tbuckley/cabot-search huggingface dataset:
Associations of occupational and leisure-time physical activity with all-cause mortality: an individual participant data meta-analysis
Authors: Pieter Coenen, Maaike A Huysmans, Andreas Holtermann, Richard P Troiano, Paul Jarle Mork, Steinar Krokstad, Els Clays, Bart Cillekens, Dirk De Bacquer, Mette Aadahl, Line Lund Kårhus, Anette Sjøl, Lars Bo Andersen, Jussi Kauhanen, Ari Voutilainen, Richard M Pulsford, Emmanuel Stamatakis, Uri Goldbourt, Annette Peters, Barbara Thorand, Annika Rosengren, Lena Björck, Kyle Sprow, Kristin Franzon, Miguel Rodriguez-Barranco, Leila Luján-Barroso, Anders Knutsson, Lars Alfredsson, Martin Bahls, Till Ittermann, Alexander Kluttig, Lamiaa Hassan, Miriam Wanner, Matthias Bopp, Jacob Louis Marott, Peter Schnohr, Børge Grønne Nordestgaard, Knut Eirik Dalene, Ulf Ekelund, Johan Clausen, Magnus Thorsten Jensen, Christina Bjørk Petersen, Niklas Krause, Jos Twisk, Willem van Mechelen, Allard J van der Beek
Journal: British Journal of Sports Medicine (2024)

Objective Health effects of different physical activity domains (ie, during leisure time, work and transport) are generally considered positive. Using Active Worker consortium data, we assessed independent associations of occupational and leisure-time physical activity (OPA and LTPA) with all-cause mortality. Design Two-stage individual participant data meta-analysis. Data source Published and unpublished cohort study data. Eligibility criteria Working participants aged 18–65 years. Methods After data harmonisation, we assessed associations of OPA and LTPA with all-cause mortality. In stage 1, we analysed data from each study separately using Cox survival regression, and in stage 2, we pooled individual study findings with random-effects modelling. Results In 22 studies with up to 590 497 participants from 11 countries, during a mean follow-up of 23.1 (SD: 6.8) years, 99 743 (16%) participants died. Adjusted for LTPA, body mass index, age, smoking and education level, summary (ie, stage 2) hazard ration (HRs) and 95% confidence interval (95% CI) for low, moderate and high OPA among men (n=2 96 134) were 1.01 (0.99 to 1.03), 1.05 (1.01 to 1.10) and 1.12 (1.03 to 1.23), respectively. For women (n=2 94 364), HRs (95% CI) were 0.98 (0.92 to 1.04), 0.96 (0.92 to 1.00) and 0.97 (0.86 to 1.10), respectively. In contrast, higher levels of LTPA were inversely associated with mortality for both genders. For example, for women HR for low, moderate and high compared with sedentary LTPA were 0.85 (0.81 to 0.89), 0.78 (0.74 to 0.81) and 0.75 (0.65 to 0.88), respectively. Effects were attenuated when adjusting for income (although data on income were available from only 9 and 6 studies, for men and women, respectively). Conclusion Our findings indicate that OPA may not result in the same beneficial health effects as LTPA.
Integrating hot topics and implementation of treatable traits in asthma
Authors: Peter G Gibson, Vanessa M McDonald
Journal: European Respiratory Journal (2024)

People with asthma experience many different problems related to their illness. The number and type of problems differs between patients. This results in asthma being a complex and heterogeneous disorder which mandates a personalised approach to management. These features pose very significant challenges for the effective implementation of evidence-based management. Treatable Traits is a model of care that has been specifically designed to address these issues. Traits are identified in the pulmonary, extra-pulmonary (comorbidity) and risk factor/behavioural domains. Traits are clinically relevant, recognisable with validated trait identification markers, and treatable using evidence-based therapies. The clinician and patient agree on a personalised management plan that addresses the relevant traits, and trials show superiority of this approach with significant improvements in asthma control and quality of life. A number of tools have now been developed to assist the clinician in the implementation of this approach. The success of the treatable traits model of care is now being realised in other disease areas.
IRS2 Signaling Protects Against Stress-Induced Arrhythmia by Maintaining Ca <sup>2+</sup> Homeostasis
Authors: Qian Shi, Jinxi Wang, Hamza Malik, Xuguang Li, Jennifer Streeter, Jacob Sharafuddin, Eric Weatherford, David Stein, Yuval Itan, Biyi Chen, Duane Hall, Long-Sheng Song, E. Dale Abel
Journal: Circulation (2024)

