tbuckley/cabot-search huggingface dataset:
Cumulative Incidence of Mortality Associated with Cardiovascular-Kidney-Metabolic Syndrome
Authors: Sophie E. Claudel, Insa M. Schmidt, Sushrut S. Waikar, Ashish Verma
Journal: Journal of the American Society of Nephrology (2025)

Background: It is imperative to critically evaluate the prognostic implications of Cardiovascular-Kidney-Metabolic (CKM) syndrome staging to inform clinical practice. The primary aims of this paper were to define the risk of mortality associated with each CKM syndrome stage and to determine the corresponding restricted mean survival time over a 15-year period. Methods: This is a longitudinal study of 50,678 community-dwelling U.S. adults aged 20 and older with baseline data for CKM stage determination participating in the 1999-2018 National Health and Nutrition Examination Survey. CKM stages defined according to the American Heart Association presidential advisory. 15-year adjusted cumulative incidences of cardiovascular mortality were calculated for each stage from confounder-adjusted survival curves using the G-formula. Results: Over a median 9.5-year follow-up, 2,564 participants experienced cardiovascular death. The 15-year adjusted cumulative incidences of cardiovascular mortality were: Stage 0, 5.5% (95% CI, 1.8-9.3); Stage 1, 5.7% (95% CI, 3.2-8.2); Stage 2, 7.9% (95% CI, 6.8-9.1); Stage 3, 8.7% (95% CI 6.7-10.8); Stage 4, 15.2% (95% CI, 13.6-16.8). The absolute risk difference between CKM Stage 4 and Stage 0 at 15 years was 9.6% (95% CI, 5.6-13.6). The survival difference between CKM stage 0 and Stage 4 at 15 years was 5.6 (95% CI, 5.5-5.7 months. Conclusions: Our findings reveal a graded risk for cardiovascular mortality associated with higher CKM syndrome stage.
Rapamycin Enhances CAR-T Control of HIV Replication and Reservoir Elimination in vivo
Authors: Wenli Mu, Shallu Tomer, Jeffrey Harding, Nandita Kedia, Valerie Rezek, Ethan Cook, Vaibhavi Patankar, Mayra A. Carrillo, Heather Martin, Hwee L. Ng, Li Wang, Matthew D. Marsden, Scott D. Kitchen, Anjie Zhen
Journal: Journal of Clinical Investigation (2025)

Chimeric Antigen Receptor (CAR) T cell therapy shows promise for various diseases. Our studies in humanized mice and non-human primates (NHPs) demonstrate that hematopoietic stem cell (HSCs) modified with anti-HIV CAR achieve lifelong engraftment, providing functional anti-viral CAR-T cells that reduce viral rebound after ART withdrawal. However, T cell exhaustion due to chronic immune activation remains a key obstacle for sustained CAR-T efficacy, necessitating additional measures to achieve functional cure. We recently showed that low dose rapamycin treatment reduced inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin enhanced CAR-T cell mitochondria respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC mice decreased chronic inflammation, prevented exhaustion of CAR-T cells and improved CAR-T control of viral replication. RNAseq analysis of CAR-T cells from humanized mice showed that rapamycin downregulated multiple checkpoint inhibitors and the upregulated key survival genes. Mice treated with CAR-HSCs and rapamycin had delayed viral rebound post-ART and reduced HIV reservoir compared to CAR-HSCs alone. These findings suggest that HSCs-based anti-HIV CAR-T combined with rapamycin treatment is a promising approach for treating persistent inflammation and improving immune control of HIV replication.
Distinct states of Nuclear Speckles emerge as new predictors of cancer prognosis
Authors: Lisa Martina, Michał Małszycki, Tuğçe Aktaş
Journal: Cancer Research (2025)

Abstract The complex environment of the mammalian nucleus is compartmentalized into functional units by membraneless organelles. Recent advancements have elevated nuclear speckles, one of the most prominent nuclear condensates, to a central role in gene expression regulation. In their recent paper, Alexander and colleagues provide insights into the involvement of nuclear speckles in cancer progression. They identify two signatures of speckle transcriptome that stratify human cancers and, in the case of the clear cell renal cell carcinoma (ccRC), strongly correlate with drug response and ultimately with patient’s survival. These signatures correspond to different morphological states of nuclear speckles and influence speckle-regulated gene expression. A deeper look into transcriptional regulation allowed the authors to identify an amino acid sequence which enables the central transcription factor responsible of ccRC oncogenesis to bring its chromatin target into nuclear speckle proximity. The findings provide new insights into the intricacies of nuclear speckle biology and offer new avenues for understanding cancer progression and developing targeted therapies.
Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance
Authors: Evi J.C. Koene, Amée M. Buziau, David Cassiman, Timothy M. Cox, Judith Bons, Jean L. J. M. Scheijen, Casper G. Schalkwijk, Steven J.R. Meex, Aditi R. Saxena, William P. Esler, Vera B. Schrauwen-Hinderling, Patrick Schrauwen, Martijn C.G.J. Brouwers
Journal: Journal of Clinical Investigation (2025)
TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism
Authors: Yu Zeng, Liqian Zhao, Kunlin Zeng, Ziling Zhan, Zhengming Zhan, Shangbiao Li, Hongchao Zhan, Peng Chai, Cheng Xie, Shengfeng Ding, Yuxin Xie, Li Wang, Cuiying Li, Xiaoxia Chen, Daogang Guan, Enguang Bi, Jian-you Liao, Fan Deng, Xiaochun Bai, Ye Song, Aidong Zhou
Journal: Journal of Clinical Investigation (2025)

Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation-induced cell death, although the precise mechanisms involved remain unclear. Herein, we report that loss of tumor necrosis factor receptor-associated factor 3 (TRAF3) in GBM critically regulates lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 is frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacts with enoyl-CoA hydratase 1 (ECH1), an enzyme catalyzing the isomerization of unsaturated fatty acids (UFAs), and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impedes TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promotes the oxidation of UFAs, preferentially the PUFAs, and limits lipid peroxidation. Overexpression of TRAF3 enhances the sensitivity of GBM to ferroptosis and anti-PD-L1 immunotherapy in mice. Thus, the TRAF3-ECH1 axis plays a key role in the metabolism of PUFAs, and is crucial for lipid peroxidation damage and immune elimination in GBM.
Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling
Authors: Moydul Islam, David R. Rawnsley, Xiucui Ma, Walter Navid, Chen Zhao, Xumin Guan, Layla Foroughi, John T. Murphy, Honora Navid, Carla J. Weinheimer, Attila Kovacs, Jessica Nigro, Aaradhya Diwan, Ryan P. Chang, Minu Kumari, Martin E. Young, Babak Razani, Kenneth B. Margulies, Mahmoud Abdellatif, Simon Sedej, Ali Javaheri, Douglas F. Covey, Kartik Mani, Abhinav Diwan
Journal: Journal of Clinical Investigation (2025)

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.
Ablating VHL in Rod Photoreceptors Modulates RPE Glycolysis and Improves Preclinical Model of Retinitis Pigmentosa
Authors: Salvatore Marco Caruso, Xuan Cui, Brian M Robbings, Noah Heaps, Aykut Demikrol, Bruna Lopes da Costa, Daniel T Hass, Peter Mj Quinn, Jianhai Du, James B Hurley, Stephen H Tsang
Journal: Journal of Clinical Investigation (2025)

Neuroretinal degenerations including retinitis pigmentosa (RP) comprise a heterogeneous collection of pathogenic mutations that ultimately result in blindness. Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, non-cell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.
Endothelial-specific postnatal deletion of Nos3 preserves intraocular pressure homeostasis via macrophage recruitment and NOS2 upregulation
Authors: Ruth A. Kelly, Megan S. Kuhn, Ester Reina-Torres, Revathi Balasubramanian, Kristin M. Perkumas, Guorong Li, Takamune Takahashi, Simon W.M. John, Michael H. Elliott, Darryl R. Overby, W. Daniel Stamer
Journal: Journal of Clinical Investigation (2025)

Polymorphisms in Nos3 increases risk for glaucoma, the leading cause of irreversible blindness worldwide. A key modifiable risk factor for glaucoma is intraocular pressure (IOP), which is regulated by nitric oxide (NO), a product of nitric oxide synthase-3 (Nos3) in Schlemm's canal of the conventional outflow pathway. We studied the effects of a conditional, endothelial-specific postnatal deletion of Nos3 (Endo-SclCre-ERT;Nos3flox/flox) on tissues of the outflow pathway. We observed that Cre-ERT expression spontaneously and gradually increased with time in vascular endothelia including Schlemm's canal, beginning at P10, with complete Nos3 deletion occurring around P90. Unlike the reduced outflow resistance in global Nos3 knockout mice, outflow resistance and IOP in Endo-SclCre-ERT;Nos3flox/flox mice were normal. Coinciding with Nos3 deletion, we observed recruitment of macrophages to, and induction of both ELAM-1 and NOS2 expression by endothelia in the distal portion of the outflow pathway, which increased vessel diameter. These adjustments reduced outflow resistance to maintain IOP in these Endo-SclCre-ERT;Nos3flox/flox mice. Selective inhibition of iNOS by 1400W resulted in narrowing of distal vessels and IOP elevation. Together, results emphasize the pliability of the outflow system, the importance of NO signaling in IOP control and implicates an important role for macrophages in IOP homeostasis.
TRIB3 mediates vascular calcification through facilitating self-ubiquitination and dissociation of Smurf1 in chronic renal disease
Authors: Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong
Journal: Journal of Clinical Investigation (2025)

