tbuckley/cabot-search huggingface dataset:
Aptamer-directed, nanovesicle-mediated targeting of undruggable molecules in preclinical cholangiocarcinoma models
Authors: Mincheng Yu, Jack W. Sample, Irene K. Yan, Shohei Takaichi, Jennifer L. Tomlinson, Emilien J. Loeuillard, Ryan D. Watkins, Nathan W. Werneburg, Amro M. Abdelrahman, Danielle Carlson, Hendrien Kuipers, Meina Cai, Enis H. Ozmert, Brooke Kimball, Jinchun Yang, Sumera I. Ilyas, Gregory J. Gores, Tushar Patel, Rory L. Smoot
Journal: Hepatology (2025)

Background and Aims: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the biliary epithelium with limited therapeutic options and poor long-term survival rates. To address the limitations in CCA treatment, we investigated cell-targeted nanovesicles as a delivery platform for transcriptome-targeting therapeutics. Approach &amp; Results: Milk-derived nanovesicles (MNVs) were loaded with short interfering RNAs targeting YAP, the downstream effector of the Hippo pathway; LCK, an upstream regulator of YAP; and tafazzin, a protein critical for the integrity of the inner mitochondrial membrane. These transcriptome-targeting nanovesicles (tMNVs) were decorated with a lipid-coupled RNA aptamer to epithelial cell adhesion molecule (EpCAM), including a tracking fluorophore. In vitro studies were conducted using multiple CCA cell lines. In vivo studies were performed using C57BL/6 and NOD/SCID mice to evaluate delivery and efficacy in both an immunocompetent syngeneic murine and a patient-derived xenograft (PDX) model. We demonstrated that tMNVs were selectively taken up by liver tumor cells, which was augmented by the incorporation of a targeting aptamer, and that MNVs loaded with siRNA effectively downregulated target gene expression, both in vitro and in vivo . Downstream effects of target gene inhibition were observed, including downregulation of YAP-TEAD target genes and an increase in reactive oxygen species production at the mitochondrial level. Administration of tMNVs targeting YAP, LCK, and tafazzin inhibited CCA growth and further synergized with chemotherapy in two preclinical CCA models. Conclusions: Herein, we show that aptamer-directed, nanovesicle-mediated targeting of YAP, LCK, and tafazzin potentiates chemosensitivity in two CCA models when delivered using aptamer-guided milk-derived nanovesicles.
Lipoprotein(a) as a Pharmacological Target: Premises, Promises, and Prospects
Authors: Antonio Greco, Simone Finocchiaro, Marco Spagnolo, Denise Cristiana Faro, Maria Sara Mauro, Carmelo Raffo, Giuseppe Sangiorgio, Antonino Imbesi, Claudio Laudani, Placido Maria Mazzone, Nicola Ammirabile, Daniele Giacoppo, Davide Landolina, Davide Capodanno
Journal: Circulation (2025)

