tbuckley/cabot-search huggingface dataset:
Clinical characteristics and outcomes of patients aged 80 years and over with heart failure: Need for better treatment
Authors: Mingming Yang, Toru Kondo, Inder S. Anand, Rudolf A. de Boer, Ross T. Campbell, Lars Køber, Carolyn S.P. Lam, Aldo P. Maggioni, Felipe A. Martinez, Eileen O'Meara, Milton Packer, Marc S. Sabatine, Jose F. Kerr Saraiva, Sanjiv J. Shah, Faiez Zannad, Michael R. Zile, Pardeep S. Jhund, Scott D. Solomon, John J.V. McMurray
Journal: European Journal of Heart Failure (2024)
The partitioning of TCR repertoires by thymic selection
Authors: Wan-Lin Lo, Eric S. Huseby
Journal: The Journal of Experimental Medicine (2024)

αβ T cells are critical components of the adaptive immune system; they maintain tissue and immune homeostasis during health, provide sterilizing immunity after pathogen infection, and are capable of eliminating transformed tumor cells. Fundamental to these distinct functions is the ligand specificity of the unique antigen receptor expressed on each mature T cell (TCR), which endows lymphocytes with the ability to behave in a cell-autonomous, disease context–specific manner. Clone-specific behavioral properties are initially established during T cell development when thymocytes use TCR recognition of major histocompatibility complex (MHC) and MHC-like ligands to instruct survival versus death and to differentiate into a plethora of inflammatory and regulatory T cell lineages. Here, we review the ligand specificity of the preselection thymocyte repertoire and argue that developmental stage–specific alterations in TCR signaling control cross-reactivity and foreign versus self-specificity of T cell sublineages.
Association of varicose veins with incidence risk of atrial fibrillation: A population-based cohort study
Authors: Soyoun Choi, Gwang-Hyun Leem, Tae-Jin Song
Journal: International Journal of Surgery (2024)

Background: Varicose veins (VV) were once considered benign and common ailments; however, recent research suggests a potential link between VV and cardiovascular diseases or mortality. VV share common risk factors and pathophysiology with cardiovascular disease, potentially influencing the vascular system. Therefore, the authors aimed to investigate the association between VV and the incidence risk of atrial fibrillation (AF) using a population-based cohort. Methods: Our retrospective cohort study included 2 680 971 individuals who underwent examination through the Korean National Health Screening Service from 2010 to 2011. VV was defined by two or more claims with the International Classification of Diseases 10th Revision diagnostic codes: I83.0, I83.1, I83.2 (VV of lower extremities with ulcer or inflammation, severe VV), and I83.9 (asymptomatic VV of lower extremities, mild VV). The 1:3 propensity score matching (PSM) was used to assess the risk of newly developed AF, identified via insurance claims coded as I48. Results: The mean age of all participants was 48.5±14.2 years, with 51.4% being male. Among the population, 24 557 (0.91%) had VV, including 3684 (0.14%) of severe VV and 20 873 (0.77%) of mild VV. During a median follow-up of 10.06 years, 24 557 (0.92%) cases of AF occurred. Participants with VV exhibited an increased incidence risk of AF compared to those without it before (HR: 1.13, 95% CI: 1.06–1.21, P &lt;0.001) and after PSM (HR: 1.17, 95% CI: 1.08–1.27, P &lt;0.001). This positive association was consistently observed in severe VV both before (HR: 1.19, 95% CI [1.09–1.28], P =0.002) and after PSM (HR: 1.20, 95% CI [1.10–1.30], P =0.003) and mild VV also before (HR: 1.10, 95% CI [1.04–1.16], P =0.003) and after PSM (HR: 1.13, 95% CI [1.03–1.–20], P &lt;0.001). Conclusions: These findings suggest that VV may be associated with an increased risk of AF. Hence, the presence of VV should be considered as an association factor for AF occurrence.
miR‐106b‐5p protects against drug‐induced liver injury by targeting vimentin to stimulate liver regeneration
Authors: Xiaoyan Lu, Lingqi Yu, Jie Zheng, Anyao Li, Junying Li, He Lou, Wentao Zhang, Hui Guo, Yuzhen Wang, Xuemei Li, Yue Gao, Xiaohui Fan, Jürgen Borlak
Journal: MedComm (2024)

