tbuckley/cabot-search huggingface dataset:
A targetable secreted neural protein drives pancreatic cancer metastatic colonization and HIF1a nuclear retention
Authors: Norihiro Yamaguchi, Y Gloria Wu, Ethan Ravetch, Mai Takahashi, Abdul G. Khan, Akimasa Hayashi, Wenbin Mei, Dennis Hsu, Shigeaki Umeda, Elisa de Stanchina, Ivo C. Lorenz, Christine A. Iacobuzio-Donahue, Sohail F. Tavazoie
Journal: Cancer Discovery (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer-secreted protein that becomes overexpressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig-like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical, and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver—the primary site of PDAC metastasis. NPTX1–AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia-inducible factor-1α (HIF1α) nuclear retention and function. NPTX1 is overexpressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1–AMIGO2 as druggable critical upstream regulators of the HIF1α hypoxic response in PDAC. Significance: We identified the NPTX1–AMIGO2 axis as a regulatory mechanism upstream of HIF1α-driven hypoxia response that promotes PDAC liver metastasis. Therapeutic NPTX1 targeting outperformed a common chemotherapy regimen in inhibiting liver metastasis and suppressed primary tumor growth in preclinical models, revealing a novel therapeutic strategy targeting hypoxic response in PDAC.
Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation
Authors: Leslie S. Kean, Linda J. Burns, Tzuyung D. Kou, Roxanne Kapikian, Karissa Lozenski, Amelia Langston, John T. Horan, Benjamin Watkins, Muna Qayed, Brandi Bratrude, Kayla Betz, Xiao-Ying Tang, Mei-Jie Zhang, Sean E. Connolly, Martin Polinsky, Brian Gavin, Andres Gomez-Caminero, Marcelo C. Pasquini
Journal: Blood (2024)
CD5 deletion enhances the antitumor activity of adoptive T cell therapies
Authors: Ruchi P. Patel, Guido Ghilardi, Yunlin Zhang, Yi-Hao Chiang, Wei Xie, Puneeth Guruprasad, Ki Hyun Kim, Inkook Chun, Mathew G. Angelos, Raymone Pajarillo, Seok Jae Hong, Yong Gu Lee, Olga Shestova, Carolyn Shaw, Ivan Cohen, Aasha Gupta, Trang Vu, Dean Qian, Steven Yang, Aditya Nimmagadda, Adam E. Snook, Nicholas Siciliano, Antonia Rotolo, Arati Inamdar, Jaryse Harris, Ositadimma Ugwuanyi, Michael Wang, Alberto Carturan, Luca Paruzzo, Linhui Chen, Hatcher J. Ballard, Tatiana Blanchard, Chong Xu, Mohamed Abdel-Mohsen, Khatuna Gabunia, Maria Wysocka, Gerald P. Linette, Beatriz Carreno, David M. Barrett, David T. Teachey, Avery D. Posey, Daniel J. Powell, C. Tor Sauter, Stefano Pileri, Vinodh Pillai, John Scholler, Alain H. Rook, Stephen J. Schuster, Stefan K. Barta, Patrizia Porazzi, Marco Ruella
Journal: Science Immunology (2024)

Most patients treated with US Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.
Cross-talk between ILC2 and Gata3 <sup>high</sup> T <sub>regs</sub> locally constrains adaptive type 2 immunity
Authors: Julie Stockis, Thomas Yip, Julia Moreno-Vicente, Oliver Burton, Youhani Samarakoon, Martijn J. Schuijs, Shwetha Raghunathan, Celine Garcia, Weike Luo, Sarah K. Whiteside, Shaun Png, Charlotte Simpson, Stela Monk, Ashley Sawle, Kelvin Yin, Johanna Barbieri, Panagiotis Papadopoulos, Hannah Wong, Hans-Reimer Rodewald, Timothy Vyse, Andrew N. J. McKenzie, Mark S. Cragg, Matthew Hoare, David R. Withers, Hans Jörg Fehling, Rahul Roychoudhuri, Adrian Liston, Timotheus Y. F. Halim
Journal: Science Immunology (2024)

