identifying potential novel and personalized therapeutic targets.
Pragmatic Randomized Study of Afatinib Versus Chemotherapy for Patients With Non–Small Cell Lung Cancer With Uncommon Epidermal Growth Factor Receptor Mutations: ACHILLES/TORG1834
Authors: Satoru Miura, Hiroshi Tanaka, Toshihiro Misumi, Hiroshige Yoshioka, Takaaki Tokito, Tatsuro Fukuhara, Yuki Sato, Yoshimasa Shiraishi, Katsuhiko Naoki, Hiroaki Akamatsu, Ou Yamaguchi, Toshihide Yokoyama, Shoichi Kuyama, Kazumi Nishino, Naoki Furuya, Takayasu Kurata, Terufumi Kato, Satoshi Ikeda, Hidehito Horinouchi, Eiki Ichihara, Masahide Mori, Yuichi Takiguchi, Kentaro Tanaka, Yasuhiro Goto, Hiroaki Okamoto
Journal: Journal of Clinical Oncology (2025)

PURPOSE To our knowledge, the ACHILLES/TORG1834 trial is the first randomized study comparing afatinib and chemotherapy in patients with non–small cell lung cancer (NSCLC) harboring sensitizing uncommon epidermal growth factor receptor ( EGFR ) mutations. METHODS This randomized, open-label study was performed at 51 Japanese institutions and recruited treatment-naïve patients with nonsquamous NSCLC with uncommon EGFR mutations, excluding exon 20 insertions and T790M mutations. Patients were randomly assigned 2:1 to receive afatinib (30 or 40 mg orally, at the treating physician's discretion) or a combination of platinum (cisplatin or carboplatin) and pemetrexed, followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, and safety. A prespecified interim analysis was planned to provide clinically meaningful information promptly, along with a crossover recommendation if necessary. RESULTS A total of 109 patients were enrolled between March 2019 and February 2023. In the interim analysis, the Data and Safety Monitoring Committee recommended early study termination. The median PFS was significantly longer in patients receiving afatinib than in those undergoing chemotherapy (10.6 v 5.7 months; hazard ratio, 0.421 [95% CI, 0.251 to 0.706]; P = .0010). ORRs to afatinib were similar across the overall population and among participants with major uncommon (G719X, L861Q, and S768I), compound, and other mutations (61.7%, 55.8%, 72.7%, and 60.0%, respectively). The most common grade 3 or higher adverse events were diarrhea, paronychia, and rash for afatinib, and appetite loss and nausea for chemotherapy. CONCLUSION Afatinib should be considered the standard initial therapy for patients with NSCLC with sensitizing uncommon EGFR mutations.
Development and Validation of an Artificial Intelligence Digital Pathology Biomarker to Predict Benefit of Long-Term Hormonal Therapy and Radiotherapy in Men With High-Risk Prostate Cancer Across Multiple Phase III Trials
Authors: Andrew J. Armstrong, Vinnie Y.T. Liu, Ramprasaath R. Selvaraju, Emmalyn Chen, Jeffry P. Simko, Sandy DeVries, Oliver Sartor, Howard M. Sandler, Osama Mohamad, Huei-Chung Huang, Jacqueline Griffin, Rikiya Yamashita, Andre Esteva, Phuoc T. Tran, Daniel E. Spratt, John Hi Carson, Christopher Peters, Elizabeth Gore, Steve P. Lee, Jedidiah M. Monson, Mark E. Augspurger, Ali El-Gayed, Joseph P. Rodgers, Rana McKay, Todd Morgan, Felix Y. Feng, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2025)