The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in endoplasmic reticulum (ER) stress in chronic renal disease (CKD). Controlling ER stress through genetic intervention is a promising approach for treating vascular calcification. In this study, we demonstrated a positive correlation between ER stress-induced tribble 3 (TRIB3) expression and progression of vascular calcification in human and rodent CKD. Increased TRIB3 expression promoted vascular smooth muscle cell (VSMC) calcification by interacting with the C2 domain of the E3 ubiquitin-protein ligase Smurf1, facilitating its K48-related self-ubiquitination at Lys381 and Lys383 and subsequent dissociation from the plasma membrane and nuclei. This degeneration of Smurf1 accelerated the stabilization of the osteogenic transcription factors RUNX Family Transcription Factor 2 (Runx2) and SMAD Family Member 1 (Smad1). C/EBP homologous protein and activating transcription factor 4 are upstream transcription factors of TRIB3 in an osteogenic environment. Genetic knockout of TRIB3 or rescue of Smurf1 ameliorated VSMC and vascular calcification by stabilizing Smurf1 and enhancing the degradation of Runx2 and Smad1. Our findings shed light on the vital role of TRIB3 as a scaffold in ER stress and vascular calcification and offer a potential therapeutic option for chronic renal disease.
Ptprz Signaling, Tubule- and Macrophage-Mediated Kidney Injury, and Subsequent CKD
Authors: Julia Weinmann-Menke, Hilda M. Gonzalez-Sanchez, Yasunori Iwata, Myriam Meineck, Najla Abassi, Federico Marini, Francisco Granados-Contreras, Ayumi Takakura, Masaharu Noda, Vicki Rubin Kelley
Journal: Journal of the American Society of Nephrology (2025)

Background: Macrophages and tubular epithelial cell interactions are integral in kidney ischemia-incited interstitial inflammation leading to acute kidney injury. Ischemia/reperfusion injury riggers tubular epithelial cells to express IL-34, a macrophage growth factor, that promotes acute kidney injury and subsequent chronic kidney disease. IL-34 engages the cognate receptor, c-FMS, expressed by macrophages, and the recently discovered Protein-Tyrosine Phosphatase ζ (Ptprz). Ptprz, binds to multiple ligands other than IL-34 that progressively increase their expression in kidneys after ischemia/reperfusion injury. Methods: We tested the hypothesis that signaling through Ptprz promotes macrophage-mediated acute kidney injury and subsequent chronic kidney disease, by comparing Ptprz knockout with wild-type mice after ischemia/reperfusion injury. Results: Ptprz was expressed by leukocytes and in tubular epithelial cells after ischemia/reperfusion injury in mice. Using Ptprz knockout mice we determined that during acute kidney injury and chronic kidney disease kidney pathology, and loss of kidney function were ameliorated. Ptprz-dependent mechanisms mediated: (i) tubular epithelial cell expression of chemokines that fostered macrophage and T cell rich renal inflammation, and (ii) tubule injury and apoptosis, that resulted in the loss of tubules and interstitial fibrosis during chronic kidney disease . Mechanistically, Ptprz dependent tubule epithelial cells released mediators that:(i) promoted tubule cytotoxicity, and thereby, shortened tubule survival, and (ii) stimulated Ptprz expressing macrophages to generate mediators that induce kidney destruction. These findings are translational, as after ischemia reperfusion injury in human kidney transplants, PTPRZ and PTPRZ ligands were upregulated and expressed by the same cell populations as in mice. Moreover, PTPRZ levels in sera were elevated in kidney transplant patients. Conclusions: Intra-renal Ptprz-dependent macrophage and tubular epithelial cell mediated mechanisms promote acute kidney injury and subsequent chronic kidney disease.
MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model
Authors: Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J. Johnson, Ayrea E. Hurley, William R. Lagor, Zheng Xia, Thomas A. Cooper
Journal: Journal of Clinical Investigation (2025)

Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the DMPK gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explore MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile dysfunction, hypertrophy, and mis-regulated alternative splicing and gene expression. While robust, rescue was partial compared to reduced CUGexp RNA and plateaued with increased exogenous MBNL expression. These findings demonstrate that MBNL loss is a major contributor to DM1 cardiac manifestations, and suggest that additional mechanisms play a role, highlighting the complex nature of DM1 pathogenesis.
Coding genes helped the origination and diversification of intragenic miRNAs
Authors: Chengzhang Liu, Xiaojun Zhang, Jianbo Yuan, Jianhai Xiang, Fuhua Li
Journal: Molecular Biology and Evolution (2025)

