tbuckley/cabot-search huggingface dataset:
Lipid-Lowering Therapy and Cardiovascular Prevention in Elderly
Authors: Francesco Baratta, Federica Moscucci, Ilaria Lospinuso, Nicholas Cocomello, Alessandra Colantoni, Alessia Di Costanzo, Daniele Tramontano, Laura D'Erasmo, Daniele Pastori, Evaristo Ettorre, Maria Del Ben, Marcello Arca, Giovambattista Desideri
Journal: Drugs (2025)

The global population aged 80 years and older will reach approximately half a billion in the coming years, and cardiovascular prevention in this group of patients will become a global health challenge. In the era of evidence-based medicine, the use of lipid-lowering therapies (LLTs) in the elderly, particularly in primary and secondary cardiovascular prevention, remains an area of active research. Although there is broad consensus on the use of LLTs in the elderly to prevent recurrent cardiovascular events in secondary prevention, there is considerable debate about their use in primary prevention. Many efforts have been made to improve cardiovascular risk stratification in patients over 75 years of age in primary prevention. In recent years, some specific risk scores have been developed, including the Systematic Coronary Risk Evaluation 2 for Older Persons (SCORE2-OP). While there are very few specific warnings to consider for LLTs in the elderly, an important challenge in this patient population is to identify the turning point at which the disutility risk outweighs the potential benefits. However, despite the widespread recognition of the importance of this issue, there is a lack of guidance on how to identify patients who should be withdrawn from therapy. The aim of this narrative review is to examine the current state of knowledge regarding the indications for LLT in elderly patients, identify outstanding issues, and discuss future developments.
PPIL2 is a target of the JAK2/STAT5 pathway and promotes myeloproliferation via p53-mediated degradation
Authors: Pan Wang, Xu Han, Kehan Ren, Ermin Li, Honghao Bi, Inci Aydemir, Madina Sukhanova, Yijie Liu, Jing Yang, Peng Ji
Journal: Journal of Clinical Investigation (2025)

The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). Pleckstrin-2 (PLEK2) signalosome is downstream of the JAK2/STAT5 pathway and plays an important role in MPN development. The detailed molecular composition of this signalosome is unclear. Here, we revealed peptidylprolyl isomerase-like 2 (PPIL2) as a critical component of the complex in regulating human and murine erythropoiesis. PPIL2 was a direct target of STAT5 and was upregulated in MPN patients and a Jak2V617F MPN mouse model. Mechanistically, PPIL2 interacted with and catalyzed p53 polyubiquitination and proteasome-mediated degradation to promote cell growth. Ppil2 deficiency, or inhibition by cyclosporin A, led to a marked upregulation of p53 in vivo and ameliorated myeloproliferative phenotypes in Jak2V617F mice. Cyclosporin A also markedly reduced JAK2 mutated erythroid and myeloid proliferation in an induced pluripotent stem cell-derived human bone marrow organoid model. Our findings revealed PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negatively regulating p53, thus providing a target and an opportunity for drug repurposing by using cyclosporin A to treat MPNs.
GluN2B suppression restores phenylalanine-induced neuroplasticity and cognition impairments in a mouse model of phenylketonuria
Authors: Woo Seok Song, Young Sook Kim, Young-Soo Bae, Sang Ho Yoon, Jae Min Lim, Myoung-Hwan Kim
Journal: Journal of Clinical Investigation (2025)

Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanisms by which elevated phenylalanine (Phe) levels cause cognitive impairment remain unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. PahEnu2 PKU model mice exhibited submillimolar and supramillimolar concentrations of Phe in the cerebrospinal fluid (CSF) and serum, respectively. L-Phe produced concentration-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDARs in hippocampal CA1 neurons. L-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in activity-dependent downregulation of AMPARs during burst or sustained synaptic activity. Administration of L-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment with GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed the impaired learning in PahEnu2 mice. Collectively, these results suggest that the concentration of Phe in the CSF of patients with PKU perturbs extrasynaptic NMDARs and synaptic plasticity, and that suppression of GluN2B may have the potential to improve cognitive function in patients with PKU.
NK cell activation and CD4 T cell α4β7 expression are associated with susceptibility to HIV-1
Authors: Kawthar Machmach, Kombo F N'guessan, Rohit Farmer, Sucheta Godbole, Dohoon Kim, Lauren McCormick, Noemia S Lima, Amy R Henry, Farida Laboune, Isabella Swafford, Sydney K Mika, Bonnie M Slike, Jeffrey R Currier, Leigh Anne Eller, Julie A Ake, Sandhya Vasan, Merlin L Robb, Shelly J Krebs, Daniel C Douek, Dominic Paquin-Proulx
Journal: Journal of Clinical Investigation (2025)

