tbuckley/cabot-search huggingface dataset:
Low-Dose Rivaroxaban Plus Aspirin in Fragile Patients After Lower Extremity Revascularization
Authors: Mario Enrico Canonico, Cecilia C Low Wang, Judith Hsia, E Sebastian Debus, Mark R Nehler, Manesh R Patel, Sonia S Anand, Joseph Ycas, Warren H Capell, Eva Muehlhofer, Lloyd P Haskell, Scott D Berkowitz, Rupert Bauersachs, Marc P Bonaca
Journal: Journal of the American College of Cardiology (2024)

Rivaroxaban 2.5 mg plus aspirin reduced limb and cardiovascular events and increased bleeding in patients with symptomatic peripheral artery disease (PAD) after lower extremity revascularization in the VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) study. Fragile patients are at heightened risk for ischemic and bleeding events.
Reply to Jan Hrudka, Petr Waldauf, and Radoslav Matěj’s Letter to the Editor re: Laura Elst, Gino Philips, Kaat Vandermaesen, et al. Single-cell Atlas of Penile Cancer Reveals TP53 Mutations as a Driver of an Aggressive Phenotype, Irrespective of Human Papillomavirus Status, and Provides Clues for Treatment Personalization. Eur Urol 2024;86:114–27
Authors: Laura Elst, Maarten Albersen
Journal: European Urology (2024)
Acetate enables metabolic fitness and cognitive performance during sleep disruption
Authors: Qinqin He, Liwei Ji, Yanyan Wang, Yarong Zhang, Haiyan Wang, Junyan Wang, Qing Zhu, Maodi Xie, Wei Ou, Jun Liu, Kuo Tang, Kening Lu, Qingmei Liu, Jian Zhou, Rui Zhao, Xintian Cai, Nanfang Li, Yang Cao, Tao Li
Journal: Cell Metabolism (2024)
Grounded in Reality: Integrating Community Values and Priorities of End Users in Human Gene Editing
Authors: Kirsten A. Riggan, Roel Feys, Assata Kokayi, Karen M. Meagher, Marsha Michie, Kiran Musunuru, Kelly E. Ormond, Andrea J. Schelhaas, Jane Q. Yap, Rosario Isasi, Megan A. Allyse
Journal: The American Journal of Bioethics (2024)
Sarah Gaffen: I thrive on turning my vision for the lab into reality
Authors: Lucie Van Emmenis
Journal: The Journal of Experimental Medicine (2024)

Sarah Gaffen, PhD, is a professor of medicine and rheumatology and holds the Gerald P. Rodnan endowed chair at the University of Pittsburgh. Her lab explores the biological function of IL-17 and its receptor in the context of fungal host defense and autoimmunity. We spoke to Sarah about where her interest in cytokines began, the importance of saying no in your career, and her interest in paleogenetics.
Global characteristics and outcomes of autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma: A study of the worldwide network for blood and marrow transplantation (<scp>WBMT</scp>)
Authors: Laurent Garderet, Luuk Gras, Linda Koster, Laurien Baaij, Nada Hamad, Anita Dsouza, Noel Estrada‐Merly, Parameswaran Hari, Wael Saber, Andrew J. Cowan, Minako Iida, Shinichiro Okamoto, Hiroyuki Takamatsu, Shohei Mizuno, Koji Kawamura, Yoshihisa Kodera, Bor‐Sheng Ko, Christopher Liam, Kim Wah Ho, A. Sim Goh, S. Keat Tan, Alaa M. Elhaddad, Ali Bazarbachi, Qamar un Nisa Chaudhry, Rozan Alfar, Mohamed‐Amine Bekadja, Malek Benakli, Cristobal Augusto Frutos Ortiz, Eloisa Riva, Sebastian Galeano, Francisca Bass, Hira S. Mian, Arleigh McCurdy, Feng Rong Wang, Ly Meng, Daniel Neumann, Mickey Koh, John A. Snowden, Stefan Schönland, Donal P. McLornan, Patrick John Hayden, Anna Sureda, Hildegard T. Greinix, Mahmoud Aljurf, Yoshiko Atsuta, Dietger Niederwieser
Journal: American Journal of Hematology (2024)