Atherosclerotic cardiovascular disease is a major health concern worldwide and requires effective preventive measures. Lp(a) (lipoprotein [a]) has recently garnered attention as an independent risk factor for astherosclerotic cardiovascular disease, with proinflammatory and prothrombotic mechanisms contributing to its atherogenicity. On an equimolar basis, Lp(a) is ~5 to 6 times more atherogenic than particles that have been widely associated with adverse cardiovascular outcomes, such as LDL (low-density lipoprotein). Lp(a) can enter the vessel wall, leading to the accumulation of oxidized phospholipids in the arterial intima, which are crucial for initiating plaque inflammation and triggering vascular disease progression. In addition, Lp(a) may cause atherothrombosis through interactions between apoA (apolipoprotein A) and the platelet PAR-1 (protease-activated receptor 1) receptor, as well as competitive inhibition of plasminogen. Because Lp(a) is mostly determined on genetic bases, a 1-time assessment in a lifetime can suffice to identify patients with elevated levels. Mendelian randomization studies and post hoc analyses of randomized trials of LDL cholesterol–lowering drugs showed a causal link between Lp(a) concentrations and cardiovascular outcomes, with therapeutic reduction of Lp(a) expected to contribute to estimated cardiovascular risk mitigation. Many Lp(a)-lowering drugs, including monoclonal antibodies, small interfering ribonucleic acids, antisense oligonucleotides, small molecules, and gene editing compounds, are at different stages of clinical investigation and show promise for clinical use. In particular, increased Lp(a) testing and treatment are expected to have a substantial impact at the population level, enabling the identification of high-risk individuals and the subsequent prevention of a large number of cardiovascular events. Ongoing phase 3 trials will further elucidate the cardiovascular benefits of Lp(a) reduction over the long term, offering potential avenues for targeted interventions and improved cardiovascular outcomes.
Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity
Authors: Lukas M. Braun, Sophie Giesler, Geoffroy Andrieux, Roxane Riemer, Nana Talvard-Balland, Sandra Duquesne, Tamina Rückert, Susanne Unger, Stefanie Kreutmair, Melissa Zwick, Marie Follo, Alina Hartmann, Natascha Osswald, Wolfgang Melchinger, Stefanie Chapman, James A. Hutchinson, Sebastian Haferkamp, Leopold Torster, Julian Kött, Christoffer Gebhardt, Dirk Hellwig, Nikolaos Karantzelis, Till Wallrabenstein, Theresa Lowinus, Mehtap Yücel, Niklas Brehm, Justyna Rawluk, Dietmar Pfeifer, Peter Bronsert, Manuel Rogg, Sven Mattern, Mathias Heikenwälder, Stefano Fusco, Nisar P. Malek, Stephan Singer, Annette Schmitt-Graeff, Fatih Ceteci, Florian R. Greten, Bruce R. Blazar, Melanie Boerries, Natalie Köhler, Justus Duyster, Gabriele Ihorst, Silke Lassmann, Philip Keye, Susana Minguet, Dirk Schadendorf, Selma Ugurel, David Rafei-Shamsabadi, Robert Thimme, Peter Hasselblatt, Bertram Bengsch, Christoph Schell, Erika L. Pearce, Frank Meiss, Burkhard Becher, Carolin Funke-Lorenz, Jan-Malte Placke, Petya Apostolova, Robert Zeiser
Journal: Cancer Cell (2025)

Highlights•Drugs currently used against irAEs reduce anti-tumor immunity•ECP induces adiponectin production in inflamed organs while sparing tumor tissue•ECP induces high response rates in patients with ICI-induced irAEsSummaryImmune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%–99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%–100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4+IFN-γ+ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.Graphical abstract
Dynamics of molecular heterogeneity in high-risk luminal breast cancer—From intrinsic to adaptive subtyping
Authors: Carsten Denkert, Sivaramakrishna Rachakonda, Thomas Karn, Karsten Weber, Miguel Martin, Frederik Marmé, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Sabine Seiler, Harry D. Bear, Agnieszka K. Witkiewicz, Seock-Ah Im, Angela DeMichele, Anika Pehl, Laura van't Veer, Nicole McCarthy, Thorsten Stiewe, Paul Jank, Karen A. Gelmon, José A. García-Sáenz, Christina C. Westhoff, Catherine M. Kelly, Toralf Reimer, Bärbel Felder, Mireia Melé Olivé, Erik S. Knudsen, Nicholas Turner, Federico Rojo, Wolfgang D. Schmitt, Peter A. Fasching, Julia Teply-Szymanski, Zhe Zhang, Masakazu Toi, Hope S. Rugo, Michael Gnant, Andreas Makris, Johannes Holtschmidt, Valentina Nekljudova, Sibylle Loibl
Journal: Cancer Cell (2025)

Highlights•Classical intrinsic subtypes change during neoadjuvant therapy from LumB to LumA•A reverse-transition back to LumB is observed in metastatic disease•Improved dimension reduction by comparison of pre- and post-therapeutic samples•Identification of adaptive prognostic subsets in high-risk luminal breast cancerSummaryWe evaluate therapy-induced molecular heterogeneity in longitudinal samples from high-risk, hormone-receptor positive/HER2-negative breast cancer patients with residual tumor after neoadjuvant chemotherapy from the Penelope-B trial (NCT01864746; EudraCT 2013-001040-62). Intrinsic subtypes are prognostic in pre-therapeutic (Tx) samples (n = 629, p < 0.0001) and post-Tx residual tumors (n = 782, p < 0.0001). After neoadjuvant chemotherapy, a shift of intrinsic subtypes is observed from pre-Tx luminal (Lum) B to post-Tx LumA, with reverse transition back to LumB in metastases. In a combined analysis of 540 paired pre-Tx and post-Tx samples, we identify five adaptive clusters (AC-1–5) based on transcriptomic changes before and after neoadjuvant chemotherapy. These AC-subtypes are prognostic beyond classical intrinsic subtyping, categorizing patients into groups with excellent prognosis (AC-1 and AC-2), poor prognosis (AC-3 and AC-4), and very poor prognosis (AC-5, enriched for basal-like subtype). Our analysis provides a basis for an extended molecular classification of breast cancer patients and improved identification of high-risk patient populations.Graphical abstract
Diet can drive the gut microbiota in children with food allergy
Authors: Irfan Ali, John Fyolek, Christopher Warren, Jialing Jiang, Lucy Bilaver, Sai Nimmagadda, Pamela Newmark, Hemant Sharma, Amal Assa'ad, Patrick Seed, Donyea Moore, Ruchi Gupta, Mahboobeh (maha) Mahdavinia
Journal: Journal of Allergy and Clinical Immunology (2025)
Deciphering the role of TYK2 in tau phosphorylation and pathology
Authors: Alexander Fröhlich, Kathryn R Bowles
Journal: Trends in Neurosciences (2025)