We leveraged specimens from the RV217 prospective study that enrolled participants at high risk of HIV-1 acquisition to investigate how NK, conventional T cells, and unconventional T cells influence HIV-1 acquisition. We observed low levels of α4β7 expression on memory CD4 T cells and iNKT cells, two cell types highly susceptible to HIV-1 infection, in highly exposed seronegative (HESN) compared to highly exposed seroconverter (HESC) participants. NK cells from HESN had higher levels of α4β7 compared to HESC, presented a quiescent phenotype, and had a higher capacity to respond to opsonized target cells. We also measured translocated microbial products in plasma and found differences in phylum distribution between HESN and HESC that were associated with the immune phenotypes impacting the risk of HIV-1 acquisition. Finally, a logistic regression model combining features of NK cells activation, α4β7 expression on memory CD4 T cells, and Tbet expression by iNKT cells achieved the highest accuracy in identifying HESN and HESC participants. This immune signature comprised of increased α4β7 on cells susceptible to HIV infection combined with higher NK cells activation and lower gut homing potential could impact the efficacy of HIV-1 prevention strategies such as vaccines.
The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies
Authors: Pedro Aguilar-Garrido, María Velasco-Estévez, Miguel Ángel Navarro-Aguadero, Alvaro Otero-Sobrino, Marta Ibañez-Navarro, Miguel Ángel Marugal, María Hernández-Sánchez, Prerna Malaney, Ashley Rodriguez, Oscar Benitez, Xiaorui Zhang, Marisa Jl Aitken, Alejandra Ortiz-Ruiz, Diego Megias, Manuel Pérez-Martínez, Gadea Mata, Jesús Gomez, Miguel Lafarga, Orlando Dominguez, Osvaldo Graña-Castro, Eduardo Caleiras, Pilar Ximenez-Embun, Marta Isasa, Paloma J de Andrés, Sandra Rodriguez-Perales, Raul Torres-Ruiz, Enrique Revilla, Rosa María García-Martín, Daniel Azorín, Josune Zubicaray, Julian Sevilla, Oleksandra Sirozh, Vanesa Lafarga, Joaquín Martinez-Lopez, Sean M Post, Miguel Gallardo
Journal: Journal of Clinical Investigation (2025)

The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein (RBP) HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation and caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell cycle arrest, senescence, and bone marrow failure phenotype, similar to what is observed in patients with ribosomopathies. Together, our findings identify HNRNPK as a master regulator of ribosome biogenesis (RiBi) and nucleolar homeostasis through p53, providing a new perspective on the orchestration of nucleolar integrity, ribosome function and cellular senescence.
Thrombospondin-1 inhibits alternative complement pathway activation in antineutrophil cytoplasmic antibody-associated vasculitis
Authors: Swagata Konwar, Sophie Schroda, Manuel Rogg, Jessika Kleindienst, Eva L Decker, Martin Pohl, Barbara Zieger, Jens Peter Panse, Hong Wang, Robert Grosse, Christoph Schell, Sabine Vidal, Xiaobo Liu, Christian Gorzelanny, Todor Tschongov, Karsten Häffner
Journal: Journal of Clinical Investigation (2025)