BACKGROUND: The docking protein IRS2 (insulin receptor substrate protein-2) is an important mediator of insulin signaling and may also regulate other signaling pathways. Murine hearts with cardiomyocyte-restricted deletion of IRS2 (cIRS2-KO) are more susceptible to pressure overload–induced cardiac dysfunction, implying a critical protective role of IRS2 in cardiac adaptation to stress through mechanisms that are not fully understood. There is limited evidence regarding the function of IRS2 beyond metabolic homeostasis regulation, particularly in the context of cardiac disease. METHODS: A retrospective analysis of an electronic medical record database was conducted to identify patients with IRS2 variants and assess their risk of cardiac arrhythmias. Arrhythmia susceptibility was examined in cIRS2-KO mice. The underlying mechanisms were investigated using confocal calcium imaging of ex vivo whole hearts and isolated cardiomyocytes to assess calcium handling, Western blotting to analyze the involved signaling pathways, and pharmacological and genetic interventions to rescue arrhythmias in cIRS2-KO mice. RESULTS: The retrospective analysis identified patients with IRS2 variants of uncertain significance with a potential association to an increased risk of cardiac arrhythmias compared with matched controls. cIRS2-KO hearts were found to be prone to catecholamine-sensitive ventricular tachycardia and reperfusion ventricular tachycardia. Confocal calcium imaging of ex vivo whole hearts and single isolated cardiomyocytes from cIRS2-KO hearts revealed decreased Ca² + transient amplitudes, increased spontaneous Ca² + sparks, and reduced sarcoplasmic reticulum Ca² + content during sympathetic stress, indicating sarcoplasmic reticulum dysfunction. We identified that overactivation of the AKT1/NOS3 (nitric oxide synthase 3)/CaMKII (Ca2+/calmodulin-dependent protein kinase II)/RyR2 (type 2 ryanodine receptor) signaling pathway led to calcium mishandling and catecholamine-sensitive ventricular tachycardia in cIRS2-KO hearts. Pharmacological AKT inhibition or genetic stabilization of RyR2 rescued catecholamine-sensitive ventricular tachycardia in cIRS2-KO mice. CONCLUSIONS: Cardiac IRS2 inhibits sympathetic stress-induced AKT/NOS3/CaMKII/RyR2 overactivation and calcium-dependent arrhythmogenesis. This novel IRS2 signaling axis, essential for maintaining cardiac calcium homeostasis under stress, presents a promising target for developing new antiarrhythmic therapies.
KPV and RAPA Self‐Assembled into Carrier‐Free Nanodrugs for Vascular Calcification Therapy
Authors: Li Zhang, Dongze Li, Yierpani Aierken, Jie Zhang, Zhenyu Liu, Zipeng Lin, Longqi Jiang, Qingzhu Li, Ya Wu, Yong Liu
Journal: Advanced Healthcare Materials (2024)

