tbuckley/cabot-search huggingface dataset:
AS-0230 Circulating Exosomal miR-16-2-3p Is Associated With Coronary Microvascular Dysfunction in Diabetes Through Regulating the Fatty Acid Degradation of Endothelial Cells
Authors: Yihai Liu, Chongxia Zhong, Shan Chen, Yanan Xue, Zhonghai Wei, Li Dong, Lina Kang
Journal: Journal of the American College of Cardiology (2024)
5-Year Results From the AMPLATZER Amulet Left Atrial Appendage Occluder Randomized Controlled Trial
Authors: Dhanunjaya Lakkireddy, Christopher R Ellis, David Thaler, Vijendra Swarup, Alok Gambhir, James Hermiller, Jens Erik Nielsen-Kudsk, Stephen Worthley, Devi Nair, Boris Schmidt, Rodney Horton, Nigel Gupta, Jordan A Anderson, Hong Zhao, Mohamad Alkhouli, Stephan Windecker
Journal: Journal of the American College of Cardiology (2024)
Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure
Authors: Christopher M Kramer, Barry A Borlaug, Michael R Zile M, Dustin Ruff, Joseph M DiMaria, Venu Menon, Yang Ou, Angela M Zarante, Karla C Hurt, Masahiro Murakami, Milton Packer
Journal: Journal of the American College of Cardiology (2024)
Semaglutide Eligibility Across All Current Indications for US Adults
Authors: Ivy Shi, Sadiya S. Khan, Robert W. Yeh, Jennifer E. Ho, Issa J. Dahabreh, Dhruv S. Kazi
Journal: JAMA Cardiology (2024)

This cross-sectional study uses National Health and Nutrition Examination Survey data to examine the number of US adults eligible for semaglutide across all current indications.
Oral Muvalaplin for Lowering of Lipoprotein(a)
Authors: Stephen J. Nicholls, Wei Ni, Grace M. Rhodes, Steven E. Nissen, Ann Marie Navar, Laura F. Michael, Axel Haupt, John H. Krege
Journal: JAMA (2024)

Importance Muvalaplin inhibits lipoprotein(a) formation. A 14-day phase 1 study demonstrated that muvalaplin was well tolerated and reduced lipoprotein(a) levels up to 65%. The effect of longer administration of muvalaplin on lipoprotein(a) levels in individuals at high cardiovascular risk remains uncertain. Objectives To determine the effect of muvalaplin on lipoprotein(a) levels and to assess safety and tolerability. Design, Setting, and Participants Phase 2, placebo-controlled, randomized, double-blind trial enrolling 233 participants with lipoprotein(a) concentrations of 175 nmol/L or greater with atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia at 43 sites in Asia, Europe, Australia, Brazil, and the United States between December 10, 2022, and November 22, 2023. Interventions Participants were randomized to receive orally administered muvalaplin at dosages of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68) or placebo (n = 67) for 12 weeks. Main Outcomes and Measures The primary end point was the placebo-adjusted percentage change from baseline in lipoprotein(a) molar concentration at week 12, using an assay to measure intact lipoprotein(a) and a traditional apolipoprotein(a)-based assay. Secondary end points included the percentage change in apolipoprotein B and high-sensitivity C-reactive protein. Results The median age of study participants was 66 years; 33% were female; and 27% identified as Asian, 4% as Black, and 66% as White. Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay. Dose-dependent reductions in apolipoprotein B were observed at 8.9% (95% CI, −2.2% to 18.8%), 13.1% (95% CI, 4.4%-20.9%), and 16.1% (95% CI, 7.8%-23.7%) at 10 mg/d, 60 mg/d, and 240 mg/d, respectively. No change in high-sensitivity C-reactive protein was observed. No safety or tolerability concerns were observed at any dosage. Conclusions and Relevance Muvalaplin reduced lipoprotein(a) measured using intact lipoprotein(a) and apolipoprotein(a)-based assays and was well tolerated. The effect of muvalaplin on cardiovascular events requires further investigation. Trial Registration ClinicalTrials.gov Identifier: NCT05563246
Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a)
Authors: Steven E. Nissen, Qiuqing Wang, Stephen J. Nicholls, Ann Marie Navar, Kausik K. Ray, Gregory G. Schwartz, Michael Szarek, Erik S. G. Stroes, Roland Troquay, Jannick A. N. Dorresteijn, Henry Fok, David A. Rider, Steven Romano, Kathy Wolski, Curtis Rambaran
Journal: JAMA (2024)

