tbuckley/cabot-search huggingface dataset:
Efficacy and safety of nerinetide in acute ischaemic stroke in patients undergoing endovascular thrombectomy without previous thrombolysis (ESCAPE-NEXT): a multicentre, double-blind, randomised controlled trial
Authors: Michael D Hill, Mayank Goyal, Andrew M Demchuk, Bijoy K Menon, Thalia S Field, William C Guest, Jorg Berrouschot, Albrecht Bormann, Mirko Pham, Karl G Haeusler, Diedrick W J Dippel, Pieter J van Doormaal, Franziska Dorn, Felix J Bode, Brian A van Adel, Demetrios J Sahlas, Richard H Swartz, Leodante Da Costa, Johanna M Ospel, Rosalie V McDonough, Karla J Ryckborst, Mohammed A Almekhlafi, Kathy J Heard, David J Garman, Corey Adams, Yatika Kohli, Bridget A Schoon, Brian H Buck, Mario Muto, Atif Zafar, Hauke Schneider, Jonathan A Grossberg, Leonard L L Yeo, Jason W Tarpley, Marios-Nikos Psychogios, Jonathan M Coutinho, Nicola Limbucci, Volker Puetz, Michael E Kelly, Bruce C V Campbell, Sven Poli, Alexandre Y Poppe, Jai J Shankar, Ronil Chandra, Dar Dowlatshahi, George A Lopez, Luigi Cirillo, Aimen Moussaddy, Michael Devlin, Pablo Garcia-Bermejo, Jennifer L Mandzia, Mona Skjelland, Anne Hege Aamodt, Frank L Silver, Timothy J Kleinig, Guglielmo Pero, Jens Minnerup, Ryan A McTaggart, Ajit S Puri, Albert H Y Chiu, Gernot Reimann, Gordon J Gubitz, Marie-Christine Camden, Seon Kyu Lee, Eric Sauvageau, Sibu Mundiyanapurath, Donald F Frei, Hana Choe, Marcello Rocha, Jan Gralla, Peter Bailey, Sebastian Fischer, Thomas Liebig, Konstantin Dimitriadis, Dheeraj Gandhi, René Chapot, Albert Jin, Ameer E Hassan, Wim van Zwam, Ilko L Maier, Martin Wiesmann, Wolf-Dirk Niesen, Rajiv Advani, Agnethe Eltoft, Negar Asdaghi, Cynthia Murphy, Luca Remonda, Darshan Ghia, Olav Jansen, Markus Holtmannspoetter, Victoria Hellstern, Karsten Witt, Annette Fromme, Shahid M Nimjee, David Turkel-Parella, Dominik Michalski, Christian Maegerlein, Carol Huilian Tham, Michael Tymianski
Journal: The Lancet (2025)
Depression and physical multimorbidity: A cohort study of physical health condition accrual in UK Biobank
Authors: Kelly J. Fleetwood, Bruce Guthrie, Caroline A. Jackson, Paul A. T. Kelly, Stewart W. Mercer, Daniel R. Morales, John D. Norrie, Daniel J. Smith, Cathie Sudlow, Regina Prigge
Journal: PLoS Medicine (2025)

Background Depression is associated with a range of adverse physical health outcomes. We aimed to quantify the association between depression and the subsequent rate of accrual of long-term physical health conditions in middle and older age. Methods and findings We included 172,556 participants from the UK Biobank (UKB) cohort study, aged 40–71 years old at baseline assessment (2006–2010), who had linked primary care data available. Using self-report, primary care, hospital admission, cancer registry, and death records, we ascertained 69 long-term physical health conditions at both UKB baseline assessment and during a mean follow-up of 6.9 years. We used quasi-Poisson models to estimate associations between history of depression at baseline and subsequent rate of physical condition accrual. Within our cohort, 30,770 (17.8%) had a history of depression. Compared to those without depression, participants with depression had more physical conditions at baseline (mean 2.9 [SD 2.3] versus 2.1 [SD 1.9]) and accrued additional physical conditions at a faster rate (mean 0.20 versus 0.16 additional conditions/year during follow-up). After adjustment for age and sex, participants with depression accrued physical morbidities at a faster rate than those without depression (RR 1.32, 95% confidence interval [CI] [1.31, 1.34]). After adjustment for all sociodemographic characteristics, the rate of condition accrual remained higher in those with versus without depression (RR 1.30, 95% CI [1.28, 1.32]). This association attenuated but remained statistically significant after additional adjustment for baseline condition count and social/lifestyle factors (RR 1.10, 95% CI [1.09, 1.12]). The main limitation of this study is healthy volunteer selection bias, which may limit generalisability of findings to the wider population. Conclusions Middle-aged and older adults with a history of depression have more long-term physical health conditions at baseline and accrue additional physical conditions at a faster rate than those without a history of depression. Our findings highlight the importance of integrated approaches to managing both mental and physical health outcomes.