Complement activation is a relevant driver in the pathomechanisms of vasculitis. The involved proteins in the interaction between endothelia, complement and platelets in these conditions are only partially understood. Thrombospondin-1 (TSP-1), found in platelet α-granules and released from activated endothelial cells, interacts with factor H (FH) and von Willebrand factor (vWF). However, direct regulatory interaction with the complement cascade has not yet been described. We could show that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins, inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. Complement-regulatory function is validated in blood samples from patients with primary complement defects. Physiological relevance of TSP-1 is demonstrated in ANCA-associated vasculitis (AAV) patients by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis following TSP-1 deficiency in an in vitro and in vivo model of AAV. The newly described complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia and complement. In particular, the interplay between released TSP-1 and the complement system locally, especially on surfaces, influences the balance between complement activation and inhibition and may be relevant in various vascular diseases.
Characterization of Research Grant Terminations at the National Institutes of Health
Authors: Michael Liu, Kushal T. Kadakia, Vishal R. Patel, Harlan M. Krumholz
Journal: JAMA (2025)

This study examines the impact of National Institutes of Health grant terminations on the US research enterprise by quantifying the number and funding amount of these terminations and characterizing their award type and institute or center.
Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration
Authors: Elise A Kellett, Adekunle T Bademosi, Adam K Walker
Journal: Molecular Neurodegeneration (2025)

Abstract Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid–liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid–liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration. Graphical Abstract TDP-43 is subject to phosphorylation by kinases and dephosphorylation by phosphatases, which variably impacts protein localisation, aggregation, and neurotoxicity in neurodegenerative diseases.
Weakly supervised language models for automated extraction of critical findings from radiology reports
Authors: Avisha Das, Ish A Talati, Juan Manuel Zambrano Chaves, Daniel Rubin, Imon Banerjee
Journal: npj Digital Medicine (2025)

Critical findings in radiology reports are life threatening conditions that need to be communicated promptly to physicians for timely management of patients. Although challenging, advancements in natural language processing (NLP), particularly large language models (LLMs), now enable the automated identification of key findings from verbose reports. Given the scarcity of labeled critical findings data, we implemented a two-phase, weakly supervised fine-tuning approach on 15,000 unlabeled Mayo Clinic reports. This fine-tuned model then automatically extracted critical terms on internal (Mayo Clinic, n = 80) and external (MIMIC-III, n = 123) test datasets, validated against expert annotations. Model performance was further assessed on 5000 MIMIC-IV reports using LLM-aided metrics, G-eval and Prometheus. Both manual and LLM-based evaluations showed improved task alignment with weak supervision. The pipeline and model, publicly available under an academic license, can aid in critical finding extraction for research and clinical use ( https://github.com/dasavisha/CriticalFindings_Extract ).
Value of Bioinformatics Models for Predicting Translational Control of Angiogenesis
Authors: Michal Shaposhnikov, Juilee Thakar, Bradford C. Berk
Journal: Circulation Research (2025)

Angiogenesis, the formation of new blood vessels, is a fundamental biological process with implications for both physiological functions and pathological conditions. While the transcriptional regulation of angiogenesis, mediated by factors such as HIF-1α (hypoxia-inducible factor 1-alpha) and VEGF (vascular endothelial growth factor), is well-characterized, the translational regulation of this process remains underexplored. Bioinformatics has emerged as an indispensable tool for advancing our understanding of translational regulation, offering predictive models that leverage large data sets to guide research and optimize experimental approaches. However, a significant gap persists between bioinformatics experts and other researchers, limiting the accessibility and utility of these tools in the broader scientific community. To address this divide, user-friendly bioinformatics platforms are being developed to democratize access to predictive analytics and empower researchers across disciplines. Translational control, compared with transcriptional control, offers a more energy-efficient mechanism that facilitates rapid cellular responses to environmental changes. Furthermore, transcriptional regulators themselves are often subject to translational control, emphasizing the interconnected nature of these regulatory layers. Investigating translational regulation requires advanced, accessible bioinformatics tools to analyze RNA structures, interacting micro-RNAs, long noncoding RNAs, and RBPs (RNA-binding proteins). Predictive platforms such as RNA structure, human internal ribosome entry site Atlas, and RBPSuite enable the study of RNA motifs and RNA-protein interactions, shedding light on these critical regulatory mechanisms. This review highlights the transformative role of bioinformatics using widely accessible user-friendly tools with a Web-browser interface to elucidate translational regulation in angiogenesis. The bioinformatics tools discussed extend beyond angiogenesis, with applications in diverse fields, including clinical care. By integrating predictive models and experimental insights, researchers can streamline hypothesis generation, reduce experimental costs, and find novel translational regulators. By bridging the bioinformatics knowledge gap, this review aims to empower researchers worldwide to adopt bioinformatics tools in their work, fostering innovation and accelerating scientific discovery.
Computationally designed proteins mimic antibody immune evasion in viral evolution
Authors: Noor Youssef, Sarah Gurev, Fadi Ghantous, Kelly P Brock, Javier A Jaimes, Nicole N Thadani, Ann Dauphin, Amy C Sherman, Leonid Yurkovetskiy, Daria Soto, Ralph Estanboulieh, Ben Kotzen, Pascal Notin, Aaron W Kollasch, Alexander A Cohen, Sandra E Dross, Jesse Erasmus, Deborah H Fuller, Pamela J Bjorkman, Jacob E Lemieux, Jeremy Luban, Michael S Seaman, Debora S Marks
Journal: Immunity (2025)