Regulatory T cells (T
Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus
Authors: Marie Jeanpierre, Jade Cognard, Maud Tusseau, Quentin Riller, Linh-Chi Bui, Jérémy Berthelet, Audrey Laurent, Etienne Crickx, Marianna Parlato, Marie-Claude Stolzenberg, Felipe Suarez, Guy Leverger, Nathalie Aladjidi, Sophie Collardeau-Frachon, Christine Pietrement, Marion Malphettes, Antoine Froissart, Christine Bole-Feysot, Nicolas Cagnard, Fernando Rodrigues Lima, Thierry Walzer, Frédéric Rieux-Laucat, Alexandre Belot, Anne-Laure Mathieu
Journal: The Journal of Experimental Medicine (2024)

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients’ T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients’ blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.
PTPN2 deficiency: Amping up JAK/STAT
Authors: Joshua M. Tobin, Megan A. Cooper
Journal: The Journal of Experimental Medicine (2024)

Identification of monogenic causes of immune dysregulation provides insight into human immune response and signaling pathways associated with autoimmunity. Here, Jeanpierre et al. (https://doi.org/10.1084/jem.20232337) identify new germline variants in the gene encoding PTPN2 associated with loss of regulatory function, enhanced JAK/STAT signaling, and early-onset autoimmunity.
When I use a word . . . Fictional drugs from Robert Heinlein, Frank Herbert, Aldous Huxley, and J R R Tolkien
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

I define fictional drugs as non-existent medicines, intended for human use, that have been invented for the purposes of some forms of fiction, usually novels, but also plays or films, including TV dramas. Here I discuss four sources of information about such drugs: Robert Heinlein's novella <i>Logic of Empire</i> (1941; rhira or happywater); Frank Herbert's <i>Dune</i> (1965: melange or spice and Water of Life); Aldous Huxley's <i>Brave New World</i> (1932; soma); and J R R Tolkien's <i>The Lord of the Rings</i> (1937–49; athelas). Apart from the last, these examples illustrate the psychotropic nature of many fictional drugs.
Risk of new tumor, carotid stenosis, and stroke after stereotactic radiosurgery for pituitary tumor: A multicenter study of 2254 patients with imaging follow-up
Authors: Chloe Dumot, Georgios Mantziaris, Sam Dayawansa, Carson Brantley, Cheng-Chia Lee, Huai-Che Yang, Selcuk Peker, Yavuz Samanci, David Mathieu, Jean-Nicolas Tourigny, Nuria Martinez Moreno, Roberto Martinez Alvarez, Thomas Chytka, Roman Liscak, Herwin Speckter, Erwin Lazo, Anderson Brito, Piero Picozzi, Andrea Franzini, Juan Alzate, Elad Mashiach, Kenneth Bernstein, Douglas Kondziolka, Manjul Tripathi, Greg N Bowden, Ronald E Warnick, Darrah Sheehan, Kimball Sheehan, Angelica Fuentes, John A Jane, Mary Lee Vance, Jason P Sheehan
Journal: Neuro-Oncology (2024)

A higher risk of secondary brain tumor, carotid stenosis, and stroke has been reported after conventional sella irradiation for pituitary neuroendocrine tumors (PitNET). Stereotactic radiosurgery (SRS), which is a more focused approach, is now increasingly used instead. The aim was to assess the risk of secondary brain tumor, carotid stenosis/occlusion, and stroke after SRS.
Diagnosing Solid Lesions in the Pancreas With Multimodal Artificial Intelligence
Authors: Haochen Cui, Yuchong Zhao, Si Xiong, Yunlu Feng, Peng Li, Ying Lv, Qian Chen, Ronghua Wang, Pengtao Xie, Zhenlong Luo, Sideng Cheng, Wujun Wang, Xing Li, Dingkun Xiong, Xinyuan Cao, Shuya Bai, Aiming Yang, Bin Cheng
Journal: JAMA Network Open (2024)