PURPOSE Long-term androgen deprivation therapy (ADT) improves survival in men with high-risk localized prostate cancer (PCa) receiving radiotherapy (RT). Predictive biomarkers are needed to guide ADT duration. METHODS A multimodal artificial intelligence (MMAI)–derived predictive biomarker was trained for long-term (LT) versus short-term (ST) ADT using pretreatment digital prostate biopsy images and clinical data (age, prostate-specific antigen, Gleason, and T stage) from six NRG Oncology phase III randomized radiotherapy trials. The novel MMAI-derived biomarker was developed to predict the differential benefit of LT-ADT on the primary end point, distant metastasis (DM). MMAI predictive utility was validated on a seventh randomized trial, RTOG 9202 (N = 1,192), which randomly assigned men to RT + ST-ADT (4 months) versus RT + LT-ADT (28 months). Fine-Gray and cumulative incidence analyses for DM, and secondarily, death with DM, were performed. Deaths without DM were treated as competing risks. RESULTS In the validation cohort (median follow-up, 17.2 years), LT-ADT significantly improved DM from 26% to 17% (subdistribution hazard ratio [sHR], 0.64 [95% CI, 0.50 to 0.82], P &lt; .001). A significant biomarker-treatment predictive interaction was observed ( P = .04) for DM, whereby MMAI biomarker–positive men (n = 785, 66%) had reduced DM with LT-ADT versus ST-ADT (sHR, 0.55 [95% CI, 0.41 to 0.73], P &lt; .001), whereas no treatment benefit was observed for MMAI biomarker–negative men (n = 407; sHR, 1.06 [95% CI, 0.61 to 1.84], P = .84). The estimated 15-year DM risk difference between RT + LT-ADT and RT + ST-ADT was 14% in MMAI biomarker–positive men and 0% in MMAI biomarker–negative men. The MMAI biomarker was also prognostic for DM, irrespective of treatment (sHR, 2.35 [95% CI, 1.72 to 3.19], P &lt; .001). CONCLUSION To our knowledge, the MMAI model is the first validated predictive biomarker to guide ADT duration with RT in localized/locally advanced PCa. Approximately one third of men with high-risk PCa could safely be spared the additional 24 months of ADT and the associated morbidity.
International Consensus Statement on Diagnosis, Evaluation, and Research of Richter Transformation: the ERIC Recommendations
Authors: Adam S Kittai, Monia Marchetti, Othman Al-Sawaf, Ohad Benjamini, Alexey V Danilov, Matthew S. Davids, Barbara F. Eichhorst, Toby A. Eyre, Anna Maria Frustaci, Michael J Hallek, Paul Joseph Hampel, Yair Herishanu, Rodney John Hicks, Arnon P. Kater, Rebecca L. King, José-Ignacio Ignacio Martín-Subero, Carolyn Owen, Erin M. Parry, Maurilio Ponzoni, Davide Rossi, Tanya Siddiqi, Stephan Stilgenbauer, Constantine S. Tam, Elisa ten Hacken, Philip A Thompson, William G. Wierda, Gianluca Gaidano, Jennifer A. Woyach, Paolo Ghia
Journal: Blood (2025)
Contemporary review of critical illness following allogeneic hematopoietic stem cell transplant in adults
Authors: Laveena Munshi, Guillaume Dumas, Bruno Ferreryro, Cristina Gutierrez, Boris Böll, Pedro Castro, Sanjay Chawla, Matteo Di Nardo, Antoine Lafarge, Colleen McEvoy, Djamel Mokart, Antonio Paulo Nassar, Judith Nelson, Frédéric Pène, Peter Schellongowski, Elie Azoulay
Journal: Intensive Care Medicine (2025)
Fidanacogene Elaparvovec for Hemophilia B — A Multiyear Follow-up Study
Authors: John E.J. Rasko, Benjamin J. Samelson-Jones, Lindsey A. George, Adam Giermasz, Jonathan M. Ducore, Jerome M. Teitel, Catherine E. McGuinn, Katherine A. High, Ype P. de Jong, Amit Chhabra, Amanda O’Brien, Lynne M. Smith, Ian Winburn, Jeremy Rupon
Journal: New England Journal of Medicine (2025)