Autologous hematopoietic cell transplantation (AHCT) is a commonly used treatment in multiple myeloma (MM). However, real-world global demographic and outcome data are scarce. We collected data on baseline characteristics and outcomes from 61 725 patients with newly diagnosed MM who underwent upfront AHCT between 2013 and 2017 from nine national/international registries. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), relapse incidence (RI) and non-relapse mortality (NRM). Median OS amounted to 90.2 months (95% CI 88.2-93.6) and median PFS 36.5 months (95% CI 36.1-37.0). At 24 months, cumulative RI was 33% (95% CI 32.5%-33.4%) and NRM was 2.5% (95% CI 2.3%-2.6%). In the multivariate analysis, superior outcomes were associated with younger age, IgG subtype, complete hematological response at auto-HCT, Karnofsky score of 100%, international staging scoring (ISS) stage 1, HCT-comorbidity index (CI) 0, standard cytogenetic risk, auto-HCT in recent years, and use of lenalidomide maintenance. There were differences in the baseline characteristics and outcomes between registries. While the NRM was 1%-3% at 12 months worldwide, the OS at 36 months was 69%-84%, RI at 12 months was 12%-24% and PFS at 36 months was 43%-63%. The variability in these outcomes is attributable to differences in patient and disease characteristics as well as the use of maintenance and macroeconomic factors. In conclusion, worldwide data indicate that AHCT in MM is a safe and effective therapy with an NRM of 1%-3% with considerable regional differences in OS, PFS, RI, and patient characteristics. Maintenance treatment post-AHCT had a beneficial effect on OS.
GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management
Authors: Jens Juul Holst
Journal: Nature Metabolism (2024)

The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15-25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules. I will classify these agents as GLP-1-based therapies in the understanding that these compounds or combinations may have actions on other receptors as well. The physiology of GLP-1 is discussed as well as its mechanisms of actions in obesity, in particular, the role of sensory afferents and GLP-1 receptors in the brain. I provide details regarding the development of GLP-1 receptor agonists for anti-obesity therapy and discuss the possible mechanism behind their beneficial effects on adverse cardiovascular events. Finally, I highlight new pharmacological developments, including oral agents, and discuss important questions regarding maintenance therapy.
GTRpmix: A linked general-time reversible model for profile mixture models
Authors: Hector Banos, Thomas K F Wong, Justin Daneau, Edward Susko, Bui Quang Minh, Robert Lanfear, Matthew W Brown, Laura Eme, Andrew J Roger
Journal: Molecular Biology and Evolution (2024)

Abstract Profile mixture models capture distinct biochemical constraints on the amino acid substitution process at different sites in proteins. These models feature a mixture of time-reversible models with a common matrix of exchangeabilities and distinct sets of equilibrium amino acid frequencies known as profiles. Combining the exchangeability matrix with each profile generates the matrix of instantaneous rates of amino acid exchange for that profile. Currently, empirically estimated exchangeability matrices (e.g. the LG matrix) are widely used for phylogenetic inference under profile mixture models. However, these were estimated using a single profile and are unlikely optimal for profile mixture models. Here, we describe the GTRpmix model that allows maximum likelihood estimation of a common exchangeability matrix under any profile mixture model. We show that exchangeability matrices estimated under profile mixture models differ from the LG matrix, dramatically improving model fit and topological estimation accuracy for empirical test cases. Because the GTRpmix model is computationally expensive, we provide two exchangeability matrices estimated from large concatenated phylogenomic-supermatrices to be used for phylogenetic analyses. One, called Eukaryotic Linked Mixture (ELM), is designed for phylogenetic analysis of proteins encoded by nuclear genomes of eukaryotes, and the other, Eukaryotic and Archaeal Linked mixture (EAL), for reconstructing relationships between eukaryotes and Archaea. These matrices, combined with profile mixture models, fit data better and have improved topology estimation relative to the LG matrix combined with the same mixture models. Starting with version 2.3.1, IQ-TREE2 allows users to estimate linked exchangeabilities (i.e. amino acid exchange rates) under profile mixture models.
Identification of tumor rejection antigens and the immunologic landscape of medulloblastoma
Authors: Changlin Yang, Vrunda Trivedi, Kyle Dyson, Tongjun Gu, Kate M. Candelario, Oleg Yegorov, Duane A. Mitchell
Journal: Genome Medicine (2024)