Importance Diagnosing solid lesions in the pancreas via endoscopic ultrasonographic (EUS) images is challenging. Artificial intelligence (AI) has the potential to help with such diagnosis, but existing AI models focus solely on a single modality. Objective To advance the clinical diagnosis of solid lesions in the pancreas through developing a multimodal AI model integrating both clinical information and EUS images. Design, Setting, and Participants In this randomized crossover trial conducted from January 1 to June 30, 2023, from 4 centers across China, 12 endoscopists of varying levels of expertise were randomly assigned to diagnose solid lesions in the pancreas with or without AI assistance. Endoscopic ultrasonographic images and clinical information of 439 patients from 1 institution who had solid lesions in the pancreas between January 1, 2014, and December 31, 2022, were collected to train and validate the joint-AI model, while 189 patients from 3 external institutions were used to evaluate the robustness and generalizability of the model. Intervention Conventional or AI-assisted diagnosis of solid lesions in the pancreas. Main Outcomes and Measures In the retrospective dataset, the performance of the joint-AI model was evaluated internally and externally. In the prospective dataset, diagnostic performance of the endoscopists with or without the AI assistance was compared. Results The retrospective dataset included 628 patients (400 men [63.7%]; mean [SD] age, 57.7 [27.4] years) who underwent EUS procedures. A total of 130 patients (81 men [62.3%]; mean [SD] age, 58.4 [11.7] years) were prospectively recruited for the crossover trial. The area under the curve of the joint-AI model ranged from 0.996 (95% CI, 0.993-0.998) in the internal test dataset to 0.955 (95% CI, 0.940-0.968), 0.924 (95% CI, 0.888-0.955), and 0.976 (95% CI, 0.942-0.995) in the 3 external test datasets, respectively. The diagnostic accuracy of novice endoscopists was significantly enhanced with AI assistance (0.69 [95% CI, 0.61-0.76] vs 0.90 [95% CI, 0.83-0.94]; P &amp;amp;lt; .001), and the supplementary interpretability information alleviated the skepticism of the experienced endoscopists. Conclusions and Relevance In this randomized crossover trial of diagnosing solid lesions in the pancreas with or without AI assistance, the joint-AI model demonstrated positive human-AI interaction, which suggested its potential to facilitate a clinical diagnosis. Nevertheless, future randomized clinical trials are warranted. Trial Registration ClinicalTrials.gov Identifier: NCT05476978
Daily Multivitamin Not Tied to Improved Longevity
Authors: Emily Harris
Journal: JAMA (2024)

Erikka Loftfield, PhD, MPH; Caitlin P. O'Connell, MPH; Christian C. Abnet, PhD, MPH; Barry I. Graubard, PhD; Linda M. Liao, PhD; Laura E. Beane Freeman, PhD; Jonathan N. Hofmann, PhD; Neal D. Freedman, PhD, MPH; Rashmi Sinha, PhD
Completion Rate and Positive Results Reporting Among Immunotherapy Trials in Breast Cancer, 2004-2023
Authors: Marco Mariani, Giulia Viale, Barbara Galbardi, Luca Licata, Carlo Bosi, Matteo Dugo, Giulia Notini, Matteo M. Naldini, Maurizio Callari, Carmen Criscitiello, Lajos Pusztai, Giampaolo Bianchini
Journal: JAMA Network Open (2024)