Tau phosphorylation plays an essential role in regulating tau's microtubule-stabilizing function, but its hyperphosphorylation drives tauopathies such as Alzheimer's disease (AD). In a recent study, Kim and colleagues decipher that tyrosine kinase 2 (TYK2) phosphorylates tau at tyrosine 29, promoting its stabilization and aggregation by interfering with autophagic clearance, providing novel insights into tau pathology and potential therapeutic strategies.
The Genomic Code: the genome instantiates a generative model of the organism
Authors: Kevin J Mitchell, Nick Cheney
Journal: Trends in Genetics (2025)

How does the genome encode the form of the organism? What is the nature of this genomic code? Inspired by recent work in machine learning and neuroscience, we propose that the genome encodes a generative model of the organism. In this scheme, by analogy with variational autoencoders (VAEs), the genome comprises a connectionist network, embodying a compressed space of 'latent variables', with weights that get encoded by the learning algorithm of evolution and decoded through the processes of development. The generative model analogy accounts for the complex, distributed genetic architecture of most traits and the emergent robustness and evolvability of developmental processes, while also offering a conception that lends itself to formalization.
Glucagon-like peptide-1 receptor agonism and end-organ protection
Authors: Samuel Daniels, Cecilia Karlsson, Patrick Schrauwen, Victoria E R Parker
Journal: Trends in Endocrinology and Metabolism (2025)

Identification of exendin-4 (a glucagon-like peptide 1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one of the most serendipitous discoveries of recent times. GLP-1RAs are now an established therapeutic approach in type 2 diabetes (T2D), body weight management, and cardiovascular (CV) risk protection. Furthermore, there is a growing platform of evidence that GLP-1RA has extended benefit in renal, hepatic, respiratory, and neurological diseases. One can speculate on the biological advantage of exendin-4 to the Gila monster, but for humankind GLP-1RAs are peptides with significant potential to improve disease-related outcomes. We report on the latest evidence and mechanisms for GLP-1RA-mediated end-organ protection that uniquely highlight its future development potential across multiple disease areas.
Promoting Reasonable Career Expectations and Maximizing Professional Fulfillment for Academic Oncologists: ASCO Recommendations for Academic Medical Centers
Authors: Eric P. Winer, Laura A. Levit, Ethan Basch, Mariana Chavez-MacGregor, Ray Dubois, S. Gail Eckhardt, Lee M. Ellis, Clifford A. Hudis, Deborah Schrag, Corey Speers, Breelyn A. Wilky, Michal Tibbits, Rebecca Spence, Elizabeth Garrett-Mayer
Journal: Journal of Clinical Oncology (2025)

In this statement, ASCO encourages academic medical centers to change their policies and expectations to enhance and promote the professional fulfillment of academic medical oncologists. The statement includes three recommendations directed to academic medical centers to further this goal: (1) establish reasonable clinical workloads for academic medical oncologists, (2) provide resources to enable medical oncologists to participate in and conduct research, and (3) develop and apply their standards for clinical workloads and research support, as well as career advancement and leadership opportunities, fairly and equitably across academic medical oncologists. Overall, improved career satisfaction is likely to result in retention of oncologists in the workforce. This is critical to support high-quality patient care, educate the next generation of cancer-focused professionals, and accelerate research discovering effective strategies for cancer prevention, diagnosis, and treatment.
SARS-CoV-2 infection is prevented by a multiple antigenic peptide containing amino acid sequence well-conserved among spike proteins in Coronaviridae
Authors: Takuya Nara, Hiroshi Shimoda, Chitose Suzuki, Kana Matsumura-Ohno, Yudai Murakami, Hiroshi Ohno, Masato Kubo, Takashi Saito, Kenichi Masuda
Journal: Journal of Allergy and Clinical Immunology (2025)
Hemochromatosis
Authors: William C. Palmer, Fernando F. Stancampiano
Journal: Annals of Internal Medicine (2025)