The current standard of care treatments for medulloblastoma are insufficient as these do not take tumor heterogeneity into account. Newer, safer, patient-specific treatment approaches are required to treat high-risk medulloblastoma patients who are not cured by the standard therapies. Immunotherapy is a promising treatment modality that could be key to improving survival and avoiding morbidity. For an effective immune response, appropriate tumor antigens must be targeted. While medulloblastoma patients with subgroup-specific genetic substitutions have been previously reported, the immunogenicity of these genetic alterations remains unknown. The aim of this study is to identify potential tumor rejection antigens for the development of antigen-directed cellular therapies for medulloblastoma.
Cancer tissue of origin constrains the growth and metabolism of metastases
Authors: Sharanya Sivanand, Yetis Gultekin, Peter S. Winter, Sidney Y. Vermeulen, Konstantine M. Tchourine, Keene L. Abbott, Laura V. Danai, Florian Gourgue, Brian T. Do, Kayla Crowder, Tenzin Kunchok, Allison N. Lau, Alicia M. Darnell, Alexandria Jefferson, Satoru Morita, Dan G. Duda, Andrew J. Aguirre, Brian M. Wolpin, Nicole Henning, Virginia Spanoudaki, Laura Maiorino, Darrell J. Irvine, Omer H. Yilmaz, Caroline A. Lewis, Dennis Vitkup, Alex K. Shalek, Matthew G. Vander Heiden
Journal: Nature Metabolism (2024)
Trajectory of brain-derived amyloid beta in Alzheimer’s disease: where is it coming from and where is it going?
Authors: Ni Liu, Anaer Haziyihan, Wei Zhao, Yu Chen, Hongbo Chao
Journal: Translational Neurodegeneration (2024)

Alzheimer's disease (AD) is a progressive neurological disorder that primarily impacts cognitive function. Currently there are no disease-modifying treatments to stop or slow its progression. Recent studies have found that several peripheral and systemic abnormalities are associated with AD, and our understanding of how these alterations contribute to AD is becoming more apparent. In this review, we focuse on amyloid‑beta (Aβ), a major hallmark of AD, summarizing recent findings on the source of brain-derived Aβ and discussing where and how the brain-derived Aβ is cleared in vivo. Based on these findings, we propose future strategies for AD prevention and treatment, from a novel perspective on Aβ metabolism.
Melon: metagenomic long-read-based taxonomic identification and quantification using marker genes
Authors: Xi Chen, Xiaole Yin, Xianghui Shi, Weifu Yan, Yu Yang, Lei Liu, Tong Zhang
Journal: Genome biology (2024)

Long-read sequencing holds great potential for characterizing complex microbial communities, yet taxonomic profiling tools designed specifically for long reads remain lacking. We introduce Melon, a novel marker-based taxonomic profiler that capitalizes on the unique attributes of long reads. Melon employs a two-stage classification scheme to reduce computational time and is equipped with an expectation-maximization-based post-correction module to handle ambiguous reads. Melon achieves superior performance compared to existing tools in both mock and simulated samples. Using wastewater metagenomic samples, we demonstrate the applicability of Melon by showing it provides reliable estimates of overall genome copies, and species-level taxonomic profiles.
Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity
Authors: Judith Lind, Osman Aksoy, Michaela Prchal-Murphy, Fengjuan Fan, Mariateresa Fulciniti, Dagmar Stoiber, Latifa Bakiri, Erwin F. Wagner, Elisabeth Zwickl-Traxler, Martin Sattler, Karoline Kollmann, Sonia Vallet, Klaus Podar
Journal: Blood Cancer Journal (2024)