Abstract Cardiovascular disease (CVD) is a leading cause of death globally, and vascular calcification (VC) is an important independent risk factor for predicting CVD. Currently, there are no established therapeutic strategies for the treatment of VC. Although recognized combination therapies of nanomedicines can provide effective strategies for disease treatment, the clinical application of nanomedicines is limited because of their complex preparation processes, low drug loading rates, and unpredictable safety risks. Thus, developing a simple, efficient, and safe nanodrug to simultaneously regulate inflammation and autophagy may be a promising strategy for treating VC. Herein, an anti‐inflammatory peptide (lysine‐proline‐valine peptides, KPV) and the autophagy activator rapamycin (RAPA) are self‐assembled to form new carrier‐free spherical nanoparticles (NPs), which shows good stability and biosafety. In vivo and in vitro, KPV‐RAPA NPs significantly inhibit VC in mice compared to the other treatment groups. Mechanistically, KPV‐RAPA NPs inhibit inflammatory responses and activated autophagy. Therefore, this study indicates that the new carrier‐free KPV‐RAPA NPs have great potential as therapeutic agents for VC combination therapy, which can promote the development of nanodrugs for VC.
Author correction to “Identification of anthelmintic parbendazole as a therapeutic molecule for HNSCC through connectivity map-based drug repositioning” [Acta Pharmaceutica Sinica B 12 (2022) 2429-2442]
Authors: Dong Liang, Chen Yu, Zhao Ma, Xingye Yang, Zhenzhen Li, Xuhui Dong, Xiaojun Qin, Lupei Du, Minyong Li
Journal: Acta Pharmaceutica Sinica B (2024)

[This corrects the article DOI: 10.1016/j.apsb.2021.12.005.].
Hydrogel Microsphere‐Encapsulated Bimetallic Nanozyme for Promoting Diabetic Bone Regeneration via Glucose Consumption and ROS Scavenging
Authors: Yujian Hui, Jiannan Mao, Min Rui, Yiyang Huang, Xinzhao Jiang, Yichang Xu, Wei Wang, Jie Wu, Liang Zhou, Kun Xi, Lixin Huang, Liang Chen
Journal: Advanced Healthcare Materials (2024)

Abstract The healing of bone defects among diabetic patients presents a critical challenge due to the pathological microenvironment, characterized by hyperglycemia, excessive reactive oxygen species (ROS) production, and inflammation. Herein, multifunctional composite microspheres, termed GMAP are developed, using a microfluidic technique by incorporating Au@Pt nanoparticles (NPs) and GelMA hydrogel to modulate the diabetic microenvironment for promoting bone regeneration. The GMAP enables the sustained release of Au@Pt NPs, which function as bimetallic nanozymes with dual enzyme‐like activities involving glucose oxidase and catalase. The synergistic effect allows for efficient glucose consumption and ROS elimination concurrently. Thus, the GMAP effectively protects the proliferation of bone marrow mesenchymal stem cells (BMSCs) under adverse high‐glucose conditions. Furthermore, it also promotes the osteogenic differentiation and paracrine capabilities of BMSCs, and subsequently inhibits inflammation and enhances angiogenesis. In vivo diabetic rats bone defect model, it is demonstrated that GMAP microspheres significantly improve bone regeneration, as verified by micro‐computed tomography and histological examinations. This study provides a novel strategy for bone regeneration by modulating the diabetic microenvironment, presenting a promising approach for addressing the complex challenges associated with bone healing in diabetic patients.
Immuno‐Rolling Circle Amplification (Immuno‐RCA): Biosensing Strategies, Practical Applications, and Future Perspectives
Authors: Limei Zhang, Hao Bai, Jie Zou, Chuyan Zhang, Weihua Zhuang, Jie Hu, Yongchao Yao, Wenchuang (Walter) Hu
Journal: Advanced Healthcare Materials (2024)