Hemochromatosis is an inheritable condition that mainly affects White populations of European descent. Most patients remain asymptomatic, but others develop advanced organ damage that reduces quality of life and long-term survival. Arthropathy, diabetes mellitus, cirrhosis, hypogonadotropic hypogonadism, and cardiomyopathy are key clinical manifestations. Primary care and hospital medicine physicians play an essential role in early identification of this disease, which can be accomplished via standard hematologic testing. Early diagnosis and therapeutic phlebotomy improve clinical outcomes.
Bleeding Risks With Non–Vitamin K Oral Anticoagulants Versus Single Antiplatelet Therapy
Authors: Michael Ke Wang, Geethan Baskaran, Ghazal Razeghi, Richard Ma, Louis S. Park, Manasi Tannu, P.J. Devereaux, William F. McIntyre, Jeff S. Healey, Ashkan Shoamanesh, David Conen
Journal: Annals of Internal Medicine (2025)

In several settings, therapeutic-dose non-vitamin K oral anticoagulants (NOACs) are superior to aspirin for the prevention of arterial and venous thromboembolism. To estimate differences in bleeding risks between NOACs and single antiplatelet therapy. MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to June 2024 without language restrictions. Randomized controlled trials (RCTs) comparing therapeutic-dose NOACs versus single antiplatelet therapy, with a minimum treatment duration of 3 months. Data extraction was done independently and in duplicate. Nine RCTs with 26 224 participants were included. All studies used aspirin as antiplatelet therapy. Compared with aspirin, apixaban had similar rates of major bleeding (risk difference [RD], 0.0 percentage point [95% CI, -1.3 to 2.6 percentage points]; 5 trials) and intracranial hemorrhage (RD, -0.2 percentage point [CI, -0.6 to 1.4 percentage points]; 5 trials). Compared with aspirin, dabigatran had similar rates of major bleeding (RD, 0.5 percentage point [CI, -2.1 to 19.6 percentage points]; 2 trials) and intracranial hemorrhage (RD, 0.0 percentage point [CI, -1.1 to 24.5 percentage points]; 2 trials). Compared with aspirin, rivaroxaban had higher rates of major bleeding (RD, 0.9 percentage point [CI, -0.1 to 3.7 percentage points]; 2 trials) and intracranial hemorrhage (RD, 0.3 percentage point [CI, -0.1 to 79.7 percentage points]; 2 trials). The evidence certainty ranged from low to moderate. Confidence intervals were wide and included the possibility of a null effect. In this systematic review of RCTs, rates of major bleeding for therapeutic-dose apixaban and dabigatran were similar to those for low-dose aspirin, whereas rates were higher for rivaroxaban. None. (PROSPERO: CRD42024553683).
How Would You Manage This Patient With Recent-Onset Atrial Fibrillation? Grand Rounds Discussion From Beth Israel Deaconess Medical Center
Authors: Gerald W. Smetana, Eli V. Gelfand, Patricia Tung, Risa B. Burns
Journal: Annals of Internal Medicine (2025)

Atrial fibrillation (AF) is the most common arrhythmia. Risk factors for AF include obstructive sleep apnea, physical inactivity, obesity, cigarette use, and alcohol misuse. Atrial fibrillation substantially increases the risk for stroke and is associated with higher rates of mortality than for individuals without AF. Strategies to prevent these risk factors and to optimize those that already exist reduce the risk for subsequent AF. Physicians play an important role in proposing strategies to reduce the risk for AF among patients. Decision making regarding management of AF is often complex and requires consideration of symptoms, burden of AF (the percentage of time in AF), comorbid conditions that increase stroke risk, and the risk for bleeding. In particular, novel risk scoring systems to predict stroke risk, and consideration of factors beyond those in these tools, refine the ability to identify patients with AF who are most likely to benefit from anticoagulation to reduce stroke risk. Early use of catheter ablation of AF in selected patients improves symptoms and reduces the potential for progression from intermittent to persistent AF. A 2023 collaborative guideline from the American College of Cardiology, American Heart Association, American College of Chest Physicians, and the Heart Rhythm Society addressed multiple aspects of care of patients with AF. Here, a general cardiologist and a cardiac electrophysiologist discuss recommendations derived from this guideline and how to apply them to the care of a particular patient.
Impact of loading, heart rate and short episodes of ischaemia on myocardial stiffness assessed using shear wave elastography in an open-chest animal model
Authors: Eric Saloux, Christophe Simard, Pauline Ruello, Adrien Lemaitre, Amir Hodzic, Alexandre Lebrun, Pierre-Antoine Dupont, Christophe Tribouilloy, Hélène Eltchaninoff, Morgane Le Garec, Christophe Fraschini, Vladimir Saplacan, Alain Manrique
Journal:  (2025)