Understanding the endogenous mechanism of adaptive response to drug-induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin-induced liver injury (TILI) of mice. Exosomal miR-106b-5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR-106b-5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR-106b-5p protects mice from liver injury. Injured hepatocytes released miR-106b-5p-enriched exosomes taken up by surrounding hepatocytes.
Role of 3D transoesophageal echocardiography in the study of infective endocarditis. Demonstration in a case collection
Authors: Roberto Baltodano-Arellano, Daniel Huaman-Carrasco, Kelly Cupe-Chacalcaje, Angela Cachicatari-Beltran, Lindsay Benites-Yshpilco, Dante Urdanivia-Ruiz, Eliana Rafael-Horna, Luis Falcón-Quispe, Alessio Demarini-Orellana, Kevin Velarde-Acosta, Xochitl Ortiz-Leon, Gerald Levano-Pachas
Journal:  (2024)

Abstract Infective endocarditis (IE) is a condition that predominantly affects native or prosthetic heart valves, which is currently on the rise due to the increase in invasive cardiology procedures, such as the utilization of cardiac implantable electronic devices and transcatheter interventions. The recommended imaging tests for diagnosis are 2D transthoracic echocardiography (2D TTE) and 2D transoesophageal echocardiography (2D TOE). However, these modalities present limitations in detecting vegetations and estimating their dimensions. These disadvantages can be overcome by 3D transoesophageal echocardiography (3D TOE), particularly with the multiplanar reconstruction tool, which allows for the visualization of infinite valve planes, thus optimizing the detection of lesions and precise measurements. Furthermore, the volume rendering provides insight into the anatomical relationships between lesions, which is particularly useful for surgical planning. In this review, we aim to discuss the role of this recent imaging modality in the diagnosis, prognosis, and therapeutic of IE. Finally, we present a collection of images that illustrate the use of 3D TOE tools.
Diabetes Overtreatment and Hypoglycemia in Older Patients With Type 2 Diabetes on Insulin Therapy: Insights From the HYPOAGE Cohort Study
Authors: Antoine Christiaens, Anne-Sophie Boureau, Béatrice Guyomarch, Laure de Decker, Benoit Boland, Samy Hadjadj, Bertrand Cariou, Bertrand Cariou, Samy Hadjadj, Pierre Morcel, Matthieu Wargny, Béatrice Guyomarch, Anne-Sophie Boureau, Guillaume Chapelet, Laure de Decker, Cédric Anweiller, Ingrid Allix, Claire Briet, Pierre Gourdy, Sophie Guyonnet, Marc Paccalin, Pierre-Jean Saulnier, Isabelle Delabrière, Rachel Litke, Nathalie Cervantes, Alfred Penfornis
Journal: Diabetes Care (2024)

OBJECTIVE To assess the accuracy of “diabetes overtreatment” proxy definitions in predicting hypoglycemia in older adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Inclusion of patients from HYPOAGE cohort with insulin-treated T2D, aged ≥75 years, and using a continuous glycemic monitoring (CGM) device for 28 days. “Diabetes overtreatment” was defined as HbA1c &amp;lt;7.0% (fixed proxy definition) or as HbA1c &amp;lt;7.0%, 7.5%, and 8.0% according to patient’s health status (individualized proxy definition). The primary outcome was time below range (TBR) ≥1%. RESULTS Of the 134 patients included (81.6 ± 5.4 years, 59% male), 25 (19%) and 53 (40%) were overtreated, based on fixed and individualized proxy definitions, respectively. CGM data showed TBR &amp;gt;1% in nearly all patients regardless of overtreatment status. Both proxy definitions had low sensitivity (20% [14; 29] and 41% [32; 50]) and accuracy (27% [20; 35] and 44% [35; 53]) in predicting hypoglycemia. CONCLUSIONS A revised definition of diabetes overtreatment is needed to better manage older insulin-treated patients and protect them from hypoglycemia.
Rewards and dangers of regulatory innovation
Authors: Luca Comai
Journal: Trends in Genetics (2024)

Adaptive evolution often involves structural variation affecting genes or cis-regulatory changes that engender novel and favorable gain-of-function gene regulation. Such mutation could result in a favorable dominant trait. At the same time, the gene product could be dosage sensitive if its change in concentration disrupts another trait. As a result, the mutant allele would display dosage-sensitive pleiotropy (DSP). By minimizing imbalance while conserving the favorable dominant effect, heterozygosity can increase fitness and result in heterosis. The properties of these alleles are consistent with evidence from multiple studies that indicate increased fitness of heterozygous regulatory mutations. DSP can help explain mysterious properties of heterosis as well as other effects of hybridization.
A narrative review of lifestyle management guidelines for metabolic dysfunction-associated steatotic liver disease
Authors: Dana Ivancovsky Wajcman, Christopher J. Byrne, John F. Dillon, Paul N. Brennan, Marcela Villota-Rivas, Zobair M. Younossi, Alina M. Allen, Javier Crespo, Lynn H. Gerber, Jeffrey V. Lazarus
Journal: Hepatology (2024)