Abstract In the rapidly evolving field of life sciences and biomedicine, detecting low‐abundance biomolecules, and ultraweak biosignals presents significant challenges. This has spurred a rapid development of analytical techniques aiming for increased sensitivity and specificity. These advancements, including signal amplification strategies and the integration of biorecognition events, mark a transformative era in bioanalytical precision and accuracy. A prominent method among these innovations is immuno‐rolling circle amplification (immuno‐RCA) technology, which effectively combines immunoassays with signal amplification via RCA. This process starts when a targeted biomolecule, such as a protein or cell, binds to an immobilized antibody or probe on a substrate. The introduction of a circular DNA template triggers RCA, leading to exponential amplification and significantly enhanced signal intensity, thus the target molecule is detectable and quantifiable even at the single‐molecule level. This review provides an overview of the biosensing strategy and extensive practical applications of immuno‐RCA in detecting biomarkers. Furthermore, it scrutinizes the limitations inherent to these sensors and sets forth expectations for their future trajectory. This review serves as a valuable reference for advancing immuno‐RCA in various domains, such as diagnostics, biomarker discovery, and molecular imaging.
High-dose Furmonertinib in patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastases: A prospective real-world study
Authors: Haiyang Chen, Sen Yang, Lili Wang, Yingxi Wu, Yufeng Wu, Shuxiang Ma, Zhen He, Cuicui Zhang, Yang Liu, Haoran Tang, Hang Dong, Qiming Wang
Journal: Journal of Thoracic Oncology (2024)
Consolidation ALK Tyrosine Kinase Inhibitors versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK+ Non-Small Cell Lung Cancer
Authors: Amin H Nassar, Ritujith Jayakrishnan, Jamie Feng, Frances Shepherd, Elio Adib, Justin M Cheung, Jessica J Lin, Yufei Liu, Steven H Lin, Kaushal Parikh, Arthi Sridhar, Purnima Shakya, Thomas J Dilling, David Kaldas, Jhanelle E Gray, Anastasiya Lobachov, Jair Bar, Heike Luders, Christian Grohe, Shruti Gupta, Ticiana Leal, Bailey Fitzgerald, Fionnuala Crowley, Yu Fujiwara, Thomas U Marron, Molly Wilgucki, Joshua Reuss, Luxi Chen, Kamya Sankar, Jacqueline V Aredo, Joel W Neal, Heather A Wakelee, Rohit Thummalapalli, Helena Yu, Ryan Whitaker, Ana Velazquez, Meera Ragavan, Alessio Cortellini, David J Kwiatkowski, Abdul Rafeh Naqash, Sarah B Goldberg, So Yeon Kim
Journal: Journal of Thoracic Oncology (2024)
Improving Ebola virus disease outbreak control through targeted post-exposure prophylaxis
Authors: Elin Hoffmann Dahl, Placide Mbala, Sylvain Juchet, Abdoulaye Touré, Alice Montoyo, Beatrice Serra, Richard Kojan, Eric D'Ortenzio, Bjorn Blomberg, Marie Jaspard
Journal: The Lancet Global Health (2024)
Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): a multicentre, single-arm, phase 2 trial
Authors: Alessandra Tedeschi, Anna Maria Frustaci, Adalgisa Condoluci, Marta Coscia, Roberto Chiarle, Pier Luigi Zinzani, Marina Motta, Gianluca Gaidano, Giulia Quaresmini, Lydia Scarfò, Gioacchino Catania, Marina Deodato, Rebecca Jones, Valentina Tabanelli, Valentina Griggio, Georg Stüssi, Angelica Calleri, Katia Pini, Roberto Cairoli, Thorsten Zenz, Alessio Signori, Emanuele Zucca, Davide Rossi, Marco Montillo
Journal: The Lancet Oncology (2024)
Savolitinib in patients in China with locally advanced or metastatic treatment-naive non-small-cell lung cancer harbouring MET exon 14 skipping mutations: results from a single-arm, multicohort, multicentre, open-label, phase 3b confirmatory study
Authors: Yongfeng Yu, Qisen Guo, Yongchang Zhang, Jian Fang, Diansheng Zhong, Baogang Liu, Pinhua Pan, Dongqing Lv, Lin Wu, Yanqiu Zhao, Juan Li, Zhihua Liu, Chunling Liu, Haichuan Su, Yun Fan, Tongmei Zhang, Anwen Liu, Bo Jin, Ye Wang, Jianying Zhou, Zhihong Zhang, Fengming Ran, Xia Song, Michael Shi, Weiguo Su, Shun Lu
Journal: The Lancet Respiratory Medicine (2024)
Mpox outbreak—tecovirimat resistance, management approaches, and challenges in HIV-endemic regions
Authors: Wyvine Ansima Bapolisi, Susanne Krasemann, Misaki Wayengera, Bruce Kirenga, Esto Bahizire, Espoir Bwenge Malembaka, Joseph Nelson Siewe Fodjo, Robert Colebunders, Patrick Dmc Katoto
Journal: The Lancet Infectious Diseases (2024)
HAF prevents hepatocyte apoptosis and progression to MASH and hepatocellular carcinoma through transcriptional regulation of the NF-κB pathway
Authors: Karen Acuña-Pilarte, Ethan C. Reichert, Yangsook Song Green, Lily M-T. Halberg, Martin Golkowski, Kathleen M. Maguire, Patrice N. Mimche, Severin Donald Kamdem, Po-An Hu, Jillian Wright, Gregory S. Ducker, Warren P. Voth, Ryan M. O’Connell, Sydney A. McFarland, Erika Said Abu Egal, Amandine Chaix, Scott. A. Summers, Jordan W. Reelitz, J. Alan Maschek, James E. Cox, Kimberley J. Evason, Mei Yee Koh
Journal: Hepatology (2024)