Shear wave elastography (SWE) is a new promising ultrasound modality that enables non-invasive measurement of the dynamic myocardial stiffness. The impact of varying physiological conditions on SWE measurement of left ventricular (LV) myocardial stiffness remains poorly investigated. Nineteen sheep were evaluated during open-chest surgery. Epicardial multiframe SWE acquisitions were performed in short-axis view simultaneously with haemodynamic acquisitions during inferior vena cava occlusion, aortic clamping, atrial pacing, and ischaemia-reperfusion. The cyclic variation in the median value of LV myocardial stiffness ranged from 1.1 m/s in diastole (Cmin) to 2.4 m/s in systole (Cmax). At steady state, intra-animal reproducibility was good for Cmin [intraclass correlation coefficient ICC = 0.77 (0.54, 0.90), P < 0.001] and Cmax [ICC = 0.92 (0.84, 0.96), P < 0.001]. Cmin was independent of loading conditions, heart rate, and short 15-minute episodes of ischaemia and reperfusion. Cmax was independent of loading conditions and moderate increase in heart rate but decreased significantly during ischaemia and reperfusion. Compared with baseline, percentage changes in Cmax was correlated to percentage changes in dP/dtmax (R = 0.47, P = 0.001) and in LV systolic pressure (R = 0.35, P = 0.013) and SW (R = 0.31, P = 0.026). In this study, LV diastolic myocardial stiffness Cmin assessed using SWE demonstrated the characteristics of a potentially useful clinical marker of LV diastolic function linked to the intrinsic elastic properties of the myocardium, whereas Cmax was an indicator of LV contractility.
PEDIATRIC EOSINOPHILIC ESOPHAGITIS: A 5-YEAR EXPERIENCE AT A TERTIARY MEDICAL CENTER
Authors: Karen Thursday Tuano, Javier Chinen, Margaret Ukandu, Keisha Barton, Andrew Chu, Allyson Wyatt, Savini Britto, Amaka Akalonu, Anthony Olive, Bryan Vartabedian, Neha Seth
Journal: Journal of Allergy and Clinical Immunology (2025)
Quality improvement for suicide prevention and self-harm intervention: addressing the implementation gap and saving lives
Authors: Nav Kapur, Su-Gwan Tham, Pauline Turnbull, Nicola Richards, Cathryn Rodway, Caroline Clements, Saied Ibrahim, Roger T Webb, Tom Ayers, Emily Cannon, Louis Appleby, Leah Quinlivan
Journal: The Lancet Psychiatry (2025)
Effect of dupilumab on exhaled nitric oxide, mucus plugs, and functional respiratory imaging in patients with type 2 asthma (VESTIGE): a randomised, double-blind, placebo-controlled, phase 4 trial
Authors: Mario Castro, Alberto Papi, Celeste Porsbjerg, Njira L Lugogo, Christopher E Brightling, Francisco-Javier González-Barcala, Arnaud Bourdin, Mykola Ostrovskyy, Maria Staevska, Pai-Chien Chou, Liliana Duca, Ana Margarida Pereira, Charles Fogarty, Rufai Nadama, Mei Zhang, Amelie Rodrigues, Xavier Soler, Harry J Sacks, Yamo Deniz, Paul J Rowe, Lucía de Prado Gómez, Juby A Jacob-Nara
Journal: The Lancet Respiratory Medicine (2025)
Targeting the SARS-CoV-2 reservoir in long COVID
Authors: Amy D Proal, Soo Aleman, Morgane Bomsel, Petter Brodin, Marcus Buggert, Sara Cherry, Daniel S Chertow, Helen E Davies, Christopher L Dupont, Steven G Deeks, E Wes Ely, Alessio Fasano, Marcelo Freire, Linda N Geng, Diane E Griffin, Timothy J Henrich, Stephen M Hewitt, Akiko Iwasaki, Harlan M Krumholz, Michela Locci, Vincent C Marconi, Saurabh Mehandru, Michaela Muller-Trutwin, Mark M Painter, Etheresia Pretorius, David A Price, David Putrino, Yu Qian, Nadia R Roan, Dominique Salmon, Gene S Tan, Michael B VanElzakker, E John Wherry, Johan Van Weyenbergh, Lael M Yonker, Michael J Peluso
Journal: The Lancet Infectious Diseases (2025)