Metabolic dysfunction-associated steatotic liver disease (MASLD) management guidelines have been published worldwide; we aimed to summarize, categorize and compare their lifestyle intervention recommendations.
TALEN-edited Allogeneic Inducible Dual CAR T-cells Enable Effective Targeting of Solid Tumors while Mitigating Off-Tumor Toxicity
Authors: Sonal Dharani, Hana Cho, Jorge Postigo Fernandez, Alexandre Juillerat, Julien Valton, Philippe Duchateau, Laurent Poirot, Shipra Das
Journal: Molecular Therapy (2024)

Adoptive cell therapy using chimeric antigen receptor (CAR) T cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has been limited in solid tumors. One key factor for this is cancer-associated fibroblasts (CAFs) that modulate the tumor microenvironment (TME) to inhibit T cell infiltration and induce "T cell dysfunction." Additionally, the sparsity of tumor-specific antigens (TSA) and expression of CAR-directed tumor-associated antigens (TAA) on normal tissues often results in "on-target off-tumor" cytotoxicity, raising safety concerns. Using TALEN-mediated gene editing, we present here an innovative CAR T cell engineering strategy to overcome these challenges. Our allogeneic "Smart CAR T cells" are designed to express a constitutive CAR, targeting FAP+ CAFs in solid tumors. Additionally, a second CAR targeting a TAA such as mesothelin is specifically integrated at a TCR signaling-inducible locus like PDCD1. FAPCAR-mediated CAF targeting induces expression of the mesothelin CAR, establishing an IF/THEN-gated circuit sensitive to dual antigen sensing. Using this approach, we observe enhanced anti-tumor cytotoxicity, while limiting "on-target off-tumor" toxicity. Our study thus demonstrates TALEN-mediated gene editing capabilities for design of allogeneic IF/THEN-gated dual CAR T cells that efficiently target immunotherapy-recalcitrant solid tumors while mitigating potential safety risks, encouraging clinical development of this strategy.Graphical abstract
Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction
Authors: Rui Sun, Jun A, Haolan Yu, Yan Wang, Miaoxia He, Lingling Tan, Honghan Cheng, Jili Zhang, Yingrui Wang, Xiaochen Sun, Mengge Lyu, Min Qu, Lingling Huang, Zijian Li, Wenhui Zhang, Kunpeng Ma, Zhenyang Dong, Weigang Ge, Yun Zhang, Xuan Ding, Bo Yang, Jianguo Hou, Chuanliang Xu, Linhui Wang, Yi Zhu, Tiannan Guo, Xu Gao, Chenghua Yang
Journal: Cell Reports Medicine (2024)

Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.
Immune checkpoint inhibitors for patients with mismatch-repair deficient or microsatellite instability-high advanced cancers: a meta-analysis of phase I-III clinical trials
Authors: Wei Wang, Zubing Mei, Yajie Chen, Jian Jiang, Yanli Qu, Keyoumu Saifuding, Ning Zhou, Gilisihan Bulibu, Yong Tang, Xinyu Zhai, Zhi Jiang
Journal: International Journal of Surgery (2024)

Mismatch-repair deficient (dMMR) and microsatellite instability-high (MSI-H) cancers are associated with an increased number of somatic mutations, which can render tumors more susceptible to immune checkpoint blockade. However, a comprehensive evaluation of the efficacy profile of immune checkpoint inhibitors in this patient population across multiple cancer types is lacking. This study aims to address this knowledge gap by synthesizing data from Phase I-III clinical trials.
Distinct relapse pattern across molecular ependymoma types
Authors: Denise Obrecht-Sturm, Melanie Schoof, Alicia Eckhardt, Martin Mynarek, Mark R Gilbert, Kenneth Aldape, Terri S Armstrong, Vijay Ramaswamy, Michael Bockmayr, Katja von Hoff, Gudrun Fleischhack, Jonas E Adolph, Stephan Tippelt, Stefan M Pfister, Kristian Pajtler, Dominik Sturm, Richard Drexler, Franz L Ricklefs, Natalia Stepien, Johannes Gojo, Torsten Pietsch, Monika Warmuth-Metz, Rolf Kortmann, Beate Timmermann, Christine Haberler, Stefan Rutkowski, Ulrich Schüller
Journal: Neuro-Oncology (2024)