Background: HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF ( SART1 +/- ) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear. Results: We generated SART1 -floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS -/- ) or myeloid cells (LysM-Cre, macS -/- ). HepS -/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-κB pathway, which was recapitulated using HAF siRNA in vitro . HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-κB activity by regulating transcription of TRADD and RIPK1 . Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-κB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver. Conclusions: HAF is novel transcriptional regulator of the NF-κB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.
Liraglutide for Children 6 to &lt;12 Years of Age with Obesity — A Randomized Trial
Authors: Claudia K. Fox, Margarita Barrientos-Pérez, Eric M. Bomberg, John Dcruz, Inge Gies, Nina M. Harder-Lauridsen, Muhammad Yazid Jalaludin, Kushal Sahu, Petra Weimers, Thomas Zueger, Silva Arslanian
Journal: New England Journal of Medicine (2024)

No medications are currently approved for the treatment of nonmonogenic, nonsyndromic obesity in children younger than 12 years of age. Although the use of liraglutide has been shown to induce weight loss in adults and adolescents with obesity, its safety and efficacy have not been established in children.
Microbiology and outcomes of tubo-ovarian abscesses: A 5-year cohort of 105 cases
Authors: Giulia Micheli, Guillaume Parpex, Asmaa Tazi, Elena Holeindre, Julien Loubinoux, Cécile Guyonnet, Jeanne Reboul-Marty, Claire Poyart, Charles Chapron, Pauline Richebé, Etienne Canouï, Roberto Cauda, Martin Belan, Camille Rasmussen, Louis Marcellin, Laetitia Campin, Caroline Charlier
Journal: Journal of Infection (2024)
Hormonally and chemically defined expansion conditions for organoids of biliary tree Stem Cells
Authors: Wencheng Zhang, Yangyang Cui, Mengqi Lu, Mingyang Xu, Yuting Li, Haimeng Song, Yi Luo, Jinjia Song, Yong Yang, Xicheng Wang, Lijun Liao, Yunfang Wang, Lola Reid, Zhiying He
Journal: Bioactive Materials (2024)
Rack1 regulates B-cell development and function by binding to and stabilizing the transcription factor Pax5
Authors: Xueting Zhang, Chenke Ma, Yuchen Lu, Jing Wang, Hongfang Yun, Hui Jiang, Mengyao Wu, Xiaoyao Feng, Wenbin Gai, Guanglei Xu, Hongbin Deng, Jiannan Feng, Wanli Liu, Taoxing Shi, Qianqian Cheng, Jiyan Zhang
Journal: Cellular and Molecular Immunology (2024)
Whole Lung Irradiation in Rhabdomyosarcoma With Lung Metastases: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group
Authors: Leo Y. Luo, Wei Xue, Amira Qumseya, Juan C. Vasquez, Rajkumar Venkatramani, Suzanne L. Wolden, Dana L. Casey
Journal: Journal of Clinical Oncology (2024)