Importance Elevated lipoprotein(a) increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Objective To evaluate the effects of zerlasiran, a small-interfering RNA targeting hepatic synthesis of apolipoprotein(a), on lipoprotein(a) serum concentration. Design, Setting, and Participants A multicenter trial in patients with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L at 26 sites in Europe and South Africa between January 3, 2023, and April 27, 2023, with last follow-up on July 1, 2024. Interventions Participants randomized to receive a subcutaneous dose of placebo every 16 weeks for 3 doses (n = 23) or every 24 weeks for 2 doses (n = 24) or zerlasiran 450 mg every 24 weeks for 2 doses (n = 45), 300 mg every 16 weeks for 3 doses (n = 42), or 300 mg every 24 weeks for 2 doses (n = 44). Main Outcome and Measures The primary outcome was the time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks, with follow-up to 60 weeks. Results Among 178 patients, mean (SD) age was 63.7 (9.4) years, 46 (25.8%) were female, with a median (IQR) baseline lipoprotein(a) concentration of 213 (177-282) nmol/L; 172 patients completed the trial. Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was −85.6% (95% CI, −90.9% to −80.3%), −82.8% (95% CI, −88.2% to −77.4%), and −81.3% (95% CI, −86.7% to −76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. Median (IQR) percent change in lipoprotein(a) concentration at week 36 was −94.5% (−97.3% to −84.2%) for the 450 mg every 24 weeks group, −96.4% (−97.7% to −92.3%) for the 300 mg every 16 weeks group, and −90.0% (−93.7% to −81.3%) for the 300 mg every 24 weeks group. The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug. Conclusions Zerlasiran was well-tolerated and reduced time-averaged lipoprotein(a) concentration by more than 80% during 36 weeks of treatment in patients with ASCVD. Trial Registration ClinicalTrials.gov Identifier: NCT05537571
Allosteric antibodies: a novel paradigm in drug discovery
Authors: Léxane Fournier, Enrico Guarnera, Harald Kolmar, Stefan Becker
Journal: Trends in Pharmacological Sciences (2024)

Allostery represents a fundamental mechanism in protein regulation, enabling modulation of protein function from sites distal to the active site. While traditionally explored in the context of small molecules, allosteric modulation is gaining traction as a main mode of action in the realm of antibodies, which offer enhanced specificity and reduced toxicity. This review delves into the rapidly growing field of allosteric antibodies, highlighting recent therapeutic advancements and novel druggability avenues. We also explore the potential of these antibodies as innovative tools in drug discovery and discuss contemporary strategies for designing novel allosteric antibodies, leveraging state-of-the-art computational approaches.
Executive control fluctuations underlie behavioral variability in anthropoids
Authors: Farshad A Mansouri, Rogier A Kievit, Mark J Buckley
Journal: Trends in Cognitive Sciences (2024)