Abstract Background Ependymoma (EPN) is not a uniform disease but represents different disease types with biological and clinical heterogeneity. However, the pattern of when and where different types of EPN relapse is not yet comprehensively described. Methods We assembled 269 relapsed intracranial EPN from pediatric (n = 233) and adult (n = 36) patients from European and Northern American cohorts and correlated DNA methylation patterns and copy-number alterations with clinical information. Results The cohort comprised the following molecular EPN types: PF-EPN-A (n = 177), ST-EPN-ZFTA (n = 45), PF-EPN-B (n = 31), PF-EPN-SE (n = 12), and ST-EPN-YAP (n = 4). First relapses of PF-EPN-B (PF: posterior-fossa) and PF-EPN-SE (SE: subependymoma) occurred later than of PF-EPN-A, ST-EPN-YAP (ST: supratentorial), or ST-EPN-ZFTA (median time to relapse: 4.3 and 6.0 years vs. 1.9/1.0/2.4 years; P &amp;lt; .01). Metastatic or combined recurrences in PF-EPN-B and -A more often involved the spinal cord than in ST-EPN-ZFTA (72.7% and 40.0 vs. 12.5%; P &amp;lt; .01). No distant relapses were observed in ST-EPN-YAP (n = 4) or PF-EPN-SE (n = 12). Post-relapse survival (PRS) was poor for PF-EPN-A and ST-EPN-ZFTA (5-year PRS: 44.5% ± 4.4%/47.8% ± 9.1%), whereas PF-EPN-B and PF-EPN-SE displayed a 5-year PRS of 89.5% ± 7.1%/90.0% ± 9.5% (P = .03). However, 10-year PRS for PF-EPN-B dropped to 45.8% ± 17.3%. Neither between the radiation field and relapse pattern nor between the radiation field and spinal involvement at relapse an impact was identified. Notably, all patients with relapsed ST-EPN-YAP did not receive upfront radiotherapy but were successfully salvaged using irradiation at relapse. Conclusions Relapse patterns of specific EPN types are different. Future clinical trials, treatment adaptions, duration of surveillance, and diagnostics should be planned to incorporate entity-specific relapse information.
Management of chimeric antigen receptor T (CAR-T) cell-associated toxicities
Authors: Torsten Schroeder, Tjark Martens, Lars Fransecky, Thomas Valerius, Natalie Schub, Christiane Pott, Claudia Baldus, Friedrich Stölzel
Journal: Intensive Care Medicine (2024)

The use of chimeric antigen receptor T (CAR-T) cells is a significant therapeutic improvement increasing the prognosis for patients with a variety of hematological malignancies. However, this therapy has also sometimes life-threatening, complications. Therefore, knowledge of the treatment and management of these complications, especially in treatment centers and intensive care units, respectively, is of outstanding importance. This review provides recommendations for the diagnosis, management, and treatment of CAR-T cell-associated complications such as cytokine release syndrome, immune effector cell associated neurotoxicity syndrome, hematotoxicity, hypogammaglobulinemia, and CAR-T cell-induced pseudo-progression amongst others for physicians treating patients with CAR-T cell-associated complications and intensivists.
Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma
Authors: Giulia Grisendi, Massimiliano Dall’Ora, Giulia Casari, Giliola Spattini, Moein Farshchian, Aurora Melandri, Valentina Masciale, Fabio Lepore, Federico Banchelli, Riccardo Cuoghi Costantini, Angela D’Esposito, Chiara Chiavelli, Carlotta Spano, Andrea Spallanzani, Tiziana Petrachi, Elena Veronesi, Manuela Ferracin, Roberta Roncarati, Jonathan Vinet, Paolo Magistri, Barbara Catellani, Olivia Candini, Caterina Marra, Albino Eccher, Luca Reggiani Bonetti, Edwin M. Horwitz, Fabrizio Di Benedetto, Massimo Dominici
Journal: Cell Reports Medicine (2024)
Digital biomarkers for precision diagnosis and monitoring in Parkinson’s disease
Authors: Yue-meng Sun, Zhi-yun Wang, Yuan-yuan Liang, Chen-wei Hao, Chang-he Shi
Journal: npj Digital Medicine (2024)