Deregulation of transcription factors (TFs) leading to uncontrolled proliferation of tumor cells within the microenvironment represents a hallmark of cancer. However, the biological and clinical impact of transcriptional interference, particularly in multiple myeloma (MM) cells, remains poorly understood. The present study shows for the first time that MYC and JUNB, two crucial TFs implicated in MM pathogenesis, orchestrate distinct transcriptional programs. Specifically, our data revealed that expression levels of MYC, JUNB, and their respective downstream targets do not correlate and that their global chromatin-binding patterns are not significantly overlapping. Mechanistically, MYC expression was not affected by JUNB knockdown, and conversely, JUNB expression and transcriptional activity were not affected by MYC knockdown. Moreover, suppression of MYC levels in MM cells via targeting the master regulator BRD4 by either siRNA-mediated knockdown or treatment with the novel proteolysis targeting chimera (PROTAC) MZ-1 overcame bone marrow (BM) stroma cell/IL-6-induced MYC- but not MEK-dependent JUNB-upregulation and transcriptional activity. Consequently, targeting of the two non-overlapping MYC- and JUNB-transcriptoms by MZ-1 in combination with genetic or pharmacological JUNB-targeting approaches synergistically enhanced MM cell death, both in 2D and our novel dynamic 3D models of the BM milieu as well as in murine xenografts. In summary, our data emphasize the opportunity to employ MYC and JUNB dual-targeting treatment strategies in MM as another exciting approach to further improve patient outcomes.
Daratumumab in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: DELPHINUS Study
Authors: Teena Bhatla, Laura Hogan, David Trent Teachey, Franciso Bautista, John P Moppett, Pablo Velasco, Concetta Micalizzi, Claudia Rossig, Neerav Narendra Shukla, Gil Gilad, Franco Locatelli, André BARUCHEL, Michel Zwaan, Natalie S. Bezler, Alba Rubio-San-Simón, David Taussig, Elizabeth A. Raetz, Zhengwei J Mao, Brent Wood, Diana Alvarez Arias, Maria Krevvata, Ivo Nnane, Nibedita Bandyopadhyay, Lorena Lopez Solano, Robyn M. Dennis, Robin Carson, Ajay Vora
Journal: Blood (2024)

Abstract Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) have poor outcomes compared with newly diagnosed, treatment-naïve patients. The phase 2, open-label DELPHINUS study evaluated daratumumab (16 mg/kg IV) plus backbone chemotherapy in children with relapsed/refractory B-cell ALL (n = 7) after ≥2 relapses, and children and young adults with T-cell ALL (children, n = 24; young adults, n = 5) or LL (n = 10) after first relapse. The primary end point was complete response (CR) in the B-cell ALL (end of cycle 2) and T-cell ALL (end of cycle 1) cohorts, after which patients could proceed off study to allogeneic hematopoietic stem cell transplant (HSCT). Seven patients with advanced B-cell ALL received daratumumab with no CRs achieved; this cohort was closed because of futility. For the childhood T-cell ALL, young adult T-cell ALL, and T-cell LL cohorts, the CR (end of cycle 1) rates were 41.7%, 60.0%, and 30.0%, respectively; overall response rates (any time point) were 83.3% (CR + CR with incomplete count recovery [CRi]), 80.0% (CR + CRi), and 50.0% (CR + partial response), respectively; minimal residual disease negativity (&amp;lt;0.01%) rates were 45.8%, 20.0%, and 50.0%, respectively; observed 24-month event-free survival rates were 36.1%, 20.0%, and 20.0%, respectively; observed 24-month overall survival rates were 41.3%, 25.0%, and 20.0%, respectively; and allogeneic HSCT rates were 75.0%, 60.0%, and 30.0%, respectively. No new safety concerns with daratumumab were observed. In conclusion, daratumumab was safely combined with backbone chemotherapy in children and young adults with T-cell ALL/LL and contributed to successful bridging to HSCT. This trial was registered at www.clinicaltrials.gov as NCT03384654.
“It’s all about setting the stage.” The nurse facilitator trial: perceived outcomes and implementation issues. A qualitative study among ICU clinicians and nurse facilitators
Authors: Anne Renet, Elie Azoulay, Jean Reignier, Alain Cariou, Anne Renault, Olivier Huet, Frédéric Pochard, Ruth A. Engelberg, Nancy Kentish-Barnes
Journal: Intensive Care Medicine (2024)
Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype
Authors: Louise A Tilley, Vanja Karamatic Crew, Tosti J Mankelow, Samah A AlSubhi, Benjamin Jones, Abigail Borowski, Vered Yahalom, Lilach Finkel, Belinda K Singleton, Piers J Walser, Ashley Mark Toye, Timothy J Satchwell, Nicole M Thornton
Journal: Blood (2024)
Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia
Authors: Xinyue Zhou, Lixia Zhang, Sajesan Aryal, Virginia Veasey, Amanda Tajik, Cecilia Restelli, Steven Moreira, Pengcheng Zhang, Yanfeng Zhang, Kristin J. Hope, Yang Zhou, Changde Cheng, Ravi Bhatia, Rui Lu
Journal: Blood (2024)

Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function.
Multimodal profiling of biostabilized human skin modules reveals a coordinated ecosystem response to injected <scp>mRNA</scp>‐1273 <scp>COVID</scp>‐19 vaccine
Authors: Manon Scholaert, Mathias Peries, Emilie Braun, Jeremy Martin, Nadine Serhan, Alexia Loste, Audrey Bruner, Lilian Basso, Benoît Chaput, Eric Merle, Pascal Descargues, Emeline Pagès, Nicolas Gaudenzio
Journal: Allergy (2024)

Abstract Background The field of drug development is witnessing a remarkable surge in the development of innovative strategies. There is a need to develop technological platforms capable of generating human data prior to progressing to clinical trials. Methods Here we introduce a new flexible solution designed for the comprehensive monitoring of the natural human skin ecosystem's response to immunogenic drugs over time. Based on unique bioengineering to preserve surgical resections in a long survival state, it allows for the first time a comprehensive analysis of resident immune cells response at both organ and single‐cell levels. Results Upon injection of the mRNA‐1273 COVID‐19 vaccine, we characterized precise sequential molecular events triggered upon detection of the exogenous substance. The vaccine consistently targets DC/macrophages and mast cells, regardless of the administration route, while promoting specific cell–cell communications in surrounding immune cell subsets. Conclusion Given its direct translational relevance, this approach provides a multiscale vision of genuine human tissue immunity that could pave the way toward the development of new vaccination and drug development strategies.
SIRPα engagement regulates ILC2 effector function and alleviates airway hyperreactivity via modulating energy metabolism
Authors: Yoshihiro Sakano, Kei Sakano, Benjamin P. Hurrell, Pedram Shafiei-Jahani, Mohammad Hossein Kazemi, Xin Li, Stephen Shen, Richard Barbers, Omid Akbari
Journal: Cellular and Molecular Immunology (2024)

Abstract Group-2 innate lymphoid cells (ILC2) are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma. The activation and function of ILC2s are regulated by various activating and inhibitory molecules, with their balance determining the severity of allergic responses. In this study, we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha (SIRPα), which interacts with CD47, in controlling ILC2-mediated airway hyperreactivity (AHR). Our data indicate that activated ILC2s upregulate the expression of SIRPα, and the interaction between SIRPα and CD47 effectively suppresses both ILC2 proliferation and effector function. To evaluate the function of SIRPα in ILC2-mediated AHR, we combined multiple approaches including genetically modified mouse models and adoptive transfer experiments in murine models of allergen-induced AHR. Our findings suggest that the absence of SIRPα leads to the overactivation of ILC2s. Conversely, engagement of SIRPα with CD47 reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR. Furthermore, the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways, thereby regulating NF-κB activity and the production of type 2 cytokines. Additionally, our studies have revealed that SIRPα is inducible and expressed on human ILC2s, and administration of human CD47-Fc effectively suppresses the effector function and cytokine production. Moreover, administering human CD47-Fc to humanized ILC2 mice effectively alleviates AHR and lung inflammation. These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.