In complex tasks requiring cognitive control, humans show trial-by-trial alterations in response time (RT), which are evident even when sensory-motor or other contextual aspects of the task remain stable. Exaggerated intra-individual RT variability is associated with brain injuries and frequently seen in aging and neuropsychological disorders. In this opinion, we discuss recent electrophysiology and imaging studies in humans and neurobiological studies in monkeys that indicate RT variability is linked with executive control fluctuation and that prefrontal cortical regions play essential, but dissociable, roles in such fluctuation of control and the resulting behavioral variability. We conclude by discussing emerging models proposing that both extremes of behavioral variability (significantly higher or lower) might reflect aberrant alterations in various aspects of decision-making processes.
Aortic Valve Replacement Versus Clinical Surveillance in Asymptomatic Severe Aortic Stenosis: A Systematic Review and Meta-Analysis
Authors: Philippe Généreux, Marko Banovic, Duk-Hyun Kang, Gennaro Giustino, Bernard D Prendergast, Brian R Lindman, David E Newby, Philippe Pibarot, Björn Redfors, Neil J Craig, Jozef Bartunek, Allan Schwartz, Roxanna Seyedin, David J Cohen, Bernard Iung, Martin B Leon, Marc R Dweck
Journal: Journal of the American College of Cardiology (2024)

Current guidelines recommend a strategy of clinical surveillance (CS) for patients with asymptomatic severe aortic stenosis (AS) and a normal left ventricular ejection fraction. The aim of this study was to conduct a study-level meta-analysis of randomized controlled trials (RCTs) evaluating the effect of early aortic valve replacement (AVR) compared with CS in patients with asymptomatic severe AS. Studies were quantitatively assessed in a meta-analysis using random-effects modeling. Prespecified outcomes included all-cause and cardiovascular mortality, unplanned cardiovascular or heart failure (HF) hospitalization, and stroke. The meta-analysis is registered at the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY202490002). Four RCTs were identified, including a total of 1,427 patients (719 in the early AVR group and 708 in the CS group). At an average follow-up time of 4.1 years, early AVR was associated with a significant reduction in unplanned cardiovascular or HF hospitalization (pooled rate 14.6% vs 31.9%; HR: 0.40; 95% CI: 0.30-0.53; I2 = 4%; P < 0.01) and stroke (pooled rate 4.5% vs 7.2%; HR: 0.62; 95% CI: 0.40-0.97; I2 = 0%; P = 0.03). No differences in all-cause mortality (pooled rate 9.7% vs 13.7%; HR: 0.68; 95% CI: 0.40-1.17; I2 = 61%; P = 0.17) and cardiovascular mortality (pooled rate 5.1% vs 8.3%; HR: 0.67; 95% CI: 0.35-1.29; I2 = 50%; P = 0.23) were observed with early AVR compared with CS, although there was a high degree of heterogeneity among studies. In this meta-analysis of 4 RCTs, early AVR was associated with a significant reduction in unplanned cardiovascular or HF hospitalization and stroke and no differences in all-cause and cardiovascular mortality compared with CS.
Progression of Low-Grade Neuroendocrine Tumors (NET) to High-Grade Neoplasms Harboring the NEC-Like Co-alteration of RB1 and TP53
Authors: Nancy M. Joseph, Sarah E. Umetsu, Grace E. Kim, Merryl Terry, Arie Perry, Emily Bergsland, Sanjay Kakar
Journal: Endocrine Pathology (2024)