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder with high prevalence among the elderly, primarily manifested by progressive decline in motor function. The aging global demographic and increased life expectancy have led to a rapid surge in PD cases, imposing a significant societal burden. PD along with other neurodegenerative diseases has garnered increasing attention from the scientific community. In PD, motor symptoms are recognized when approximately 60% of dopaminergic neurons have been damaged. The irreversible feature of PD and benefits of early intervention underscore the importance of disease onset prediction and prompt diagnosis. The advent of digital health technology in recent years has elevated the role of digital biomarkers in precisely and sensitively detecting early PD clinical symptoms, evaluating treatment effectiveness, and guiding clinical medication, focusing especially on motor function, responsiveness and sleep quality assessments. This review examines prevalent digital biomarkers for PD and highlights the latest advancements.
A pan-cancer screen identifies drug combination benefit in cancer cell lines at the individual and population level
Authors: Daniel J Vis, Patricia Jaaks, Nanne Aben, Elizabeth A Coker, Syd Barthorpe, Alexandra Beck, Caitlin Hall, James Hall, Howard Lightfoot, Ermira Lleshi, Tatiana Mironenko, Laura Richardson, Charlotte Tolley, Mathew J Garnett, Lodewyk F A Wessels
Journal: Cell Reports Medicine (2024)

Combining drugs can enhance their clinical efficacy, but the number of possible combinations and inter-tumor heterogeneity make identifying effective combinations challenging, while existing approaches often overlook clinically relevant activity. We screen one of the largest cell line panels (N = 757) with 51 clinically relevant combinations and identify responses at the level of individual cell lines and tissue populations. We establish three response classes to model cellular effects beyond monotherapy: synergy, Bliss additivity, and independent drug action (IDA). Synergy is rare (11% of responses) and frequently efficacious (>50% viability reduction), whereas Bliss and IDA are more frequent but less frequently efficacious. We introduce "efficacious combination benefit" (ECB) to describe high-efficacy responses classified as either synergy, Bliss, or IDA. We identify ECB biomarkers in vitro and show that ECB predicts response in patient-derived xenografts better than synergy alone. Our work here provides a valuable resource and framework for preclinical evaluation and the development of combination treatments.
Targeting miR-29 mitigates skeletal senescence and bolsters therapeutic potential of mesenchymal stromal cells
Authors: Zhen Ding, Guixing Ma, Bo Zhou, Siyuan Cheng, Wanze Tang, Yingying Han, Litong Chen, Wei Pang, Yangshan Chen, Dazhi Yang, Huiling Cao
Journal: Cell Reports Medicine (2024)
Uncovering molecular mechanisms for amelanotic/hypopigmented primary cutaneous melanoma
Authors: Richard A Sturm, Darren J Smit, David L Duffy, Catriona McLean, Richard A Scolyer, Grant A McArthur, Anthony T Papenfuss, Mitchell S Stark, H Peter Soyer, Victoria J Mar
Journal: British Journal of Dermatology (2024)

A portion of approximately 2-20% of cutaneous melanoma (CM) are diagnosed as amelanotic/hypopigmented melanoma (AHM) and represent a challenge for early diagnosis.
Camu-camu decreases hepatic steatosis and liver injury markers in overweight, hypertriglyceridemic individuals: A randomized crossover trial
Authors: Anne-Laure Agrinier, Arianne Morissette, Laurence Daoust, Théo Gignac, Julie Marois, Thibault V Varin, Geneviève Pilon, Éric Larose, Claudia Gagnon, Yves Desjardins, Fernando F Anhê, Anne-Marie Carreau, Marie-Claude Vohl, André Marette
Journal: Cell Reports Medicine (2024)
Machine learning-based analysis identifies and validates serum exosomal proteomic signatures for the diagnosis of colorectal cancer
Authors: Haofan Yin, Jinye Xie, Shan Xing, Xiaofang Lu, Yu Yu, Yong Ren, Jian Tao, Guirong He, Lijun Zhang, Xiaopeng Yuan, Zheng Yang, Zhijian Huang
Journal: Cell Reports Medicine (2024)
Forgetting unwanted memories in sleep
Authors: Scott A. Cairney, Aidan J. Horner
Journal: Trends in Cognitive Sciences (2024)

Memories are sometimes best forgotten, but how do our brains weaken unwanted details of the past? We propose a theoretical framework in which memory reactivation during sleep supports adaptive forgetting. This mnemonic rebalancing underpins the affective benefits of sleep by ensuring that our memories remain aligned with our emotional goals.