PURPOSE Patients with rhabdomyosarcoma with metastatic disease have a poor prognosis despite therapy intensification. The aim of this study was to investigate the efficacy of whole lung irradiation (WLI) in patients with rhabdomyosarcoma and lung metastases. METHODS Patients with rhabdomyosarcoma with lung metastases enrolled on four Children's Oncology Group protocols (D9802, D9803, ARST08P1, ARST0431) were retrospectively reviewed. Event-free survival (EFS) and overall survival (OS) were compared between patients who received and did not receive WLI. RESULTS In 143 patients with rhabdomyosarcoma with lung metastases, 65 patients (45.5%) received WLI and 78 patients (54.5%) did not receive WLI despite protocol requirements. The 5-year EFS was 38.3% (95% CI, 24.8 to 51.8) in patients who received WLI and 25.2% (95% CI, 13.8 to 36.6) in patients who did not receive WLI ( P = .0496). The 5-year OS was 45.5% (95% CI, 31.8 to 59.3) in patients who received WLI and 32.4% (95% CI, 20.4 to 44.4) in patients who did not receive WLI ( P = .08). In exploratory subgroup analyses, the benefit of WLI on EFS and OS was significant in patients 10 years and older. Other clinical factors associated with EFS on univariable analysis included age, histology FOXO1 fusion status, number of metastatic sites, location of metastatic sites, and Oberlin Score. CONCLUSION WLI is associated with improved EFS in patients with rhabdomyosarcoma with lung metastases. These results highlight the potential importance of WLI and need for more stringent protocol compliance for administering WLI.
STRIvE-02: A First-in-Human Phase I Study of Systemically Administered B7-H3 Chimeric Antigen Receptor T Cells for Patients With Relapsed/Refractory Solid Tumors
Authors: Navin Pinto, Catherine M. Albert, Mallory R. Taylor, Heidi B. Ullom, Ashley L. Wilson, Wenjun Huang, Jason Wendler, Sowmya Pattabhi, Kristy Seidel, Christopher Brown, Joshua A. Gustafson, Stephanie D. Rawlings-Rhea, Safia H.E. Cheeney, Katelyn Burleigh, Heather H. Gustafson, Rimas J. Orentas, Nicholas A. Vitanza, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park
Journal: Journal of Clinical Oncology (2024)

PURPOSE B7-H3 is an immunoregulatory protein overexpressed by many pediatric solid tumors with limited expression on critical organs, making it an attractive immunotherapy target. We present a first-in-human phase I clinical trial systemically administered B7-H3 chimeric antigen receptor (CAR) T cells for young patients with relapsed or refractory solid tumors. PATIENTS AND METHODS Patients were enrolled onto a phase I trial to examine the safety of B7-H3–specific CARs at various dose levels (DLs) using a standard 3 + 3 dose escalation design. RESULTS Sixteen patients (range, 11-24 years; median, 18.5 years) were enrolled, and nine were treated at DL1 (0.5 × 10 6 CAR T cells/kg; n = 3) or DL2 (1 × 10 6 CAR T cells/kg; n = 6). There were no first infusion dose-limiting toxicities. Maximum first-infusion circulating CAR T cells detected in the peripheral blood were 4.98 cells/μL (range, 0-4.98 cells/μL) with detection of CAR T cells colocalizing with tumor cells at the site of metastatic disease in one patient. Patients were eligible for subsequent infusions. An objective partial response by PERCIST criteria was observed 28 days after a second CAR T cell infusion in a patient who did not have an objective response after the first infusion. The second infusion demonstrated marked enhancement of CAR T cell expansion to 1,590 cells/μL and was accompanied by cytokine release syndrome and dose-limiting transaminitis. Detailed peripheral blood cytokine profiling revealed elevated IL-21 levels preinfusion 2 compared with infusion 1. CONCLUSION B7-H3 CAR T cells are tolerable and demonstrate limited antitumor activity without acute on-target, off-tumor toxicity. High levels of CAR T cell expansion may be necessary to achieve objective responses, but undefined host and tumor microenvironment factors appear to be critical (ClinicalTrials.gov identifier: NCT04483778 ).