Recurrent waves of viral infection necessitate vaccines and therapeutics that remain effective against emerging viruses. Our ability to evaluate interventions is currently limited to assessments against past or circulating variants, which likely differ in their immune escape potential compared with future variants. To address this, we developed EVE-Vax, a computational method for designing antigens that foreshadow immune escape observed in future viral variants. We designed 83 SARS-CoV-2 spike proteins that transduced ACE2-positive cells and displayed neutralization resistance comparable to variants that emerged up to 12 months later in the COVID-19 pandemic. Designed spikes foretold antibody escape from B.1-BA.4/5 bivalent booster sera seen in later variants. The designed constructs also highlighted the increased neutralization breadth elicited by nanoparticle-based, compared with mRNA-based, boosters in non-human primates. Our approach offers targeted panels of synthetic proteins that map the immune landscape for early vaccine and therapeutic evaluation against future viral strains.
Spatial Multi-Omics Reveals the Potential Involvement of SPP1+ Fibroblasts in Determining Metabolic Heterogeneity and Promoting Metastatic Growth of Colorectal Cancer Liver Metastasis
Authors: Yuzhen Gao, Xiuping Zhang, Shenglong Xia, Qing Chen, Qinchao Tong, Shaobo Yu, Rui An, Cheng Cheng, Wenbo Zou, Leilei Liang, Xinyou Xie, Zhangfa Song, Rong Liu, Jun Zhang
Journal: Molecular Therapy (2025)
Grading Differentiation in Cutaneous Squamous Cell Carcinoma: A Modified Delphi Consensus Panel
Authors: Kathryn T Shahwan, Trent D Walker, Claire Diede, Melica Nikahd, Sumaira Z Aasi, Jeremy S Bordeaux, Sean R Christensen, Catherine Chung, Dirk M Elston, Jane M Grant-Kels, Christine J Ko, Justin J Leitenberger, Daniel D Miller, Melissa Piliang, Leslie Robinson-Bostom, Emily S Ruiz, Michelle Tarbox, Allison Vidimos, David R Carr
Journal: Journal of the American Academy of Dermatology (2025)
An Advanced Inhalable Dry Powder, Mucus-Penetrating Aerosol Platform: Bridging Andrographolide Delivery with Clinical Translation
Authors: Decui Cheng, Tingting Pan, Xiaoli Wang, Rui Tian, Huizhen Fan, Li Wei, Shiyuan He, Ruonan Dong, Xiangqun Yan, Mei X Wu, Ruoming Tan, Hongping Qu, Min Lu
Journal: Biomaterials (2025)
Satisfaction with telemedicine versus in-person visits in rheumatology: a noninferiority randomised controlled trial
Authors: Lesley E Jackson, Jinoos Yazdany, Justin M Leach, Kenneth G Saag, Kiara Aaron, Jeffrey R Curtis, Sarah Goglin, Mary Margaretten, David H Chae, Diana Paez, Gary Cutter, Maria I Danila
Journal: Annals of the Rheumatic Diseases (2025)

