tbuckley/cabot-search huggingface dataset:
Weight Loss Blockbuster Development: A Role for Unimolecular Polypharmacology
Authors: Qingtong Zhou, Guanyi Li, Kaini Hang, Jie Li, Dehua Yang, Ming-Wei Wang
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Obesity and type 2 diabetes mellitus (T2DM) impact more than 2.5 billion adults worldwide, necessitating innovative therapeutic approaches. Unimolecular polypharmacology, which involves designing single molecules to target multiple receptors or pathways simultaneously, has revolutionized treatment strategies. Blockbuster drugs such as tirzepatide and retatrutide have shown unprecedented success in managing obesity and T2DM, demonstrating superior efficacy compared to conventional single agonists. Tirzepatide, in particular, has garnered tremendous attention for its remarkable effectiveness in promoting weight loss and improving glycemic control, while offering additional cardiovascular and renal benefits. Despite their promises, such therapeutic agents also face challenges that include gastrointestinal side effects, patient compliance issues, and body weight rebound after cessation of the treatment. Nonetheless, the development of these therapies marks a significant leap forward, underscoring the transformative potential of unimolecular polypharmacology in addressing metabolic diseases and paving the way for future innovations in personalized medicine.
Tissue-based Biomarkers Steering Clinical Decisions in Patients with Urothelial Cancer
Authors: Luca Afferi, Alessia Cimadamore, Andrea Gallioli, Benjamin Pradere, Laura S Mertens, Gautier Marcq, Georgia Anguera, Andrea Necchi, Alberto Briganti, Francesco Montorsi, Morgan Rouprêt, Paolo Gontero, Alberto Breda, Marco Moschini
Journal: European Urology (2024)
Radical Prostatectomy Versus Stereotactic Radiotherapy for Clinically Localised Prostate Cancer: Results of the PACE-A Randomised Trial
Authors: Nicholas van As, Binnaz Yasar, Clare Griffin, Jaymini Patel, Alison C Tree, Peter Ostler, Hans van der Voet, Daniel Ford, Shaun Tolan, Paula Wells, Rana Mahmood, Mathias Winkler, Andrew Chan, Alan Thompson, Chris Ogden, Olivia Naismith, Julia Pugh, Georgina Manning, Stephanie Brown, Stephanie Burnett, Emma Hall
Journal: European Urology (2024)
Myocardial Strain Imaging
Authors: Otto A Smiseth, Oliver Rider, Marta Cvijic, Ladislav Valkovič, Espen W Remme, Jens-Uwe Voigt
Journal: JACC. Cardiovascular imaging (2024)

Myocardial strain imaging by echocardiography or cardiac magnetic resonance (CMR) is a powerful method to diagnose cardiac disease. Strain imaging provides measures of myocardial shortening, thickening, and lengthening and can be applied to any cardiac chamber. Left ventricular (LV) global longitudinal strain by speckle-tracking echocardiography is the most widely used clinical strain parameter. Several CMR-based modalities are available and are ready to be implemented clinically. Clinical applications of strain include global longitudinal strain as a more sensitive method than ejection fraction for diagnosing mild systolic dysfunction. This applies to patients suspected of having heart failure with normal LV ejection fraction, to early systolic dysfunction in valvular disease, and when monitoring myocardial function during cancer chemotherapy. Segmental LV strain maps provide diagnostic clues in specific cardiomyopathies, when evaluating LV dyssynchrony and ischemic dysfunction. Strain imaging is a promising modality to quantify right ventricular function. Left atrial strain may be used to evaluate LV diastolic function and filling pressure.
Coronary Microvascular Function in Asymptomatic Middle-Aged Individuals With Cardiometabolic Risk Factors
Authors: Ana Devesa, Valentin Fuster, Inés García-Lunar, Belén Oliva, Ana García-Alvarez, Andrea Moreno-Arciniegas, Ravi Vazirani, Cristina Pérez-Herreras, Pablo Marina, Héctor Bueno, Leticia Fernández-Friera, Antonio Fernández-Ortiz, Javier Sanchez-Gonzalez, Borja Ibanez
Journal: JACC. Cardiovascular imaging (2024)
Predictors for Vulnerable Plaque in Functionally Significant Lesions
Authors: Seokhun Yang, Doyeon Hwang, Koshiro Sakai, Takuya Mizukami, Jonathon Leipsic, Marta Belmonte, Jeroen Sonck, Bjarne L Nørgaard, Hiromasa Otake, Brian Ko, Michael Maeng, Jesper Møller Jensen, Dimitri Buytaert, Daniel Munhoz, Daniele Andreini, Hirofumi Ohashi, Toshiro Shinke, Charles A Taylor, Emanuele Barbato, Bernard De Bruyne, Carlos Collet, Bon-Kwon Koo
Journal: JACC. Cardiovascular imaging (2024)
Evaluating Mitral TEER in the Management of Moderate Secondary Mitral Regurgitation Among Heart Failure Patients
Authors: Anita W Asgar, Gilbert H L Tang, Jason H Rogers, Wolfgang Rottbauer, M Andrew Morse, Paolo Denti, Paul Mahoney, Michael J Rinaldi, Federico M Asch, Jose L Zamorano, Melody Dong, Rong Huang, Joann Lindenfeld, Francesco Maisano, Ralph Stephan von Bardeleben, Saibal Kar, Evelio Rodriguez
Journal: JACC Heart Failure (2024)
Avoiding Treatment in Hospital With Subcutaneous Furosemide for Worsening Heart Failure
Authors: Marvin A Konstam, Joseph Massaro, Ravi Dhingra, Mary Walsh, Linda Ordway, Michael S Pursley, Dalton S McLean, Sandeep Saha, Nicole Close, Jeremy M Konstam, Katherine H Luepke, John F Mohr, James E Udelson
Journal: JACC Heart Failure (2024)
Dapagliflozin in Heart Failure, Type 2 Diabetes, and Neuropathy
Authors: Jawad H Butt, Li Shen, Silvio E Inzucchi, Kieran F Docherty, Pardeep S Jhund, Felipe A Martinez, Marc S Sabatine, Muthiah Vaduganathan, Scott D Solomon, John J V McMurray
Journal: JACC Heart Failure (2024)
Gut microbiota mediate early life stress-induced social dysfunction and anxiety-like behaviors by impairing amino acid transport at the gut
Authors: Jiushuang Zhu, Zhuoting Zhong, Lijie Shi, Ling Huang, Chunqiao Lin, Yan He, Xiuwen Xia, Tiane Zhang, Weijun Ding, Youjun Yang
Journal: Gut Microbes (2024)