Importance Clinical trials are the path to test and introduce new therapies in the clinic. Trials that are unable to produce results represent inefficiency in the system and may also undermine patient confidence in the new drug development process. Objectives To survey the immunotherapy clinical trial landscape of breast cancer between January 2004 and April 2023 and examine what fraction of trials with primary completion date up to November 30, 2022, failed to report outcome, assessing the proportion of trials that yielded positive results and describing trial features associated with these 2 outcomes. Design, Setting, and Participants This cross-sectional study included breast cancer immunotherapy trials identified in ClinicalTrials.gov. Trial details and results were retrieved in December 2023. Google Scholar, PubMed, and LARVOL CLIN websites were also searched for reports. Main Outcomes and Measures Trial outcome reported as abstract or manuscript. Reported trials were categorized as positive (ie, met its end point) or negative. Association between reporting and trial features were tested using Fisher exact test. Results A total of 331 immuno-oncology trials were initiated in breast cancer by April 2023; 242 trials were phase II, 47 were phase I, and 42 phase III. By setting, 212 studies (64.0%) were conducted in metastatic, 94 (28.4%) in neoadjuvant, and 25 (7.6%) in adjuvant settings. Among phase II and III trials, 168 (59.2%) were nonrandomized. One hundred twenty trials had primary completion dates up to November 30, 2022, of which 30 (25.0%; enrolling a combined 2428 patients) failed to report their outcomes; 7 phase I trials (31.8%), 21 phase II trials (23.6%), and 2 phase III trials (22.2%) were unreported. Single-center studies were significantly more likely to be unreported than multicenter studies (19 of 54 [35.2%] vs 9 of 60 [15.0%]; P = .02). Of the 90 reported trials, 47 (52.2%) and 43 (47.8%) were positive and negative, respectively. Seventeen of 19 (89.5%) of the reported randomized trials (accruing a total of 4189 patients) were negative. Conclusions and Relevance In this cross-sectional study of immunotherapy breast cancer trials, the large number of trials yielded modest clinical impact. Single-center trials commonly failed to report their outcomes and many phase II studies have not translated into corresponding successful phase III trials.
Medicare Advantage Plan and Health System Vertical Integration, 2011-2020
Authors: Geronimo Bejarano, Andrew Ryan, Amal Trivedi, Kendra Offiaeli, David J. Meyers
Journal: JAMA Network Open (2024)

This cross-sectional study compares the beneficiary and plan characteristics and trends in enrollment, premiums, star ratings, and benefits of nonintegrated, non–legacy-integrated, and legacy-integrated Medicare Advantage plans between 2011 and 2020.
Byline Errors
Journal: JAMA Network Open (2024)

Conall Francoeur, MDCM; Alicia M. Alcamo, MD, MPH; Courtney L. Robertson, MD; Mark S. Wainwright, MD, PhD; Juan D. Roa, MD, MS; Marlina E. Lovett, MD; Casey Stulce, MD; Mais Yacoub, MD; Renee M. Potera, MD; Elizabeth Zivick, MD; Adrian Holloway, MD; Ashish Nagpal, MD; Kari Wellnitz, MD; Katelyn M. Even, MD; Werther Brunow de Carvalho, PhD; Isadora S. Rodriguez, MD; Stephanie P. Schwartz, MD; Tracie C. Walker, MD; Santiago Campos-Miño, MD, MSc; Leslie A. Dervan, MD, MS; Andrew S. Geneslaw, MD, MS; Taylor B. Sewell, MD, MBA; Patrice Pryce, MD; Wendy G. Silver, MD, MA; Jieru E. Lin, MD, PhD; Wendy S. Vargas, MD; Alexis Topjian, MD, MSCE; Jennifer L. McGuire, MD, MSCE; Jesus Angel Domínguez Rojas, MD; Jaime Tasayco-Muñoz, MD; Sue J. Hong, MD; William J. Muller, MD, PhD; Matthew Doerfler, MD; Cydni N. Williams, MD, MCR; Kurt Drury, MD; Dhristie Bhagat, MD; Aaron Nelson, MD, MBS; Dana Price, MD; Heda Dapul, MD; Laura Santos, MD, MS; Robert Kahoud, MD; Brian Appavu, MD; Kristin P. Guilliams, MD, MSCI; Shannon C. Agner, MD, PhD; Karen H. Walson, MD; Lindsey Rasmussen, MD; Ria Pal, MD; Anna Janas, MD, PhD; Peter Ferrazzano, MD; Raquel Farias-Moeller, MD; Kellie C. Snooks, DO, MPH; Chung-Chou H. Chang, PhD; Tomás Iolster, MD; Jennifer C. Erklauer, MD; Facundo Jorro Baron, MD; Evangeline Wassmer, MSC; Michael Yoong, MD; Michelle Jardine, MD; Zoha Mohammad, MD; Akash Deep, MD; Tanil Kendirli, MD; Karen Lidsky, MD; Samantha Dallefeld, MD; Helen Flockton, MD; Shruti Agrawal, MD; Krishna Sumanth Siruguppa, MBBS; Michaela Waak, MD; Alfonso Gutiérrez-Mata, MD; Warwick Butt, MBBS; Sixto Bogantes-Ledezma, PhD; Fabricio Sevilla-Acosta, MD; Andres Umaña-Calderón, MD; Adriana Ulate-Campos, MD; Adriana Yock-Corrales, MD, MSc; Victor Brodzik Talisa, PhD; Hari Krishnan Kanthimathinathan, MD; Michelle E. Schober, MD; Ericka L. Fink, MD, MS; Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID) Investigators
US Surgeon General Vivek Murthy: Firearm Violence Is a Public Health Crisis
Authors: Jennifer Abbasi, Yulin Hswen
Journal: JAMA (2024)