Abstract High-grade or grade 3 epithelial neuroendocrine neoplasms (G3 NEN) are now divided into grade 3 well-differentiated neuroendocrine tumor (G3 NET) and neuroendocrine carcinoma (NEC), both defined by Ki-67 &gt; 20% and/or &gt; 20 mitoses per 2 mm 2 . NET and NEC are thought to be distinct tumors with different genetic profiles: NEC classically harbors co-alteration of TP53 and RB1 , whereas NET genetics are site-dependent with frequent alterations in MEN1 , ATRX , DAXX , and TSC1/2 in pancreatic NETs. Progression from NET to NEC is considered rare and is not well described. While both TP53 and RB1 alterations were initially thought to be rare in NET, recent work has demonstrated the former in up to 35% of high-grade G3 NET and the latter in rare high-grade NEN that progressed from NET. Here, we describe the clinical, pathologic, and molecular features associated with tumor evolution in a series of five patients that had low-grade NET that progressed to high-grade NEN with co-alteration of RB1 and TP53 , similar to NEC. Morphology of the high-grade neoplasms remained well-differentiated in some cases despite RB1 / TP53 co-alteration and had some NEC-like features in other cases. All five patients died of disease, with a mean overall survival of 41 months from the first metastatic disease and 12 months from acquisition of RB1/TP53 co-alteration. Our data demonstrate that low-grade NET can progress via the acquisition of both TP53 and RB1 alteration, similar to NEC, but whether this represents a transformation from NET to NEC remains unclear.
Semaglutide Improves Cardiovascular Outcomes in Patients With History of Coronary Artery Bypass Graft and Obesity
Authors: Subodh Verma, Scott Emerson, Jorge Plutzky, Steven E Kahn, Signe Stensen, Peter E Weeke, Derrick Musinga, Paul Poirier, Ildiko Lingvay, A Michael Lincoff
Journal: Journal of the American College of Cardiology (2024)
Enhanced Photothermal Therapy under Low‐Power Near‐Infrared Irradiation Enabled by a Si‐Cyclopentadithiophene‐Based Organic Molecule
Authors: Kexin Fan, Qingyang Li, Yuping Qian, Ludan Zhang, Di Lu, Ling Zhu, Shouke Yan, Bowei Xu, Yuguang Wang
Journal: Advanced Healthcare Materials (2024)

Due to the inadequate photothermal conversion efficiency (PCE), most photothermal agents (PTAs) have to be used under high-power near-infrared (NIR) irradiation, which significantly exceeds medical safety standards, for achieving effective photothermal therapy (PTT) in antitumor treatment. This significantly hinders practical PTT application. Herein, three acceptor-donor-acceptor(A-D-A)-type molecules are synthesized based on cyclopentadithiophene unit to develop effective PTAs. By incorporating the large-size Si atom in the A-D-A molecules, the photosensitizer displays an increased packing distance in the aggregate state, leading to a blue-shifted absorption spectrum that better matches the medial laser wavelength. Also, the Si incorporation strategy elevates the nonradiative decay rate constants (k
Oral Infigratinib Therapy in Children with Achondroplasia
Authors: Ravi Savarirayan, Josep Maria De Bergua, Paul Arundel, Jean Pierre Salles, Vrinda Saraff, Borja Delgado, Antonio Leiva-Gea, Helen McDevitt, Marc Nicolino, Massimiliano Rossi, Maria Salcedo, Valerie Cormier-Daire, Mars Skae, Peter Kannu, John Phillips, Howard Saal, Paul Harmatz, Toby Candler, Dawn Hill, Elena Muslimova, Richard Weng, Yun Bai, Supriya Raj, Julie Hoover-Fong, Melita Irving, Daniela Rogoff
Journal: New England Journal of Medicine (2024)

Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and medical complications throughout life. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia.
Size‐Tunable Boron Nanoreactors for Boron Neutron Capture Synergistic Chemodynamic Therapy of Tumor
Authors: Lin Li, Qian Zhao, Zhiqing Chen, Zican Zhao, Baojie Du, Mixue Wang, Peirong Bai, Xiaozhe Wang, Xiaofeng Ren, Liping Li, Ruiping Zhang
Journal: Advanced Healthcare Materials (2024)