Early life stress alters gut microbiota and increases the risk of neuropsychiatric disorders, including social deficits and anxiety, in the host. However, the role of gut commensal bacteria in early life stress-induced neurobehavioral abnormalities remains unclear. Using the maternally separated (MS) mice, our research has unveiled a novel aspect of this complex relationship. We discovered that the reduced levels of amino acid transporters in the intestine of MS mice led to low glutamine (Gln) levels in the blood and synaptic dysfunction in the medial prefrontal cortex (mPFC). Abnormally low blood Gln levels limit the brain's availability of Gln, which is required for presynaptic glutamate (Glu) and γ-aminobutyric acid (GABA) replenishment. Furthermore, MS resulted in gut microbiota dysbiosis characterized by a reduction in the relative abundance of
Advances in bio-integrated wearable and implantable optoelectronic devices for cardiac healthcare
Authors: Cheng Li, Yangshuang Bian, Zhiyuan Zhao, Yunqi Liu, Yunlong Guo
Journal: Cyborg and Bionic Systems (2024)

With the prevalence of cardiovascular disease, it is imperative that medical monitoring and treatment become more instantaneous and comfortable for patients. Recently, wearable and implantable optoelectronic devices can be seamlessly integrated into human body to enable physiological monitoring and treatment in an imperceptible and spatiotemporally unconstrained manner, opening countless possibilities for the intelligent healthcare paradigm. To achieve biointegrated cardiac healthcare, researchers have focused on novel strategies for the construction of flexible/stretchable optoelectronic devices and systems. Here, we overview the progress of biointegrated flexible and stretchable optoelectronics for wearable and implantable cardiac healthcare devices. Firstly, the device design is addressed, including the mechanical design, interface adhesion, and encapsulation strategies. Next, the practical applications of optoelectronic devices for cardiac physiological monitoring, cardiac optogenetics, and nongenetic stimulation are presented. Finally, an outlook on biointegrated flexible and stretchable optoelectronic devices and systems for intelligent cardiac healthcare is discussed.
BATF is a major driver of NK cell epigenetic reprogramming and dysfunction in AML
Authors: Bijender Kumar, Anand Singh, Rafet Basar, Nadima Uprety, Ye Li, Huihui Fan, Ana Karen Nunez Cortes, Mecit Kaplan, Sunil Acharya, Hila Shaim, Anna C Xu, Manrong Wu, Emily Ensley, Dexing Fang, Pinaki P. Banerjee, Luciana Melo Garcia, Silvia Tiberti, Paul Lin, Hind Rafei, Maliha Nuzhat Munir, Madison Moore, Mayra Shanley, Mayela Mendt, Lucila N. Kerbauy, Bin Liu, Alexander Biederstädt, Elif Gokdemir, Susmita Ghosh, Kiran Kundu, Francia Reyes-Silva, Xin Ru Jiang, Xinhai Wan, April L. Gilbert, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Patrick Zhang, Enli Liu, Luis Muniz-Feliciano, Gary M. Deyter, Abhinav K. Jain, Juan Jose Rodriguez-Sevilla, Simona Colla, Guillermo Garcia-Manero, Elizabeth J. Shpall, Ken Chen, Hussein A. Abbas, Kunal Rai, Katayoun Rezvani, May Daher
Journal: Science Translational Medicine (2024)

Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2 , LAG3 , TIGIT , and CTLA4 . BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.
Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging
Authors: Sanjeeb Kumar Sahu, Pradeep Reddy, Jinlong Lu, Yanjiao Shao, Chao Wang, Mako Tsuji, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
Journal: Science Translational Medicine (2024)

Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 ( Oct4 ), sex-determining region Y-box 2 ( Sox2 ), Kruppel-like factor 4 ( Klf4 ), and cellular myelocytomatosis oncogene ( cMyc ) ( OSKM ) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a ( Cdkn2a ) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a - OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A - OSK in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.
A spatially resolved single-cell lung atlas integrated with clinical and blood signatures distinguishes COVID-19 disease trajectories
Authors: João Da Silva Filho, Vanessa Herder, Matthew P. Gibbins, Monique Freire dos Reis, Gisely Cardoso Melo, Michael J. Haley, Carla Cristina Judice, Fernando Fonseca Almeida Val, Mayla Borba, Tatyana Almeida Tavella, Vanderson de Sousa Sampaio, Charalampos Attipa, Fiona McMonagle, Derek Wright, Marcus Vinicius Guimaraes de Lacerda, Fabio Trindade Maranhão Costa, Kevin N. Couper, Wuelton Marcelo Monteiro, Luiz Carlos de Lima Ferreira, Christopher Alan Moxon, Massimo Palmarini, Matthias Marti
Journal: Science Translational Medicine (2024)

COVID-19 is characterized by a broad range of symptoms and disease trajectories. Understanding the correlation between clinical biomarkers and lung pathology during acute COVID-19 is necessary to understand its diverse pathogenesis and inform more effective treatments. Here, we present an integrated analysis of longitudinal clinical parameters, peripheral blood markers, and lung pathology in 142 Brazilian patients hospitalized with COVID-19. We identified core clinical and peripheral blood signatures differentiating disease progression between patients who recovered from severe disease compared with those who succumbed to the disease. Signatures were heterogeneous among fatal cases yet clustered into two patient groups: “early death” (&lt;15 days until death) and “late death” (&gt;15 days). Progression to early death was characterized systemically and in lung histopathological samples by rapid endothelial and myeloid activation and the presence of thrombi associated with SARS-CoV-2 + macrophages. In contrast, progression to late death was associated with fibrosis, apoptosis, and SARS-CoV-2 + epithelial cells in postmortem lung tissue. In late death cases, cytotoxicity, interferon, and T helper 17 (T H 17) signatures were only detectable in the peripheral blood after 2 weeks of hospitalization. Progression to recovery was associated with higher lymphocyte counts, T H 2 responses, and anti-inflammatory–mediated responses. By integrating antemortem longitudinal blood signatures and spatial single-cell lung signatures from postmortem lung samples, we defined clinical parameters that could be used to help predict COVID-19 outcomes.
Choline Metabolites and 15-Year Risk of Incident Diabetes in a Prospective Cohort of Adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Jessica K. Sprinkles, Anju Lulla, Autumn G. Hullings, Isis Trujillo-Gonzalez, Kevin C. Klatt, David R. Jacobs, Ravi V. Shah, Venkatesh L. Murthy, Annie Green Howard, Penny Gordon-Larsen, Katie A. Meyer
Journal: Diabetes Care (2024)