Overdiagnosis of Lung Cancer due to Introduction of Low-Dose Computed Tomography in Average-Risk Populations in China
Authors: Dongchen Xie, Li Zhang, Na He, Chen Yang, Ruoxin Zhang, Haiquan Chen, Xing Liu, Chen Suo, Mengyan Wang, Yan Wei, Lipeng Hao, Wanghong Xu
Journal: Journal of Thoracic Oncology (2025)
Safety and efficacy of nerinetide in patients with acute ischaemic stroke enrolled in the early window: a post-hoc meta-analysis of individual patient data from three randomised trials
Authors: Michael Tymianski, Michael D Hill, Mayank Goyal, Jim Christenson, Bijoy K Menon, Richard H Swartz, Corey Adams, Kathy Heard, Yatika Kohli
Journal: The Lancet Neurology (2025)
Management of alcohol use disorder: a gastroenterology and hepatology-focused perspective
Authors: Luis Antonio Díaz, Daniel König, Sabine Weber, Gustavo Ayares, José Miguel Fuentealba, Valeria Vázquez, Ramon Bataller, Patrick S Kamath, Gerald Scott Winder, Lorenzo Leggio, Juan Pablo Arab
Journal: The Lancet. Gastroenterology & hepatology (2025)
Global guideline for the diagnosis and management of candidiasis: an initiative of the ECMM in cooperation with ISHAM and ASM
Authors: Oliver A Cornely, Rosanne Sprute, Matteo Bassetti, Sharon C-A Chen, Andreas H Groll, Oliver Kurzai, Cornelia Lass-Flörl, Luis Ostrosky-Zeichner, Riina Rautemaa-Richardson, Gunturu Revathi, Maria E Santolaya, P Lewis White, Ana Alastruey-Izquierdo, Maiken C Arendrup, John Baddley, Aleksandra Barac, Ronen Ben-Ami, Adrian J Brink, Jan H Grothe, Jesus Guinea, Ferry Hagen, Bruno Hochhegger, Martin Hoenigl, Shahid Husain, Kauser Jabeen, Henrik E Jensen, Souha S Kanj, Philipp Koehler, Thomas Lehrnbecher, Russell E Lewis, Jacques F Meis, M Hong Nguyen, Zoi D Pana, Peter-Michael Rath, Ilana Reinhold, Danila Seidel, Takahiro Takazono, Donald C Vinh, Sean X Zhang, Javier Afeltra, Abdullah M S Al-Hatmi, Amir Arastehfar, Sevtap Arikan-Akdagli, Felix Bongomin, Fabianne Carlesse, Methee Chayakulkeeree, Louis Y A Chai, Leili Chamani-Tabriz, Tom Chiller, Anuradha Chowdhary, Cornelius J Clancy, Arnaldo L Colombo, Andrea Cortegiani, Dora E Corzo Leon, Lubos Drgona, Anna Dudakova, Joveria Farooqi, Sara Gago, Macit Ilkit, Jeffrey D Jenks, Nikolai Klimko, Robert Krause, Anil Kumar, Katrien Lagrou, Michail S Lionakis, Badre E Lmimouni, Michael K Mansour, Joseph Meletiadis, Sibylle C Mellinghoff, Mervyn Mer, Malgorzata Mikulska, Philippe Montravers, Chin Fen Neoh, Volkan Ozenci, Livio Pagano, Peter Pappas, Thomas F Patterson, Pedro Puerta-Alcalde, Laman Rahimli, Sebastian Rahn, Emmanuel Roilides, Coleman Rotstein, Tamara Ruegamer, Raquel Sabino, Jon Salmanton-García, Ilan S Schwartz, Esther Segal, Neeraj Sidharthan, Tanu Singhal, Janos Sinko, Rajeev Soman, Andrej Spec, Joerg Steinmann, Jannik Stemler, Saad J Taj-Aldeen, Alida Fe Talento, George R Thompson, Christina Toebben, Hiram Villanueva-Lozano, Retno Wahyuningsih, Barbora Weinbergerová, Nathan Wiederhold, Birgit Willinger, Patrick C Y Woo, Li-Ping Zhu