Treatment with fidanacogene elaparvovec, a recombinant adeno-associated virus (AAV) vector developed for the treatment of hemophilia B, led to sustained expression of the high-activity factor IX variant (FIX-R338L, or FIX-Padua) in a phase 1-2a study. The long-term safety and efficacy of this treatment are not known. In a 12-month study, 15 participants with severe or moderately severe hemophilia B (factor IX coagulant activity, ≤2% of the normal value) received fidanacogene elaparvovec at a dose of 5×1011 vector genomes (vg) per kilogram of body weight; thereafter, participants could enroll in a 5-year follow-up study. Safety end points included adverse events and changes in laboratory measures. Efficacy end points included the annualized rate of treated bleeding events (annualized bleeding rate) and factor IX activity. A total of 14 participants provided consent and completed at least 3 years of follow-up (median, 5.5; range 3 to 6); participation was ongoing among 8 at the data cutoff. None of the participants reported treatment-related adverse events after year 1. Throughout follow-up, nine serious adverse events were noted in 4 participants; none were thrombotic or treatment-related. No factor IX inhibitors were detected. Throughout follow-up, mean factor IX activity was in the mild hemophilia range; the mean annualized bleeding rate was less than 1, and 10 participants had no treated bleeding episodes. Surveillance liver ultrasounds obtained from year 1 onward showed no evidence of cancer but showed steatosis in 4 participants who had weight gain and elevated aminotransferase levels (maximum alanine aminotransferase level, 77 U per liter). One participant with a history of hepatitis C, hepatitis B, human immunodeficiency virus infection, and an elevated body-mass index had progression of underlying advanced liver fibrosis. A total of 13 surgical procedures were performed in 8 participants; exogenous factor IX was administered for 10 procedures, and no associated unexpected bleeding complications occurred. Fidanacogene elaparvovec was associated with no or only low-grade adverse effects over a period of 3 to 6 years. Efficacy was maintained in the long term at 5×1011 vg per kilogram, one of the lowest intravenous doses of AAV used for any indication. (Funded by Pfizer; ClinicalTrials.gov number, NCT03307980.).
Disseminated Syphilis Caused by Two Recombining <i>Treponema pallidum</i> Strains
Authors: Nicole A.P. Lieberman, Shah A.K. Mohamed Bakhash, B. Ethan Nunley, Muyi Li, Brian Mau, John S. Pauk, Paul Swanson, Anand Baxi, Joshua A. Lieberman, Alexander L. Greninger
Journal: New England Journal of Medicine (2025)
Artificial intelligence tools in supporting healthcare professionals for tailored patient care
Authors: Jiyeong Kim, Michael L Chen, Shawheen J Rezaei, Tina Hernandez-Boussard, Jonathan H Chen, Fatima Rodriguez, Summer S Han, Rayhan A Lal, Sun H Kim, Chrysoula Dosiou, Susan M Seav, Tugce Akcan, Carolyn I Rodriguez, Steven M Asch, Eleni Linos
Journal: npj Digital Medicine (2025)

Artificial intelligence (AI) tools to support clinicians in providing patient-centered care can contribute to patient empowerment and care efficiency. We aimed to draft potential AI tools for tailored patient support corresponding to patients' needs and assess clinicians' perceptions about the usefulness of those AI tools. To define patients' issues, we analyzed 528,199 patient messages of 11,123 patients with diabetes by harnessing natural language processing and AI. Applying multiple prompt-engineering techniques, we drafted a series of AI tools, and five endocrinologists evaluated them for perceived usefulness and risk. Patient education and administrative support for timely and streamlined interaction were perceived as highly useful, yet deeper integration of AI tools into patient data was perceived as risky. This study proposes assorted AI applications as clinical assistance tailored to patients' needs substantiated by clinicians' evaluations. Findings could offer essential ramifications for developing potential AI tools for precision patient care for diabetes and beyond.
Climate Change, Extreme Weather Events, Food Security, and Nutrition: Evolving Relationships and Critical Challenges
Authors: Jessica Fanzo, Bianca Carducci, Jochebed Louis-Jean, Mario Herrero, Kevin Karl, Cynthia Rosenzweig
Journal: Annual Review of Nutrition (2025)

Climate change, also known as global warming, poses significant challenges for both the planet and humanity. With further warming, every region across the world is projected to increasingly experience concurrent and multiple changes in climate, compounding overall risk. Long-term climate change and near-term extreme weather events have multiple negative effects on food security, diets, and nutrition via complex, multidirectional pathways through food, health, water, and social protection systems. However, measuring climate-attributable malnutrition impacts, especially among the most vulnerable populations, remains challenging. Changes in climate across a range of geographies have been modeled, projected, and observed showing detrimental associations with dietary and nutrition outcomes, particularly undernutrition. Many of these undernourished populations are climate vulnerable due to a variety of determinants challenging their ability to adapt to impending risks. While nutrition integration within climate adaptation plans have lagged, there is momentum for robust collaboration between climate and nutrition communities to fill data gaps that are critical for joint decision-making.
Erratum: Fertility Preservation in People With Cancer: ASCO Guideline Update
Authors: H. Irene Su, Christina Lacchetti, Joseph Letourneau, Ann H. Partridge, Rubina Qamar, Gwendolyn P. Quinn, Joyce Reinecke, James F. Smith, Megan Tesch, W. Hamish Wallace, Erica T. Wang, Alison W. Loren
Journal: Journal of Clinical Oncology (2025)