Boron neutron capture therapy (BNCT) stands out as a noninvasive potential modality for invasive malignant tumors, with boron drugs playing a crucial role in its efficacy. Nevertheless, the development of boron drugs with biodegradability, as well as high permeability and retention effects, continues to present significant challenges. Here, we fabricate a size-tunable boron nanoreactor (TBNR) via assembling boron nitride quantum dots (BNQDs) and Fe3+ for tumor BNCT and chemodynamic (CDT) synergistic treatment. The obtained TBNR with an appropriate size exhibits superior tumor accumulation and retention. Upon stimulation by the tumor microenvironment (TME), the contained Fe3+ undergo redox reactions with glutathione (GSH) to produce Fe2+ Fenton reagents, which in turn activate CDT function and simultaneously induce TBNR depolymerization. Subsequently, the released ultrasmall BNQDs exhibit intra-deep penetration characteristic and are fully enriched at the tumor site. The in vivo experiments reveal that TBNR possesses excellent biocompatibility and superior synergistic anti-tumor ability post neutron irradiation, resulting in significant shrinkage of subcutaneous 4T1 tumors. Moreover, the TBNR-mediated BNCT has triggered an obvious immune response, which contributes to the long-term suppression of tumors after neutron irradiation. To conclude, this study provides a new approach for constructing more efficient versatile nanocarriers for BNCT-induced combination cancer therapies.
Methods for <scp>3D</scp> evaluation and quantification of gingival recessions and gingival margin changes: Advancements from conventional techniques
Authors: Nikolaos Gkantidis, Konstantinos Dritsas, Mohammed Ghamri, Demetrios Halazonetis, Anton Sculean
Journal: Periodontology 2000 (2024)

In an era of increasing life expectancy and growing patient demands towards lifelong natural tooth retention, accurate assessment of gingival recessions is crucial for diagnosing periodontal diseases, planning preventive or restorative interventions, and evaluating their outcomes. The traditional two-dimensional (2D) methods, while useful, often fall short in capturing the complex topography of gingival tissue margins and their changes over time. By examining relevant published studies, this review highlights the transition from 2D to 3D techniques, analyzing the limitations of widely used 2D approaches, while emphasizing the potential of novel 3D tools and techniques. It discusses their comparative effectiveness, accuracy, and application challenges in clinical and research settings. Advancements in three-dimensional (3D) imaging regarding methodologies for the precise evaluation and quantification of free gingival margin changes and gingival recessions are explored and critically evaluated. The review underscores the potential for these technologies to enhance patient outcomes through more precise diagnosis and data generation. It also identifies gaps in current research and suggests directions for future investigation. Overall, this review provides a comprehensive overview of the state of the art in 3D evaluation methods for gingival recessions and gingival margin changes, offering valuable insights for clinicians and researchers.
Boosting Tumor Accumulation of Phthalocyanine through Sialylation Engineering for Superior Cancer Phototherapy
Authors: Jian Li, Tingting Wang, Cijuan Li, Xun Zhang, Jingchao Li, Dongsheng Zhang, Yafei Zhang, Jun Yang, Xinhui Su, Nian Liu
Journal: Advanced Healthcare Materials (2024)

Phthalocyanines (Pcs) are widely developed in cancer phototherapy due to their definite chemical structure and tunable photosensitivity. However, their in vivo application is hampered by low water solubility and non-specific biodistribution. Here,a strategy of sialylation-modulation is developed for the first time to highly improve the bioavailability of Pcs. The sialylated Pcs (ZnPc-4SA) not only has good hydrophilicity, but also can self-assemble into nanoparticles (ZnPc-4SA NPs). These nanoformulations retain the excellent photophysical properties of Pcs, which in turn reflects excellent optoacoustic and phototherapeutic properties. Importantly, ZnPc-4SA NPs exhibit boosted tumor accumulation due to the passive targeting and sialic acid-mediated E-selectin targeting. Besides, the phototoxicity of ZnPc-4SA NPs can effectively trigger cell apoptosis and tumor elimination upon laser irradiation. Therefore, sialylation engineering strategy provides a new option for hydrophobic drugs modification with enhanced tumor theranostics.
Cordycepin‐Loaded Dental Pulp Stem Cell‐Derived Exosomes Promote Aged Bone Repair by Rejuvenating Senescent Mesenchymal Stem Cells and Endothelial Cells
Authors: Yu Wang, Shanshan Jin, Yaru Guo, Lisha Zhu, Yilong Lu, Jing Li, Boon Chin Heng, Yan Liu, Xuliang Deng
Journal: Advanced Healthcare Materials (2024)