OBJECTIVE The potential for choline metabolism to influence the development of diabetes has received increased attention. Previous studies on circulating choline metabolites and incident diabetes have been conducted in samples of older adults, often with a high prevalence of risk factors. RESEARCH DESIGN AND METHODS Participants were from year 15 of follow-up (2000-2001) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 3,133, aged 33–45 years) with plasma choline metabolite (choline, betaine, and trimethylamine N-oxide [TMAO]) data. We quantified associations between choline metabolites and 15-year risk of incident diabetes (n = 387) among participants free of diabetes at baseline using Cox proportional hazards regression models adjusted for sociodemographics, health behaviors, and clinical variables. RESULTS Betaine was inversely associated with 15-year risk of incident diabetes (hazard ratio 0.76 [95% CI 0.67, 0.88] per 1-SD unit betaine), and TMAO was positively associated with 15-year risk of incident diabetes (1.11 [1.01, 1.22] per 1-SD unit). Choline was not significantly associated with 15-year risk of incident diabetes (1.05 [0.94, 1.16] per 1-SD). CONCLUSIONS Our findings are consistent with other published literature supporting a role for choline metabolism in diabetes. Our study extends the current literature by analyzing a racially diverse population-based cohort of early middle-aged individuals in whom preventive activities may be most relevant.
The role of dietary modification in the prevention and management of metabolic dysfunction-associated fatty liver disease: an international multidisciplinary expert consensus
Authors: Xu-Fen Zeng, Krista A Varady, Xiang-Dong Wang, Giovanni Targher, Christopher D Byrne, Reema Tayyem, Giovanni Latella, Ina Bergheim, Rodrigo Valenzuela, Jacob George, Carolyn Newberry, Ju-Sheng Zheng, Elena S George, C Wendy Spearman, Meropi D Kontogianni, Danijela Ristic-Medic, Wilza Arantes Ferreira Peres, Gamze Yurtdaş Depboylu, Wanshui Yang, Xu Chen, Fredrik Rosqvist, Christos S Mantzoros, Luca Valenti, Hannele Yki-Järvinen, Antonella Mosca, Silvia Sookoian, Anoop Misra, Yusuf Yilmaz, Won Kim, Yasser Fouad, Giada Sebastiani, Vincent Wai-Sun Wong, Fredrik Åberg, Yu Jun Wong, Pianhong Zhang, Francisco-Javier Bermúdez-Silva, Yan Ni, Monica Lupsor-Platon, Wah Kheong Chan, Nahum Méndez-Sánchez, Robert J de Knegt, Shahinul Alam, Sombat Treeprasertsuk, Li Wang, Mulong Du, Tiejun Zhang, Ming-Lung Yu, Huijie Zhang, Xingshun Qi, Xin Liu, Kanokwan Pinyopornpanish, Yu-Chen Fan, Kaijun Niu, Josep C Jimenez-Chillaron, Ming-Hua Zheng
Journal: Metabolism (2024)
Consensus on a Patient-Centered Definition of Atopic Dermatitis Flare
Authors: Aaron M. Drucker, Isabelle J. C. Thibau, Bryan Mantell, Katie N. Dainty, Matthew Wyke, Wendy Smith Begolka
Journal: JAMA Dermatology (2024)

Importance Flare is a term commonly used in atopic dermatitis (AD) care settings and clinical research, but little consensus exists on what it means. Meanwhile, flare management is an important unmet research and treatment need. Understanding how various therapies might comparatively improve AD flares as a measure of treatment effectiveness may facilitate shared decision-making and enable assessment of effectiveness within and outside clinical settings. Objective To identify patient-reported attributes associated with an AD flare to develop a patient-centered, consensus-based working definition. Design, Setting, and Participants This consensus survey study used a modified eDelphi method involving consensus-building focus groups and a survey conducted from January 10 through October 24, 2023. Focus groups were conducted virtually, and the online survey was advertised to National Eczema Association members. US adults aged 18 years or older with AD were recruited via convenience sampling. Exposure Lived experience of AD. Main Outcomes and Measures The main outcome was consensus on which attributes of AD to include in a patient-centric definition of flare. Using a rating scale (range, 1-9), consensus for the modified eDelphi statement rating was defined as at least 70% of participants rating a statement as 7 to 9 (critical to a flare definition) and less than 15% rating it as 1 to 3 (not important). Results Twenty-six participants with AD who completed focus group activities (24 aged 18-44 years [92.3%] and 2 aged 45-64 years [7.7%]; 18 women [69.2%]) and 631 participants with AD (mean [SD] age, 45.5 [18.1] years; 533 women [84.5%]) who completed the survey were included in the analysis. Fifteen statements reached consensus from the focus groups, and of those, 12 reached consensus from survey participants. More than half (334 of 631 [52.9%]) of survey participants reported alignment with their health care practitioner on what a flare is, and most (478 of 616 [77.6%]) reported that a patient-centered definition would be useful when communicating with their health care practitioner about their condition. Conclusions and Relevance In this study, participants with AD reached consensus on what an AD flare means from the patient perspective. This understanding may improve research and care by addressing this key patient-centered aspect of evaluating treatment effectiveness.
Teaching Bleeding Control and Building Trust With a Community Affected by Firearm Injuries
Authors: Kathryn M. Stadeli, Farah B. Mohamed, Lauren L. Agoubi, Abdifatah Dahiye, Elina Serrano, Maymuna Haji-Eda, Monica S. Vavilala
Journal: JAMA Surgery (2024)

This survey study evaluates a program for increasing bystander bleeding control skills, improving self-efficacy for bleeding control, and building trust between community participants and first responders in a Somali community in the US affected by firearm-related deaths.
Eravacycline improves the efficacy of anti-PD1 immunotherapy via AP1/CCL5 mediated M1 macrophage polarization in melanoma
Authors: Nian Liu, Mingjie Yan, Can Lu, Qian Tao, Jie Wu, Zhaokai Zhou, Jing Chen, Xiang Chen, Cong Peng
Journal: Biomaterials (2024)