Journal: The Lancet Infectious Diseases (2025)
Author Correction: Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial
Authors: Saad Z. Usmani, Thierry Facon, Vania Hungria, Nizar J. Bahlis, Christopher P. Venner, Marc Braunstein, Ludek Pour, Josep M. Martí, Supratik Basu, Yael C. Cohen, Morio Matsumoto, Kenshi Suzuki, Cyrille Hulin, Sebastian Grosicki, Wojciech Legiec, Meral Beksac, Angelo Maiolino, Hiroyuki Takamatsu, Aurore Perrot, Mehmet Turgut, Tahamtan Ahmadi, Weiping Liu, Jianping Wang, Katherine Chastain, Jessica Vermeulen, Maria Krevvata, Lorena Lopez-Masi, Jodi Carey, Melissa Rowe, Robin Carson, Sonja Zweegman
Journal: Nature Medicine (2025)
Overall survival and quality of life with [177Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): secondary outcomes from a multicentre, open-label, randomised, phase 2 trial
Authors: Louise Emmett, Shalini Subramaniam, Megan Crumbaker, Anthony M Joshua, Shahneen Sandhu, Andrew Nguyen, Andrew Weickhardt, Sze-Ting Lee, Siobhan Ng, Roslyn J Francis, Jeffrey C Goh, David A Pattison, Thean Hsiang Tan, Ian D Kirkwood, Craig Gedye, Natalie K Rutherford, Aravind S Ravi Kumar, David Pook, Shakher Ramdave, David P Nadebaum, Mark Voskoboynik, Andrew D Redfern, William Macdonald, Laurence Krieger, Geoff Schembri, Wei Chua, Peter Lin, Lisa Horvath, Patricia Bastick, Patrick Butler, Alison Yan Zhang, Margaret McJannett, Hayley Thomas, Ailsa Langford, Michael S Hofman, Andrew James Martin, Ian D Davis, Martin R Stockler
Journal: The Lancet Oncology (2025)
Exploring the role of dimensionality transformation in episodic memory
Authors: Casper Kerrén, Daniel Reznik, Christian F Doeller, Benjamin J Griffiths
Journal: Trends in Cognitive Sciences (2025)

Episodic memory must accomplish two adversarial goals: encoding and storing a multitude of experiences without exceeding the finite neuronal structure of the brain, and recalling memories in vivid detail. Dimensionality reduction and expansion ('dimensionality transformation') enable the brain to meet these demands. Reduction compresses sensory input into simplified, storable codes, while expansion reconstructs vivid details. Although these processes are essential to memory, their neural mechanisms for episodic memory remain unclear. Drawing on recent insights from cognitive psychology, systems neuroscience, and neuroanatomy, we propose two accounts of how dimensionality transformation occurs in the brain: structurally (via corticohippocampal pathways) and functionally (through neural oscillations). By examining cross-species evidence, we highlight neural mechanisms that may support episodic memory and identify crucial questions for future research.
A comprehensive scoping review of methodological approaches and clinical applications of tear fluid biomarkers.