Aging impairs bone marrow mesenchymal stem cell (BMSC) functions as well as associated angiogenesis which is critical for bone regeneration and repair. Hence, repairing bone defects in elderly patients poses a formidable challenge in regenerative medicine. Here, the engineered dental pulp stem cell-derived exosomes loaded with the natural derivative of adenosine Cordycepin (CY@D-exos) are fabricated by means of the intermittent ultrasonic shock, which dually rejuvenates both senescent BMSCs and endothelial cells and significantly improve bone regeneration and repair in aged animals. CY@D-exos can efficiently overcome the senescence of aged BMSCs and enhance their osteogenic differentiation by activating NRF2 signaling and maintaining heterochromatin stability. Importantly, CY@D-exos also potently overcomes the senescence of vascular endothelial cells and promotes angiogenesis. In vivo injectable gelatin methacryloyl (GelMA) hydrogels with sustained release of CY@D-exos can accelerate bone injury repair and promote new blood vessel formation in aged animals. Taken together, these results thus demonstrate that cordycepin-loaded dental pulp stem cell-derived exosomes display considerable potential to be developed as a next-generation therapeutic agent for promoting aged bone regeneration and repair.
Cartilage Endplate‐Targeted Engineered Exosome Releasing and Acid Neutralizing Hydrogel Reverses Intervertebral Disc Degeneration
Authors: Jiawen Zhan, Yongzhi Cui, Ping Zhang, Yuxuan Du, Prisca Hecker, Shuaiqi Zhou, Yupeng Liang, Weiye Zhang, Zhefeng Jin, Yuan Wang, Weihang Gao, Oleksandr Moroz, Liguo Zhu, Xiaoguang Zhang, Ke Zhao
Journal: Advanced Healthcare Materials (2024)

Abstract Cartilage endplate cell (CEPC) and nucleus pulposus cell (NPC) inflammation are critical factors that contribute to intervertebral disc degeneration (IVDD). Recent evidence indicated that iron ion influx, reactive oxygen species (ROS), and the cGAS‐STING pathway are involved in CEPC inflammatory degeneration. Moreover, cytokines produced by degenerating CEPCs and lactic acid accumulation within the microenvironment significantly contribute to NPC inflammation. Consequently, simultaneous alleviation of CEPC inflammation and correction of the acidic microenvironment are anticipated to reverse IVDD. Herein, CEPC‐targeted engineered exosomes loaded with salvianolic acid A are incorporated into a CaCO 3 /chitosan hydrogel, forming a composite gel, CAP‐sEXOs@Gel. Notably, CAP‐sEXOs@Gel shows long local retention, realizes the slow release of CAP‐sEXOs and specific uptake by CEPCs. After uptake by CEPCs, CAP‐sEXOs reduce intracellular iron ion and ROS by inhibiting hypoxia‐inducible factor‐2α (HIF‐2α)/TfR1 expression. Iron ion influx and ROS inhibition contribute to the maintenance of normal mitochondrial function and reduced mtDNA leakage, suppresing the cGAS‐STING pathway. Additionally, the CaCO 3 component of CAP‐sEXOs@Gel neutralizes H + , thereby alleviating NPC inflammation. Collectively, this novel composite hydrogel demonstrates the ability to concurrently inhibit CEPC and NPC inflammation, thereby presenting a promising therapeutic approach for IVDD.
Dysrupted microbial tryptophan metabolism associates with SARS-CoV-2 acute inflammatory responses and long COVID
Authors: Lu Yao, Hannah Devotta, Junhui Li, Nonhlanhla Lunjani, Corinna Sadlier, Aonghus Lavelle, Werner C. Albrich, Jens Walter, Paul W. O’Toole, Liam O’Mahony
Journal: Gut Microbes (2024)

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and risk of long COVID has been associated with the depletion or over-abundance of specific taxa within the gut microbiome. However, the microbial mechanisms mediating these effects are not yet known. We hypothesized that altered microbial production of tryptophan and its downstream derivatives might contribute to inappropriate immune responses to viral infection. In patients hospitalized with COVID-19 (