tbuckley/cabot-search huggingface dataset:
Cost-Effectiveness of Medical Therapy for Heart Failure With Mildly Reduced and Preserved Ejection Fraction
Authors: Neal M. Dixit, Katie P. Truong, Muthiah Vaduganathan, Boback Ziaeian, Gregg C. Fonarow
Journal: JACC Heart Failure (2024)

Three medications are now guideline-recommended treatments for heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), however, the cost-effectiveness of these agents in combination has yet to be established. The purpose of this study was to determine the cost-effectiveness of mineralocorticoid receptor antagonists (MRA), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium glucose co-transporter 2 inhibitors (SGLT2is) in individuals with HFmrEF/HFpEF. Using a 3-state Markov model, we performed a cost-effectiveness study using simulated cohorts of 1,000 patients with HFmrEF and HFpEF. Treatment with 1-, 2-, and 3-drug combinations was modeled. Based on a United States health care sector perspective, outcome data was used to calculate incremental cost-effectiveness ratios (ICERs) in 2023 United States dollars based on a 30-year time horizon. Treatment with MRA, MRA+SGLT2i, and MRA+SGLT2i+ARNI therapy resulted in an increase in life years of 1.04, 1.58, and 1.80 in the HFmrEF subgroup, respectively, and 0.99, 1.54, and 1.77 in the HFpEF subgroup, respectively, compared with placebo. At a yearly cost of $18, MRA therapy resulted in ICERs of $10,000 per quality-adjusted life year (QALY) in both subgroups. The ICER for the addition of SGLT2i therapy ($4,962 per year) was $113,000 per QALY in the HFmrEF subgroup and $141,000 in the HFpEF subgroup. The addition of ARNI therapy ($5,504 per year) resulted in ICERs >$250,000 per QALY in both subgroups. If SGLT2i and ARNI were available at generic pricing the ICERs become <$10,000 per QALY in both EF subgroups. Outcomes were highly sensitive to assumed benefit in cardiovascular death. For patients with heart failure, MRA was of high value, SGLT2i was of intermediate value, and ARNI was of low value in both HFmrEF and HFpEF subgroups. For patients with HFmrEF/HFpEF increased use of MRA and SGLT2i therapies should be encouraged and be accompanied with efforts to lower the cost of SGLT2i and ARNI therapies.
Mitral Annular Disjunction in the Context of Mitral Valve Prolapse
Authors: Pieter Van der Bijl, Jan Stassen, Kristina H Haugaa, Benjamin Essayagh, Cristina Basso, Gaetano Thiene, Francesco F Faletra, Thor Edvardsen, Maurice Enriquez-Sarano, Petros Nihoyannopoulos, Nina Ajmone Marsan, Yellapragada S Chandrashekhar, Jeroen J Bax
Journal: JACC. Cardiovascular imaging (2024)

Mitral annular disjunction (MAD), a separation between the left atrium/mitral valve annulus and the left ventricular myocardium, is frequently seen in patients with arrhythmic mitral valve prolapse. Although an association exists between MAD and ventricular arrhythmias, little is known regarding the identification of individuals at high risk. Multimodality imaging including echocardiography, computed tomography, cardiac magnetic resonance, and positron emission tomography can play an important role in both the diagnosis and risk stratification of MAD. Due to a paucity of data, clinical decision making in a patient with MAD is challenging and remains largely empirical. Although MAD itself can be corrected surgically, the prevention and treatment of associated arrhythmias may require medical therapy, catheter ablation, and an implantable cardioverter-defibrillator. Prospective data are required to define the role of implantable cardioverter-defibrillators, targeted catheter ablation, and surgical correction in selected, at-risk patients.
Molecular, clinical, and therapeutic determinants of outcome in <i>NPM1</i>-mutated AML
Authors: Jad Othman, Nicola Potter, Adam Ivey, Yanis Tazi, Elli Papaemmanuil, Jelena Jovanovic, Sylvie D. Freeman, Amanda Gilkes, Rosemary Gale, Tanya Rapoz-D’Silva, Manohursingh Runglall, Michelle Kleeman, Pawan Dhami, Ian Thomas, Sean Johnson, Joanna Canham, Jamie Cavenagh, Panagiotis Kottaridis, Claire Arnold, Hans Beier Ommen, Ulrik Malthe Overgaard, Mike Dennis, Alan Burnett, Charlotte Wilhelm-Benartzi, Brian Huntly, Nigel H. Russell, Richard Dillon
Journal: Blood (2024)
A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with <i>BRAF</i>-Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation
Authors: Rona Yaeger, Meredith A. McKean, Rizwan Haq, J. Thaddeus Beck, Matthew H. Taylor, Jonathan Eliezer. Cohen, Daniel W. Bowles, Shirish M. Gadgeel, Catalin Mihalcioiu, Kyriakos P. Papadopoulos, Eli L. Diamond, Keren B. Sturtz, Gang Feng, Stefanie K. Drescher, Micaela B. Reddy, Bhaswati Sengupta, Arnab K. Maity, Suzy A. Brown, Anurag Singh, Eric N. Brown, Brian R. Baer, Jim Wong, Tung-Chung Mou, Wen-I Wu, Dean R. Kahn, Sunyana Gadal, Neal Rosen, John J. Gaudino, Patrice A. Lee, Dylan P. Hartley, S. Michael. Rothenberg
Journal: Cancer Discovery (2024)

RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development.
Vaccination for healthy aging
Authors: David E. Bloom, Simone Pecetta, Francesco Berlanda Scorza, Andrea Carfi, Bruce Carleton, Mariateresa Cipriano, Kathryn Edwards, Gianmarco Gasperini, Richard Malley, Arindam Nandi, Aurelia Nguyen, Lynda Stuart, Steve Black, Rino Rappuoli
Journal: Science Translational Medicine (2024)

As the world's population grows older, vaccination is becoming a key strategy for promoting healthy aging. Despite scientific progress in adult vaccine development, obstacles such as immunosenescence and vaccine hesitancy remain. To unlock the potential of adult vaccines fully, we must enhance immunization programs, dispel misinformation, and invest in research that deepens our understanding of aging and immunity.
Electronic health record signatures identify undiagnosed patients with common variable immunodeficiency disease
Authors: Ruth Johnson, Alexis V. Stephens, Rachel Mester, Sergey Knyazev, Lisa A. Kohn, Malika K. Freund, Leroy Bondhus, Brian L. Hill, Tommer Schwarz, Noah Zaitlen, Valerie A. Arboleda, Lisa A. Bastarache, Bogdan Pasaniuc, Manish J. Butte
Journal: Science Translational Medicine (2024)

Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases.
Vaccination with antigenically complex hemagglutinin mixtures confers broad protection from influenza disease
Authors: Zhaochen Luo, Hector A. Miranda, Kaitlyn N. Burke, M. Ariel Spurrier, Madison Berry, Erica L. Stover, Rachel L. Spreng, Greg Waitt, Erik J. Soderblom, Andrew N. Macintyre, Kevin Wiehe, Nicholas S. Heaton
Journal: Science Translational Medicine (2024)

Current seasonal influenza virus vaccines induce responses primarily against immunodominant but highly plastic epitopes in the globular head of the hemagglutinin (HA) glycoprotein. Because of viral antigenic drift at these sites, vaccines need to be updated and readministered annually. To increase the breadth of influenza vaccine-mediated protection, we developed an antigenically complex mixture of recombinant HAs designed to redirect immune responses to more conserved domains of the protein. Vaccine-induced antibodies were disproportionally redistributed to the more conserved stalk of the HA without hindering, and in some cases improving, antibody responses against the head domain. These improved responses led to increased protection against homologous and heterologous viral challenges in both mice and ferrets compared with conventional vaccine approaches. Thus, antigenically complex protein mixtures can at least partially overcome HA head domain antigenic immunodominance and may represent a step toward a more universal influenza vaccine.
Multimodal MRI reveals brainstem connections that sustain wakefulness in human consciousness
Authors: Brian L. Edlow, Mark Olchanyi, Holly J. Freeman, Jian Li, Chiara Maffei, Samuel B. Snider, Lilla Zöllei, J. Eugenio Iglesias, Jean Augustinack, Yelena G. Bodien, Robin L. Haynes, Douglas N. Greve, Bram R. Diamond, Allison Stevens, Joseph T. Giacino, Christophe Destrieux, Andre van der Kouwe, Emery N. Brown, Rebecca D. Folkerth, Bruce Fischl, Hannah C. Kinney
Journal: Science Translational Medicine (2024)