Authors: Marlies Gijs, Nienke van de Sande, Clémence Bonnet, Jente Schmeetz, Rosa Fernandes, Sònia Travé-Huarte, Marcela Huertas-Bello, Jeremy Chung Bo Chiang, Nikolay Boychev, Shruti Sharma
Journal: Progress in Retinal and Eye Research (2025)
Predicting Dose-Response to Prostate Cancer Radiotherapy: Validation of a Radiation Signature in the Randomized Phase III NRG/RTOG 0126 and SAKK 09/10 Trials
Authors: A Dal Pra, P Ghadjar, H M Ryu, J A Proudfoot, S Hayoz, J M Michalski, D E Spratt, Y Liu, C Schär, A M Berlin, D R Zwahlen, J P Simko, T Hölscher, J A Efstathiou, B Polat, H M Sandler, G Hildebrandt, M B Parliament, A-C Mueller, I S Dayes, L Plasswilm, R J M Correa, J M Robertson, T G Karrison, E Davicioni, W A Hall, F Y Feng, A Pollack, G N Thalmann, P L Nguyen, D M Aebersold, P T Tran, S G Zhao
Journal: Annals of Oncology (2025)
Allogeneic CAR T Cell Products Cemacabtagene Ansegedleucel/ALLO-501 in Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Experience From the ALPHA2/ALPHA Clinical Studies
Authors: Frederick L. Locke, Javier L. Munoz, Michael T. Tees, Lazaros J. Lekakis, Sven de Vos, Rajneesh Nath, Don A. Stevens, Shahbaz A. Malik, Geoffrey P. Shouse, Mehdi Hamadani, Olalekan O. Oluwole, Miguel-Angel Perales, David B. Miklos, Paul W. Fisher, Amy Feng, Lynn Navale, John B. Le Gall, Sattva S. Neelapu
Journal: Journal of Clinical Oncology (2025)

Purpose Off-the-shelf, allogeneic CD19 chimeric antigen receptor (CAR) T cell products may improve access to treatment versus autologous ones. We report the phase 1 experience of the allogeneic CD19 CAR T-cell product cemacabtagene ansegedleucel (cema-cel) and its predecessor, ALLO-501, in CD19 CAR T-naive patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Patients and Methods In the ALPHA2/ALPHA studies, safety and efficacy of allogeneic CD19 CAR T cells were evaluated in CD19 CAR T treatment-naive patients with R/R LBCL. Patients received healthy donor-derived, human leukocyte antigen–unmatched cema-cel/ALLO-501 following a 3-day lymphodepletion regimen of fludarabine (30 mg/m 2 /day), cyclophosphamide (300 or 500 mg/m 2 /day), and escalating doses of the anti-CD52 monoclonal antibody, ALLO-647. Results As of September 26, 2024, 33 CD19 CAR T-naive patients with LBCL (median age, 66 years; median number of prior therapies, 3) received allogeneic CAR T cells. CAR T cell expansion was observed following infusion, with persistence observed up to 4 months. Overall and complete response rates were 58% and 42%, respectively; median duration of response in patients with a complete response was 23.1 months. The most common treatment-emergent adverse events were hematologic toxicities. No cases of graft-versus-host disease, immune effector cell-associated neurotoxicity syndrome, or grade ≥3 cytokine release syndrome were reported. Conclusion Allogeneic CD19 CAR T cells demonstrated promising overall and durable complete response rates with a manageable safety profile in CD19 CAR T-naive patients with R/R LBCL, supporting additional evaluation of cema-cel in patients with LBCL.
Micropore structure engineering of injectable granular hydrogels via controlled liquid-liquid phase separation facilitates regenerative wound healing in mice and pigs
Authors: Qifeng Guan, Sen Hou, Kai Wang, Linhao Li, Yating Cheng, Mingxia Zheng, Chen Liu, Xinbin Zhao, Jin Zhou, Ping Li, Xufeng Niu, Lizhen Wang, Yubo Fan
Journal: Biomaterials (2025)
Uptake of the Harmonizing Outcome Measures for Eczema (HOME) core outcome set in eczema systematic reviews
Authors: Isabel Bunola-Hadfield, Ayley Loh, Kim Thomas
Journal: British Journal of Dermatology (2025)

Core outcome sets reduce selective reporting bias and increase homogeneity by providing a pre-defined set of outcomes that should always be reported. The Harmonizing Outcome Measures for Eczema (HOME) initiative has developed a core outcome set (COS) for randomised control trials (RCTs) of eczema intervention. We assessed the COS uptake in systematic reviews in order to appreciate changes in the research landscape. In systematic reviews, uptake of the COS reduces research waste and facilitates updating reviews. We found positive improvements in COS implementation although it is yet to be uniformly implemented in systematic reviews.
An evidence-driven classification of non-filtering ingredients for topical photoprotection
Authors: Anthony Brown, Thierry Passeron, Corinne Granger, Yolanda Gilaberte, Carles Trullas, Jaime Piquero-Casals, Giovanni Leone, Sergio Schalka, Henry W Lim, Jean Krutmann
Journal: British Journal of Dermatology (2025)

This article provides an evidence-driven classification of non-filtering photoprotective ingredients that modulate skin's biological response to sunlight.
Decoding <i>COL7A1</i>: A Genetic Roadmap to Prognostication and Personalised Medicine in Recessive Dystrophic Epidermolysis Bullosa
Authors: Su M Lwin
Journal: British Journal of Dermatology (2025)

Journal Article Accepted manuscript Decoding COL7A1: A Genetic Roadmap to Prognostication and Personalised Medicine in Recessive Dystrophic Epidermolysis Bullosa Get access Su M Lwin Su M Lwin St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK Correspondence: Su M. Lwin, Email:[email protected] https://orcid.org/0000-0002-3325-3675 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljaf056, https://doi.org/10.1093/bjd/ljaf056 Published: 13 February 2025 Article history Received: 08 February 2025 Accepted: 10 February 2025 Published: 13 February 2025
cGAMP-targeting injectable hydrogel system promotes periodontal restoration by alleviating cGAS-STING pathway activation
Authors: Xiang Liu, Hua Zhang, Lei Xu, Huayu Ye, Jinghuan Huang, None Jing Xiang, Yunying He, Huan Zhou, Lingli Fang, Yunyan Zhang, Xuerong Xiang, Richard D Cannon, Ping Ji, Qiming Zhai
Journal: Bioactive Materials (2025)
Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy
Authors: Weiliang Deng, Zhixin Xu, Tong Hua, Guangbo Ji, Zihang Wang, Pei Liu, Yupeng Zhang, Shuo Li, Yuqiu Chao, Meng Qian, Qiang Zhao, Jinwei Tian
Journal: Bioactive Materials (2025)
Conversion surgery after immune checkpoint inhibitor-based combination therapy for initially unresectable hepatocellular carcinoma: A retrospective cohort study
Authors: Mingjian Piao, Chengjie Li, Ziyue Huang, Nan Zhang, Jiongyuan Li, Xu Yang, Shuofeng Li, Shanshan Wang, Ziyu Xun, Longhao Zhang, Boyu Sun, Ting Zhang, Xiaobo Yang, Haitao Zhao
Journal: Liver Cancer (2025)

Introduction: Hepatocellular carcinoma (HCC) has a high incidence rate and is often asymptomatic in its early stages. Combination therapies using immune checkpoint inhibitors (ICIs) have demonstrated survival benefits and high objective response rates, offering hope for conversion surgery in patients with initially unresectable HCC. We aimed to investigate the oncological outcomes of conversion surgery compared to those with continuing systemic treatment alone in patients who responded well to ICIs-based therapy, as well as the surgical outcomes associated with conversion surgery. Methods: We consecutively enrolled patients diagnosed with HCC between January 1, 2019 and February 1, 2024. These patients received treatment with ICIs combined with either anti-VEGF antibodies or tyrosine kinase inhibitors. Tumor response and resectability were assessed every 2 months. Patients who responded positively and met the criteria for conversion surgery were included. Results: Among 613 patients with initially unresectable HCC, 128 achieved conversion and met the surgical resection criteria during combination therapy. Of these, 54 continued non-surgical comprehensive treatment, 74 underwent conversion surgery, and 57 continued their original treatment post-surgery. The median follow-up time was 24.1 and 42.5 months for the surgery and non-surgery groups, respectively. The median PFS was 29.4 months in the surgery group versus 11.2 months in the non-surgery group (P&lt;0.0001, hazard ratio [HR]=0.39 [0.24–0.63]). The median OS was not reached in the surgery group, compared to 25.4 months in the non-surgery group (P&lt;0.0001, HR=0.26 [0.14–0.46]). Multivariate Cox regression analysis indicated that conversion surgery was independently associated with improved OS and PFS (P&lt;0.001), and continuing the original treatment post-surgery significantly influenced OS and recurrence -free survival. Conclusion: Conversion surgery after meeting the surgical criteria during immunotherapy provides significant prognostic benefits for patients with initially unresectable HCC, demonstrating high safety and R0 resection rates. For those undergoing conversion surgery, promptly resuming the original treatment after surgery is necessary.
Mortality and sequelae associated with regional use of intracranial devices among patients with pneumococcal meningitis; a nationwide, population-based cohort study
Authors: Isabella L Platz, Malte M Tetens, Nanna S Andersen, Jacob Bodilsen, Ram B Dessau, Svend Ellermann-Eriksen, Jens K Møller, Lene Nielsen, Alex Christian Yde Nielsen, Kirstine K Søgaard, Christian Østergaard, Anne-Mette Lebech, Lars Haukali Omland, Niels Obel
Journal: Clinical Microbiology and Infection (2025)
MiR-19-loaded oxidative stress-relief microgels with immunomodulatory and regeneration functions to reduce cardiac remodeling after myocardial infarction
Authors: Kai Wang, Jun Wen, Wen-Yao Wang, Kefei Zhao, Tong Zhou, Shunqin Wang, Qiaoxuan Wang, Liyin Shen, Yanxin Xiang, Tanchen Ren, Jinghai Chen, Yi-Da Tang, Yang Zhu, Changyou Gao
Journal: Bioactive Materials (2025)
PGLYRP2 drives hepatocyte-intrinsic innate immunity by trapping and clearing hepatitis B virus
Authors: Ying Li, Huihui Ma, Yongjian Zhang, Tinghui He, Binyang Li, Haoran Ren, Jia Feng, Jie Sheng, Kai Li, Yu Qian, Yunfeng Wang, Haoran Zhao, Jie He, Huicheng Li, Hongjin Wu, Yuanfei Yao, Ming Shi
Journal: Journal of Clinical Investigation (2025)

Spontaneous clearance of hepatitis B virus (HBV) is frequent in adults (95%) but rare in infants (5%), emphasizing the critical role of age-related hepatic immunocompetence. However, the underlying mechanisms of hepatocyte-specific immunosurveillance and age-dependent HBV clearance remain unclear. Here, we identified PGLYRP2 as a hepatocyte-specific pattern recognition receptor with age-dependent expression, and demonstrated that phase separation of PGLYRP2 was a critical driver of spontaneous HBV clearance in hepatocytes. Mechanistically, PGLYRP2 recognized and potentially eliminated covalently closed circular DNA (cccDNA) via phase separation, coordinated by its intrinsically disordered region and HBV DNA-binding domain (PGLYRP2IDR/209-377) in the nucleus. Additionally, PGLYRP2 suppressed HBV capsid assembly by directly interacting with the viral capsid, mediated by its PGRP domain. This interaction promoted the nucleocytoplasmic translocation of PGLYRP2 and subsequent secretion of the PGLYRP2-HBV capsid complex, thereby bolstering the hepatic antiviral response. Pathogenic variants or deletions in PGLYRP2 impaired its ability to inhibit HBV replication, highlighting its essential role in hepatocyte-intrinsic immunity. These findings suggest that targeting the PGLYRP2-mediated host-virus interaction may offer a potential therapeutic strategy for the development of anti-HBV treatments, representing a promising avenue for achieving a functional cure for HBV infection.
Toward Noninvasive Biomarkers of Renal Senescence
Authors: David P. Baird, David A. Ferenbach
Journal: Journal of the American Society of Nephrology (2025)

1Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, EH16 4UU, UK. *Corresponding author: Dr. David A. Ferenbach, [email protected]
Metastatic Tumor Growth in Steatotic Liver is Promoted by HAS2-Mediated Fibrotic Tumor Microenvironment
Authors: Yoon Mee Yang, Jieun Kim, Zhijun Wang, Jina Kim, So Yeon Kim, Gyu Jeong Cho, Jee Hyung Lee, Sun Myoung Kim, Takashi Tsuchiya, Michitaka Matsuda, Vijay Pandyarajan, Stephen J Pandol, Michael S Lewis, Alexandra Gangi, Paul W Noble, Dianhua Jiang, Akil Merchant, Edwin M Posadas, Neil A Bhowmick, Shelly C Lu, Sungyong You, Alexander M Xu, Ekihiro Seki
Journal: Journal of Clinical Investigation (2025)

Steatotic liver enhances liver metastasis of colorectal cancer, but this process is not fully understood. Steatotic liver induced by a high-fat diet (HFD) increases cancer-associated fibroblast (CAF) infiltration and collagen and hyaluronic acid (HA) production. We investigated the role of HA synthase 2 (HAS2) in the fibrotic tumor microenvironment in steatotic liver using Has2ΔHSC mice, in which Has2 is deleted from hepatic stellate cells. Has2ΔHSC mice had reduced steatotoic liver-associated metastatic tumor growth of MC38 colorectal cancer cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found low-molecular-weight HA activates yes-associated protein (YAP) in cancer cells, which then releases connective tissue growth factor to further activate CAFs for HAS2 expression. Single-cell analyses revealed a link between CAF-derived HAS2 with M2 macrophages and colorectal cancer cells through CD44; these cells associated with exhausted CD8 T cells via programmed death-ligand 1 and programmed cell death protein 1. The HA synthesis inhibitors reduced steatotic liver-associated metastasis of colorectal cancer, YAP expression, CAF and M2 macrophage infiltration. In conclusion, steatotic liver modulates a fibrotic tumor microenvironment to enhance metastatic cancer activity through a bidirectional regulation between CAFs and metastatic tumors, enhancing the metastatic potential of colorectal cancer in the liver.