We tested whether a rheumatology telemedicine visit was noninferior to an in-person visit for patient satisfaction and care effectiveness, including for subgroups of age, sex, race and ethnicity, income, and employment status. This multicenter noninferiority trial randomised patients to 1 in-person or telemedicine visit. The primary outcome was the proportion of high visit satisfaction (9 or 10 on a 0-10 scale). The primary analysis tested whether patient satisfaction with telemedicine was noninferior to in-person care (10% noninferiority margin). Secondary and exploratory outcomes included preference for next visit type, satisfaction in subgroups, and immunosuppressant toxicity monitoring. We performed modified intent-to-treat (mITT) and per-protocol analyses. Among 651 randomised patients (in-person, n = 323; telemedicine n = 328), 500 (76.8%) had a visit defining the mITT population. Satisfaction with telemedicine was not noninferior to in-person; 77.0% telemedicine, 90.1% in-person, difference 13.1% (90% CI, 7.7%-18.5%). Per-protocol analysis results were consistent. More participants in the in-person group compared with those in telemedicine preferred the same visit type for their next visit vs a different visit type/no preference (55.6% in-person, 19.1% telemedicine, P < .0001, mITT analysis). Men were equally satisfied with both visit types (90.0%), while women were more likely to be satisfied with in-person visits (90.2% vs 74.7%). Toxicity monitoring rates were higher in in-person vs telemedicine (eg, hepatic function: 92.1% vs 66.3%, P = .0001, per-protocol analysis). Among a large group of diverse patients, satisfaction with telemedicine was not noninferior to in-person rheumatology visits. More participants preferred in-person visits in the mITT and per-protocol analyses. Appropriate toxicity monitoring was lower in telemedicine vs in-person groups.
European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2025 Update on Male Hypogonadism, Erectile Dysfunction, Premature Ejaculation, and Peyronie’s Disease
Authors: Andrea Salonia, Paolo Capogrosso, Luca Boeri, Andrea Cocci, Giovanni Corona, Marij Dinkelman-Smit, Marco Falcone, Christian Fuglesang Jensen, Murat Gül, Arif Kalkanli, Ates Kadioğlu, Juan I Martinez-Salamanca, L Afonso Morgado, Giorgio I Russo, Ege Can Serefoğlu, Paolo Verze, Suks Minhas
Journal: European Urology (2025)
Corrigendum to “RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression” [Eur. Urol. 76(2) (2019) 157–166]
Authors: Yinan Li, Ning Xie, Ruiqi Chen, Ahn R Lee, Jessica Lovnicki, Emma A Morrison, Ladan Fazli, Qingfu Zhang, Catherine A Musselman, Yuzhuo Wang, Jiaoti Huang, Martin E Gleave, Colin Collins, Xuesen Dong
Journal: European Urology (2025)
Neutrophil membrane engineered human umbilical cord MSC-derived sEVs enhance anti-tumor efficacy for gastric cancer via delivering pentraxin 3
Authors: Yuting Tang, Ye Shen, Xueyan Zang, Peipei Wu, Linli Li, Hui Qian, Xu Zhang, Wenrong Xu, Jiajia Jiang
Journal: Journal of Controlled Release (2025)
Erratum to “Intranasal delivery of extracellular vesicles: A promising new approach for treating neurological and respiratory disorders” [Journal of Controlled Release, Volume 379, 10 March 2025, Pages 489–523, 13427]
Authors: Sofía V Sánchez, Gabriela N Otavalo, Florence Gazeau, Amanda K A Silva, Javier O Morales
Journal: Journal of Controlled Release (2025)
Dupilumab-induced inhibition of myeloid dendritic cells function via TIM-3-TGF-β1 feedback loop in treatment of atopic dermatitis
Authors: Yishan Chen, Yuyang Tian, Siqi Liu, Kefan Lin, Rong Tao, Bocheng Wang, Yijia Ruan, Mingjun Hou, Di Wang, Yurong Luo, Chunyan Li, Puyu Zou, Yunsheng Liang, Pan Lai, Danchen Hu, Weiwei Deng
Journal: Journal of Allergy and Clinical Immunology (2025)