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.
Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome
Authors: Giulia Consiglieri, Francesca Tucci, Maurizio De Pellegrin, Barbara Guerrini, Alessandro Cattoni, Giulia Risca, Stefano Scarparo, Marina Sarzana, Silvia Pontesilli, Renata Mellone, Serena Gasperini, Stefania Galimberti, Paolo Silvani, Chiara Filisetti, Silvia Darin, Giulia Forni, Simona Miglietta, Ludovica Santi, Marcella Facchini, Ambra Corti, Francesca Fumagalli, Maria Pia Cicalese, Valeria Calbi, Maddalena Migliavacca, Federica Barzaghi, Francesca Ferrua, Vera Gallo, Salvatore Recupero, Daniele Canarutto, Matteo Doglio, Lucia Tedesco, Nicola Volpi, Attilio Rovelli, Giancarlo la Marca, Maria Grazia Valsecchi, Stefano Zancan, Fabio Ciceri, Luigi Naldini, Cristina Baldoli, Rossella Parini, Bernhard Gentner, Alessandro Aiuti, Maria Ester Bernardo
Journal: Science Translational Medicine (2024)

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell–gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT’s impact on MPSIH skeletal dysplasia.
Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models
Authors: Yongzhen Wei, Huan Jiang, Fengjuan Li, Chao Chai, Yaping Xu, Mengmeng Xing, Weiliang Deng, He Wang, Yuexin Zhu, Sen Yang, Yongquan Yu, Wenming Wang, Yan Wei, Yu Guo, Jinwei Tian, Jie Du, Zhikun Guo, Yuan Wang, Qiang Zhao
Journal: Science Translational Medicine (2024)

An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell- or fibroblast-specific knockout of
The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischaemic heart failure
Authors: Kim L Ho, Qutuba G Karwi, Faqi Wang, Cory Wagg, Liyan Zhang, Sai Panidarapu, Brandon Chen, Simran Pherwani, Amanda A Greenwell, Gavin Y Oudit, John R Ussher, Gary D Lopaschuk
Journal: Cardiovascular Research (2024)

Cardiac energy metabolism is perturbed in ischaemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure.
Targeting the Dendritic Cell-Secreted Immunoregulatory Cytokine CCL22 Alleviates Radioresistance
Authors: Jason Bugno, Liangliang Wang, Xianbin Yu, Xuezhi Cao, Jiaai Wang, Xiaona Huang, Kaiting Yang, Andras Piffko, Katherine Chen, Stephen Y. Luo, Emile Naccasha, Yuzhu Hou, Sherry Fu, Chuan He, Yang-xin Fu, Hua L. Liang, Ralph R. Weichselbaum
Journal: Clinical Cancer Research (2024)

Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that conventional dendritic cells (cDC) maintain Treg, we sought to identify and target cDC signaling to block Treg infiltration after radiation.
Mg-gallate metal-organic framework-based sprayable hydrogel for continuously regulating oxidative stress microenvironment and promoting neurovascular network reconstruction in diabetic wounds
Authors: Chenxi Lian, Jiawei Liu, Wenying Wei, Xiaopei Wu, Takashi Goto, Haiwen Li, Rong Tu, Honglian Dai
Journal: Bioactive Materials (2024)

Chronic diabetic wounds are the most common complication for diabetic patients. Due to high oxidative stress levels affecting the entire healing process, treating diabetic wounds remains a challenge. Here, we present a strategy for continuously regulating oxidative stress microenvironment by the catalyst-like magnesium-gallate metal-organic framework (Mg-GA MOF) and developing sprayable hydrogel dressing with sodium alginate/chitosan quaternary ammonium salts to treat diabetic wounds. Chitosan quaternary ammonium salts with antibacterial properties can prevent bacterial infection. The continuous release of gallic acid (GA) effectively eliminates reactive oxygen species (ROS), reduces oxidative stress, and accelerates the polarization of M1-type macrophages to M2-type, shortening the transition between inflammation and proliferative phase and maintaining redox balance. Besides, magnesium ions adjuvant therapy promotes vascular regeneration and neuronal formation by activating the expression of vascular-associated genes. Sprayable hydrogel dressings with antibacterial, antioxidant, and inflammatory regulation rapidly repair diabetic wounds by promoting neurovascular network reconstruction and accelerating re-epithelialization and collagen deposition. This study confirms the feasibility of catalyst-like MOF-contained sprayable hydrogel to regulate the microenvironment continuously and provides guidance for developing the next generation of non-drug diabetes dressings.
Author Correction: PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy
Authors: Xuefeng Dou, Qiang Fu, Qilai Long, Shuning Liu, Yejun Zou, Da Fu, Qixia Xu, Zhirui Jiang, Xiaohui Ren, Guilong Zhang, Xiaoling Wei, Qingfeng Li, Judith Campisi, Yuzheng Zhao, Yu Sun
Journal: Nature Metabolism (2024)
Water‐Mediated on‐Demand Detachable Solid‐State Adhesive of Porous Hydroxyapatite for Internal Organ Retractions
Authors: Masahiro Okada, Shi Chao Xie, Yusuke Kobayashi, Hiroaki Yanagimoto, Daisuke Tsugawa, Masaru Tanaka, Takayoshi Nakano, Takumi Fukumoto, Takuya Matsumoto
Journal: Advanced Healthcare Materials (2024)

Abstract Novel adhesives for biological tissues offer an advanced surgical approach. Here, the authors report the development and application of solid‐state adhesives consisting of porous hydroxyapatite (HAp) biocompatible ceramics as novel internal organ retractors. The operational principles of the porous solid‐state adhesives are experimentally established in terms of water migration from biological soft tissues into the pores of the adhesives, and their performance is evaluated on several soft tissues with different hydration states. As an example of practical medical utility, HAp adhesive devices demonstrate the holding ability of porcine livers and on‐demand detachability in vivo, showing great potential as internal organ retractors in laparoscopic surgery.
A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification
Authors: Chunhong Liu, Hiroyuki Nagashima, Nilisha Fernando, Victor Bass, Jaanam Gopalakrishnan, Sadie Signorella, Will Montgomery, Ai Ing Lim, Oliver Harrison, Lauren Reich, Chen Yao, Hong-Wei Sun, Stephen R Brooks, Kan Jiang, Vijayaraj Nagarajan, Yongbing Zhao, Seolkyoung Jung, Rachael Phillips, Yohei Mikami, Caleb A Lareau, Yuka Kanno, Dragana Jankovic, Martin J Aryee, Aleksandra Pękowska, Yasmine Belkaid, John O'Shea, Han-Yu Shih
Journal: Immunity (2024)
N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation
Authors: Alexander D. Gitlin, Allie Maltzman, Yuzuka Kanno, Klaus Heger, Rohit Reja, Alexander F. Schubert, Linsey J. Wierciszewski, Homer Pantua, Sharookh B. Kapadia, Seth F. Harris, Joshua D. Webster, Kim Newton, Vishva M. Dixit
Journal: Immunity (2024)
Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation
Authors: Marleen Bérouti, Katja Lammens, Matthias Heiss, Larissa Hansbauer, Stefan Bauernfried, Jan Stöckl, Francesca Pinci, Ignazio Piseddu, Wilhelm Greulich, Meiyue Wang, Christophe Jung, Thomas Fröhlich, Thomas Carell, Karl-Peter Hopfner, Veit Hornung
Journal: Immunity (2024)

Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. TLR7 contains two ligand-binding pockets that recognize different RNA degradation products: pocket 1 recognizes guanosine, while pocket 2 coordinates pyrimidine-rich RNA fragments. We found that the endonuclease RNase T2, along with 5′ exonucleases PLD3 and PLD4, collaboratively generate the ligands for TLR7. Specifically, RNase T2 generated guanosine 2′,3′-cyclic monophosphate-terminated RNA fragments. PLD exonuclease activity further released the terminal 2′,3′-cyclic guanosine monophosphate (2',3'-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. Loss-of-function studies in cell lines and primary cells confirmed the critical requirement for PLD activity. Biochemical and structural studies showed that PLD enzymes form homodimers with two ligand-binding sites important for activity. Previously identified disease-associated PLD mutants failed to form stable dimers. Together, our data provide a mechanistic basis for the detection of RNA fragments by TLR7.
Belimumab ameliorates symptoms and disease activity in patients with dermatomyositis and juvenile dermatomyositis refractory to standard therapy: A retrospective observational study
Authors: Yu Liu, Yongzhen Li, Tian Shen, Huiming Zhang, Shuangyan Luo, Qing Zhang, Xiqiang Dang, Xiaoyan Li, Hai Long
Journal: Journal of the American Academy of Dermatology (2024)
Integrating population and single-cell variations in vaccine responses identifies a naturally adjuvanted human immune setpoint
Authors: Matthew P. Mulè, Andrew J. Martins, Foo Cheung, Rohit Farmer, Brian A. Sellers, Juan A. Quiel, Arjun Jain, Yuri Kotliarov, Neha Bansal, Jinguo Chen, Pamela L. Schwartzberg, John S. Tsang
Journal: Immunity (2024)