Abstract Noncoding miRNAs tend to evolve within introns of coding genes who provide them with transcriptional opportunity. As an outcome of natural selection, the intragenic position of miRNAs is crucial for their expression, evolution and functional cooperation with the host gene. Therefore, understanding the evolution of intragenic miRNA structures may bring novel insights into genetic and phenotypic evolution. However, it remains largely unexplored. Here, by analysing miRNA genomics in 34 metazoan species, we found that the majority (630/1154) of miRNA families originated from introns of coding genes which provided them with initial transcriptional capacity. The most rapid expansion of intragenic miRNAs happened at the advent of vertebrates when 21 miRNA families emerged from introns of neural genes and reorganized the gene regulatory network, leading to the rise of vertebrate-specific neural crest (NC) cells, which transformed the invertebrate head and enabled the ecological shift from filter feeding to active predation. Intragenic miRNAs gradually gain independence from their host genes, which is accelerated by whole genome duplications (WGDs). After a WGD, the purging of redundant host genes often set an orphaned miRNA “free” to diversify with the transcriptional elements inherited from the host. WGDs facilitated a dramatic miRNA diversification during the initial divergence of vertebrates, as the intragenic status of twelve NC-regulating miRNAs was retained in jawed vertebrates but was lost in jawless cyclostomes, which diverged their neural crest development. We propose that coding genes not only facilitate the origination of new miRNAs, but also “sacrifice” themselves to help miRNA diversification.
A Multicenter Study of Contemporary Long-Term Tafamidis Outcomes in Transthyretin Amyloid Cardiomyopathy
Authors: Ahmad Masri, Priyanka Bhattacharya, Brent Medoff, Ain U Ejaz, Miriam R Elman, Pranav Chandrashekar, Lauren Ives, Alfonsina Mirabal Santos, Sergio L Teruya, Yuanzi Zhao, Shuaiqi Huang, Xiaofeng Wang, Brett W Sperry, Mathew S Maurer, Prem Soman, Mazen Hanna
Journal: JACC CardioOncology (2025)

Tafamidis improved survival and decreased cardiovascular hospitalizations in the ATTR-ACT trial. Due to improved recognition and earlier diagnosis, the epidemiology of transthyretin amyloid cardiomyopathy (ATTR-CM) is rapidly evolving. The authors sought to evaluate the contemporary long-term outcomes of patients with ATTR-CM treated with tafamidis. Patients with ATTR-CM who received at least 1 dose of tafamidis between 2018 and 2021 at 5 amyloidosis centers in the United States were enrolled. Primary outcome was all-cause mortality. Among 624 patients, mean age was 76.9 ± 8.4 years, 12.5% were female, 17.5% were Black, and 17.5% had variant ATTR-CM. At the time of tafamidis start, 52% had NYHA functional class II, 34% had NYHA functional class III, 40% were in National Amyloidosis Center (NAC) Stage ≥II, 38% were in Columbia Stage ≥II, and the median NT-proBNP level was 1,914 (Q1-Q3: 957-3914) pg/mL. Over a median follow-up of 43.2 months (Q1-Q3: 25.2-52.8 months), 241 patients (38.6%) died. The probability of freedom from death at 65 months was 54.1% (95% CI: 47.4%-60.4%). Similarly, restricting the cohort to patients who received tafamidis within 6 months of their ATTR-CM diagnosis (n = 397, 63.6%) showed similar results, with a survival probability of 49.6% (95% CI: 37.6%-60.5%) at 65 months. In a contemporary cohort of tafamidis-treated patients with ATTR-CM, 39% of patients died over a median of 43 months. Further work is needed to improve our understanding of ATTR-CM, its natural history, and how to further improve survival and prevent progression of heart failure.
The foundational capabilities of large language models in predicting postoperative risks using clinical notes
Authors: Charles Alba, Bing Xue, Joanna Abraham, Thomas Kannampallil, Chenyang Lu
Journal: npj Digital Medicine (2025)

Clinical notes recorded during a patient's perioperative journey holds immense informational value. Advances in large language models (LLMs) offer opportunities for bridging this gap. Using 84,875 preoperative notes and its associated surgical cases from 2018 to 2021, we examine the performance of LLMs in predicting six postoperative risks using various fine-tuning strategies. Pretrained LLMs outperformed traditional word embeddings by an absolute AUROC of 38.3% and AUPRC of 33.2%. Self-supervised fine-tuning further improved performance by 3.2% and 1.5%. Incorporating labels into training further increased AUROC by 1.8% and AUPRC by 2%. The highest performance was achieved with a unified foundation model, with improvements of 3.6% for AUROC and 2.6% for AUPRC compared to self-supervision, highlighting the foundational capabilities of LLMs in predicting postoperative risks, which could be potentially beneficial when deployed for perioperative care.
What Is the Optimal Locoregional Approach for Recurrent Hepatocellular Carcinoma?
Authors: Neil B. Newman, Colin M. Court, Alexander A. Parikh
Journal: Journal of Clinical Oncology (2025)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice.