tbuckley/cabot-search huggingface dataset:
MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor-positive HER2-negative breast cancer
Authors: Yuwen Cai, Cui-cui Liu, Yanwu Zhang, Yiming Liu, Lie Chen, Xin Xiong, Zhiming Shao, Ke-Da Yu
Journal: Journal of Clinical Investigation (2024)

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common type of breast cancer, is facing challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of HR+/HER2- breast cancer patients (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to MAP3K1 mutation and we validated experimentally that MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2- breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as a novel therapeutic strategy to enhance the efficacy of immunotherapy.
Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice
Authors: Wenli Liu, Brian D. Hardaway, Eunyoung Kim, Jessica Pauli, Justus Leonard Wettich, Mustafa Yalcinkaya, Cheng-Chieh Hsu, Tong Xiao, Muredach P. Reilly, Ira Tabas, Lars Maegdefessel, Kai Schlepckow, Haass Christian, Nan Wang, Alan R. Tall
Journal: Journal of Clinical Investigation (2024)

Clonal hematopoiesis (CH) increases inflammasome-linked atherosclerosis but the mechanisms by which CH mutant cells transmit inflammatory signals to non-mutant cells are largely unknown. To address this question we transplanted 1.5% Jak2VF bone marrow (BM) cells with 98.5% WT BM cells into hyperlipidemic Ldlr-/- mice. Low allele burden (LAB) mice showed accelerated atherosclerosis with increased features of plaque instability, decreased levels of macrophage phagocytic receptors MERTK and TREM2, and increased neutrophil extracellular traps (NETs). These changes were reversed when Jak2VF BM was transplanted with Il1r1-/- BM. LAB mice with non-cleavable MERTK in WT BM showed improvements in necrotic core and fibrous cap formation and reduced NETs. An agonistic TREM2 antibody (4D9) markedly increased fibrous caps in both control and LAB mice eliminating the difference between groups. Mechanistically, 4D9 increased TREM2+PDGFB+ macrophages and PDGF receptor-α positive fibroblast-like cells in the cap region. TREM2 and PDGFB mRNA levels were positively correlated in human carotid plaques and co-expressed in macrophages. In summary, low frequency Jak2VF mutations promote atherosclerosis via IL-1 signaling from Jak2VF to WT macrophages and neutrophils promoting cleavage of phagocytic receptors and features of plaque instability. Therapeutic approaches that stabilize MERTK or TREM2 could promote plaque stabilization especially in CH- and inflammasome-driven atherosclerosis.
In utero human cytomegalovirus infection expands NK-like FcγRIII+ CD8+ T cells that mediate Fc antibody functions
Authors: Eleanor C. Semmes, Danielle R. Nettere, Ashley N. Nelson, Jillian H. Hurst, Derek W. Cain, Trevor D. Burt, Joanne Kurtzberg, R. Keith Reeves, Carolyn B. Coyne, Genevieve G. Fouda, Justin Pollara, Sallie R. Permar, Kyle M. Walsh
Journal: Journal of Clinical Investigation (2024)

Human cytomegalovirus (HCMV) profoundly impacts host T and natural killer (NK) cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells following HCMV exposure in utero. Most FcγRIII+ CD8+ T cells express the canonical αβ T cell receptor (TCR) but a proportion express non-canonical γδ TCR. FcγRIII+ CD8+ T cells are highly differentiated and have increased expression of NK cell markers and cytolytic molecules. Transcriptional analysis reveals FcγRIII+ CD8+ T cells upregulate T-bet and downregulate BCL11B, known transcription factors that govern T/NK cell fate. We show that FcγRIII+ CD8+ T cells mediate antibody-dependent IFNγ production and degranulation against IgG-opsonized target cells, similar to NK cell antibody-dependent cellular cytotoxicity (ADCC). FcγRIII+ CD8+ T cell Fc effector functions were further enhanced by interleukin-15 (IL-15), as has been observed in neonatal NK cells. Our study reveals that FcγRIII+ CD8+ T cells elicited in utero by HCMV infection can execute Fc-mediated effector functions bridging cellular and humoral immunity and may be a promising target for antibody-based therapeutics and vaccination in early life.
State of the Science of Structural Stigma and LGBTQ+ Health: Meta-Analytic Evidence, Research Gaps, and Future Directions
Authors: Micah R. Lattanner, Sarah McKetta, John E. Pachankis, Mark L. Hatzenbuehler
Journal: Annual Review of Public Health (2024)

While public health practitioners and scholars have long theorized that structural forms of stigma shape the health of disadvantaged groups, they have frequently bemoaned the lack of research on this topic. A unique opportunity to address this lacuna occurred in the past two decades, with the advent of dramatic changes in laws, social attitudes, and other structural manifestations of stigma surrounding LGBTQ+ individuals. In a review of this literature, we conducted a meta-analysis of LGBTQ+ structural stigma and health, finding an effect size comparable to several other well-established macrolevel risk factors for poor health (e.g., income inequality, racial residential segregation, neighborhood socioeconomic status). In addition, we enumerated a range of established methodological strategies that studies have used to strengthen inferences; these strategies include documenting result specificity (i.e., structural stigma is unrelated to the health of cisgender heterosexuals), addressing alternative explanations (e.g., social selection), and triangulating evidence across multiple methods, measures, and health outcomes. We offer suggestions for future research to advance this rapidly expanding field, including identifying sources of unexplained heterogeneity in the structural stigma-health association. Finally, we discuss implications for other marginalized groups and for public health interventions and policies to reduce LGBTQ+ health disparities.
Stagnating Life Expectancy Among American Indians and Alaska Natives: Understanding the Drivers and Recommendations for Research, Policy, and Practice
Authors: Valarie Blue Bird Jernigan, Tara L. Maudrie, Susanna V. Lopez
Journal: Annual Review of Public Health (2024)

Life expectancy among American Indians and Alaska Natives (AI/ANs) has declined from 72 years in 2019 to 68 years in 2021. This current life expectancy for AI/ANs is equivalent to the overall life expectancy in the United States population in the 1940s. The significant and persistent nature of AI/AN health inequities, and the lack of clarity around what is driving them, requires urgent action. The purpose of this article is threefold. First, we provide a comprehensive conceptual framework of health that presents Indigenous perspectives of health and recognizes settler colonialism as a key structural determinant of the health of AI/ANs. Second, we underscore the importance of Tribal self-determination and sovereignty in public health research and practice and identify successful initiatives centering these efforts. Finally, we conclude with recommendations for future research, practice, and policy.
DGKH-mediated phosphatidic acid oncometabolism as a driver of self-renewal and therapy resistance in hepatocellular carcinoma
Authors: Jia Jian Loh, Kai Yu Ng, Ianto Bosheng Huang, Mingdan Deng, Yanyan Wang, Ki Fong Man, Ka Hei Lam, Terence Kin-Wah Lee, Jia Yan Tan, Yalu Cui, Huajian Yu, Tin Lok Wong, Yuan Gao, Jing-Ping Yun, Stephanie Ma
Journal: Hepatology (2024)

HCC is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence.
Primary Biliary Cholangitis: Personalizing Second-Line Therapies-R1
Authors: Cynthia Levy, Christopher L. Bowlus
Journal: Hepatology (2024)

Primary biliary cholangitis (PBC) is an enigmatic, autoimmune disease targeting the small intralobular bile ducts resulting in cholestasis and potentially progression to biliary cirrhosis. Primarily affecting middle-aged women, the diagnosis of PBC is typically straightforward, with most patients presenting with cholestatic liver tests and the highly specific antimitochondrial antibody. For decades, the foundational treatment of PBC has been ursodeoxycholic acid, which delays disease progression in most patients but has no impact on PBC symptoms. Large cohort studies of patients with PBC have established the benefit of maximizing the reduction in serum alkaline phosphatase levels with ursodeoxycholic acid and the need to add second-line agents in patients who do not achieve an adequate response. Advances in the understanding of bile acid physiology have led to the development of new agents that improve cholestasis in patients with PBC and are predicted to reduce the risk of disease progression. Obeticholic acid, the first second-line therapy to be approved for PBC, significantly improves liver biochemistries and has been associated with improved long-term clinical outcomes but is limited by its propensity to induce pruritus. Elafibranor and seladelpar are peroxisome proliferator-activated receptor agonists recently approved for use in patients with PBC, whereas bezafibrate and fenofibrate are available as off-label therapies. They also have shown biochemical improvements among patients with an inadequate response to ursodeoxycholic acid but may improve symptoms of pruritus. Herein, we review the patient features to consider when deciding whether a second-line agent is indicated and which agent to consider for a truly personalized approach to PBC patient care.
Cure as a treatment target in rheumatoid arthritis and systemic sclerosis—achievable aim or mission impossible? FOREUM stimulates new industry-academia collaboration
Authors: Kenneth Frank Baker, Julia Spierings, Martin Brom, Timothy Radstake, Emma Smith, Roberta Weiss, Gerd R. Burmester, Johannes WJ Bijlsma, Iain McInnes, Kenneth Baker, Rik Lories, Costantino Pitzalis, Jörg HW Distler, Gerd Burmester, Andrew P Cope, Oliver Distler, Julia Spierings, Anna Maria Hoffmann-Vold, Tim Radstake, Christian A Goess, Lauren Reinke-Breen, Bernard Lauwerys, Danielle M Gerlag, Emma Smith, Ruchi Singh, Roberta Weiss, Martin Hegen, Martin Brom, Stephen Oliver, Richard Vesely
Journal: Annals of the Rheumatic Diseases (2024)
Reply: Quality indicator and the safety profile of endoscopic inervention in patients with bleeding esophageal varices
Authors: Yu Jun Wong, Margaret Teng, Alyssa Sim, Juan G. Abraldes, Jason Chang
Journal: Hepatology (2024)

Wong, Yu Jun; Teng, Margaret; Sim, Alyssa; Abraldes, Juan G.; Chang, Jason; for the Singapore Acute Variceal Bleeding Study Group Collaborators THET, Htay Myat; TEOH, Xuhui; DE ROZA, Marianne Anastasia; Sen KEW, Guan; KOH, Jia Hong; LOI, Pooi Ling; LIM, Kai; KANG, Garrett; KUANG, Jonathan; LOW, En Xian Sarah; Jing Liang, HO; CHER, Liu Yuan Gabriel; SZE, Kenny; WONG, Guan Wee; KWEK, Boon Yew Andrew; YANG, Wei Lyn Author Information
Hematological traits in sodium-glucose cotransporter-2 efficacy: mediators or confounders ?
Authors: Yuanhao Wei, Lanlan Chen, Kun Zhao
Journal: Hepatology (2024)

1School of Public Health, Harbin Medical University, Harbin, China 2Department of Gastroenterology & Hepatology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin 3Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai, China Correspondence Kun Zhao, Shanghai Jiaotong University Affiliated Sixth People Hospital South Campus. No.6600. Nanfeng Highway, Fengxian District. Shanghai, 201499, China. Email: [email protected]
Reprogramming macrophages to treat liver diseases
Authors: Blanca Simón-Codina, Júlia Cacho-Pujol, Anna Moles, Pedro Melgar-Lesmes
Journal: Hepatology (2024)

Cutting-edge research has expanded our understanding of the macrophage activation programs in liver diseases making this immune cell type a therapeutic target. Clinical data on macrophage infiltration and polarization states have been used to help predict mortality or poor prognosis in patients with liver cirrhosis and/or HCC. The latest single-cell and spatial transcriptomics studies have dissected unforeseen aspects depicting the immense heterogeneity of macrophages and their multifaceted role in both promoting and resolving hepatic inflammation, injury, and fibrosis. Hepatic macrophages (resident tissue KCs and monocyte-derived macrophages) display such plasticity and phenotypic diversity that macrophages with antagonistic functions may coexist in adjacent regions of the liver. In this scenario, the analysis of macrophage-derived inflammatory and anti-inflammatory circulating soluble markers in patients with liver disease only offers a partial picture of the full complexity of the hepatic macrophage subsets. The reprogramming of macrophages involves understanding the multiple regulatory mechanisms and diverse populations of hepatic macrophages and the design of macrophage-targeted therapeutic interventions to restore hepatic homeostasis. Here we review the potential targets to modulate macrophage behavior in liver diseases and nanoscale therapeutics that aim to target and treat macrophages. We will summarize current knowledge on the diverse macrophage programs activated in chronic liver inflammation, cirrhosis, and HCC that may be of therapeutic interest for precision medicine.
Letter to editor: Use of HBV RNA and to predict change in serological status and disease activity in CHB
Authors: Yanfei Yang, Jiaqi Yao, Xu Luo, Guang Tan, Chi Ma
Journal: Hepatology (2024)

1Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, China 2Department of Anesthesiology, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, China Yanfei Yang, Jiaqi Yao, Xu Luo are contributed equally as co-first authors. Chi Ma and Guang Tan are contributed equally as co-corresponding authors. Correspondence Chi Ma, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, China. Email: [email protected] Correspondence Guang Tan, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, China. Email: [email protected] This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
The effects of a digital health intervention on patient activation in chronic kidney disease
Authors: Courtney J. Lightfoot, Thomas J. Wilkinson, Gurneet K. Sohansoha, Clare L. Gillies, Noemi Vadaszy, Ella C. Ford, Melanie J. Davies, Thomas Yates, Alice C. Smith, Matthew P. M. Graham-Brown, Kieran McCafferty, Thomas Phillips, Barbara Winter-Goodwin, Siva Sridharan, Timothy Doulton, Carlito Adan, Kate Bramham, Aimun Ahmed, Andrew Nixon, Chris Goldsmith, Matthew Howse, Sandip Mitra, Sumith Abeygunasekara, Gowrie Balasubramaniam, Georgia Winnett, Sohail Ahmed, Rosie Donne, Sarah Brand, Robert Lewis, Nicholas Sangala, Steve Dickinson, Maarten Taal, Coralie Bingham, Simon Curran, Joyce Popoola, Andrew Stein, Kristin Veighey, Annika Wallis, Paul Laboi, Vicky Robins
Journal: npj Digital Medicine (2024)

My Kidneys & Me (MK&M), a digital health intervention delivering specialist health and lifestyle education for people with CKD, was developed and its effects tested (SMILE-K trial, ISRCTN18314195, 18/12/2020). 420 adult patients with CKD stages 3-4 were recruited and randomised 2:1 to intervention (MK&M) (n = 280) or control (n = 140) groups. Outcomes, including Patient Activation Measure (PAM-13), were collected at baseline and 20 weeks. Complete case (CC) and per-protocol (PP) analyses were conducted. 210 (75%) participants used MK&M more than once. PAM-13 increased at 20 weeks compared to control (CC: +3.1 (95%CI: -0.2 to 6.4), P = 0.065; PP: +3.6 (95%CI: 0.2 to 7.0), P = 0.041). In those with low activation at baseline, significant between-group differences were observed (CC: +6.6 (95%CI: 1.3 to 11.9), P = 0.016; PP: +9.2 (95%CI: 4.0 to 14.6), P < 0.001) favouring MK&M group. MK&M improved patient activation in those who used the resource compared to standard care, although the overall effect was non-significant. The greatest benefits were seen in those with low activation.
Chlorhexidine-alcohol compared with povidone-iodine-alcohol skin antisepsis protocols in major cardiac surgery: a randomized clinical trial
Authors: Matthieu Boisson, Géraldine Allain, Jean-Christian Roussel, Nicolas d’Ostrevy, Silvia Burbassi, Pierre Demondion, Paul-Michel Mertes, François Labaste, Thomas Kerforne, Bertrand Rozec, Vedat Eljezi, Konstantinos Zannis, Pascal Leprince, Walid Oulehri, Vincent Minville, Sabrina Seguin, Ambre Loiodice, Stéphane Ruckly, Jean-Christophe Lucet, Jean-François Timsit, Olivier Mimoz
Journal: Intensive Care Medicine (2024)

Whether skin disinfection of the surgical site using chlorhexidine-alcohol is superior to povidone-iodine-alcohol in reducing reoperation and surgical site infection rates after major cardiac surgery remains unclear.
Optimizing CAR-T Treatment: A T2EVOLVE Guide to Raw and Starting Material Selection
Authors: Sergio Navarro, Carole Moukheiber, Susana Inogés Sancho, Marta Ruiz Guillén, Ascensión López-Díaz de Cerio, Carmen Sanges, Toshimitsu Tanaka, Sylvain Arnould, Javier Briones, Harry Dolstra, Michael Hudecek, Rashmi Choudhary, Inga Schapitz, Manel Juan, Nina Worel, Delphine Ammar, Maik Luu, Mirko Müller, Bernd Schroeder, Hélène Negre, Paul Franz
Journal: Molecular Therapy (2024)

Chimeric antigen receptor (CAR)-T cell products, classified as Advanced Therapy Medicinal Products (ATMPs), have shown promising outcomes in cancer immunotherapy. The quality of raw and starting materials used in manufacturing is critical to ensure the efficacy and safety of CAR-T cell products and depends primarily on the selection of the right materials and the right suppliers. It is essential to consider a long-term strategy when selecting raw and starting materials to prevent delays in the supply of innovative, high-quality, and safe therapies to patients. A thorough assessment will allow developers not only to select suppliers who comply with regulatory requirements but also to ensure a sustainable supply of materials throughout the development and the commercial phases. A careful selection of materials and suppliers can avoid the need of comparability studies due to changes in the supply of materials, impacting costs and causing significant delays in development and treatment readiness for patients. This work, coordinated by the T2EVOLVE IMI consortium, provides guidance for the selection and handling of raw and starting materials. By following these suggestions, developers can ensure that they use high quality raw and starting materials through the product development and life cycle, resulting in safe and effective CAR-T therapies for patients.
DSTYK Inhibition Sensitizes Non-Small Cell Lung Cancer To Taxane-Based Chemotherapy
Authors: Mirari Echepare, Beñat Picabea, Andrea Arricibita, Álvaro Teijeira, Andrea Pasquier, Carolina Zandueta, Nerea Otegui, Enrique Santamaría, Joaquín Fernández-Irigoyen, Octavio Romero, Montse Sanchez-Cespedes, Fernando Lecanda, Javier Hernández, Enriqueta Felip, Alberto Cruz-Bermúdez, Mariano Provencio, Marco Gentili, Federica Facchinetti, Luca Roz, Luis M Montuenga, Karmele Valencia
Journal: Journal of Thoracic Oncology (2024)
Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2
Authors: Lyudmila Bazhenova, Nofisat Ismaila, Fawzi Abu Rous, Krishna Alluri, Janet Freeman-Daily, Balazs Halmos, Narinder Malhotra, Kristen A. Marrone, Sonam Puri, Angel Qin, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2024)

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JCCG ALL-B12: Evaluation of Intensified Therapies With Vincristine/Dexamethasone Pulses and Asparaginase and Augmented High-Dose Methotrexate for Pediatric B-ALL
Authors: Motohiro Kato, Yasuhiro Okamoto, Toshihiko Imamura, Akiko Kada, Akiko M. Saito, Yuka Iijima-Yamashita, Takao Deguchi, Kentaro Ohki, Takashi Fukushima, Kenichi Anami, Masashi Sanada, Tomohiko Taki, Yoshiko Hashii, Takeshi Inukai, Nobutaka Kiyokawa, Yoshiyuki Kosaka, Nao Yoshida, Yuki Yuza, Masakatsu Yanagimachi, Kenichiro Watanabe, Atsushi Sato, Chihaya Imai, Takashi Taga, Souichi Adachi, Keizo Horibe, Atsushi Manabe, Katsuyoshi Koh
Journal: Journal of Clinical Oncology (2024)

The JCCG ALL-B12 clinical trial aimed to evaluate the effectiveness of unvalidated treatment phases for pediatric ALL and develop a safety-focused treatment framework.
Healthy and Unhealthy Aging and the Human Microbiome
Authors: Kseniya Y. Simbirtseva, Paul W. O'Toole
Journal: Annual Review of Medicine (2024)

An altered gut microbiome is a feature of many multifactorial diseases, and microbiome effects on host metabolism, immune function, and possibly neurological function are implicated. Increased biological age is accompanied by a change in the gut microbiome. However, age-related health loss does not occur uniformly across all subjects but rather depends on differential loss of gut commensals and gain of pathobionts. In this article, we summarize the known and possible effects of the gut microbiome on the hallmarks of aging and describe the most plausible mechanisms. Understanding and targeting these factors could lead to prolonging health span by rationally maintaining the gut microbiome.
Sleep Health Disparities
Authors: Seyni Gueye-Ndiaye, Susan Redline
Journal: Annual Review of Medicine (2024)

Sleep is an important and potentially modifiable determinant of many severe health outcomes. Sleep health disparities exist and are exemplified by reported differential rates of prevalence, severity, and outcomes among minority groups and low-socioeconomic-status backgrounds. In this review we highlight the concept of sleep health, review the evidence for disparities in sleep health, examine risk factors and consequences of poor sleep health, and discuss policy implications.
Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial
Authors: Yvonne M Mowery, Karla V Ballman, Angela M Hong, Scott M Schuetze, Andrew J Wagner, Varun Monga, Rachel S Heise, Steven Attia, Edwin Choy, Melissa A Burgess, Susie Bae, David I Pryor, Brian A Van Tine, Gabriel Tinoco, Bartosz Chmielowski, Carolyn Freeman, Alessandro Gronchi, Christian F Meyer, Mark A Dickson, Lee Hartner, Lara E Davis, Benjamin C Powers, Everett J Moding, Kent J Weinhold, Matt van de Rijn, Brian E Brigman, Richard F Riedel, David G Kirsch
Journal: The Lancet (2024)