This Medical News article is an interview with US Surgeon General Vivek Murthy, MD, MBA, and JAMA Editor in Chief Kirsten Bibbins-Domingo, PhD, MD, MAS, about a new advisory that declares gun violence a public health crisis.
Management of scabies in children under 15 kg and pregnant or breastfeeding women: recommendations supported by the Centre of Evidence of the French Society of Dermatology
Authors: Aurelie Morand, Amandine Weill, Juliette Miquel, Olivier Chosidow, Bernard Guillot, Julio Tannous, Ludovic de Gentile, Emmanuel Parant, Béatrice Quinet, Marie Boyer, Annabel Maruani, Nathalie Bodak, Alice Phan, Arezki Izri, Barthélémy Tosello, Florence Bretelle, Elisabeth Elefant, Franck Boralevi, Catherine Letord, Thomas Hubiche, Stephanie Mallet
Journal: British Journal of Dermatology (2024)

Although scabies is a common disease, questions concerning efficacy, safety, tolerance and galenic formulation persist, in particular regarding its treatment in young children under 15 kg and in pregnant or breastfeeding women. This manuscript reports the recommendations developed by the Centre of Evidence of the French Society of Dermatology. Ivermectin can be proposed as first-line treatment from 2 years on, especially if in doubt about compliance or damaged skin, or in grouped cases; ivermectin can also be proposed as second-line treatment, if necessary, after 2 months.
Long-Term Use of Oral Corticosteroids and Safety Outcomes for Patients With Atopic Dermatitis
Authors: Yong Hyun Jang, Eun-Young Choi, Hyesung Lee, Jieun Woo, Sohee Park, Yunha Noh, Ja-Young Jeon, Eun-Young Yoo, Ju-Young Shin, Yang Won Lee
Journal: JAMA Network Open (2024)

Importance The use of oral corticosteroids for prolonged periods may be associated with adverse events (AEs). Nevertheless, the risk of AEs with oral corticosteroids, especially among patients with atopic dermatitis (AD), has not been comprehensively investigated and lacks evidence on duration of treatment. Objective To assess the association between long-term exposure to oral corticosteroids and AEs among adult patients with AD. Design, Setting, and Participants This nested case-control study used data from the Health Insurance Review and Assessment Service database of South Korea between January 1, 2012, and October 31, 2021, which included 1 year prior to the cohort entry date of January 1, 2013, for assessing exclusion criteria and baseline characteristics, and 1 year after the study end date of October 31, 2020, to ensure a minimum duration for assessing exposure. Among the population of adults with AD, patients diagnosed with any of 11 AEs were matched with patients who had never received a diagnosis of any of the 11 AEs. Exposure Long-term use of oral corticosteroids was defined as cumulative supply of more than 30 days or more than 90 days of oral corticosteroid prescription per year. Main Outcomes and Measures We used multivariable conditional logistic regression analyses to measure the risk of 11 individual outcomes (osteoporosis, fracture, type 2 diabetes, hyperlipidemia, hypertension, myocardial infarction, stroke, heart failure, avascular necrosis, cataract, or glaucoma) as the composite outcome, controlling for potential confounders. We further classified the composite outcome to individual outcomes to evaluate the AE-specific risk. Results Among 1 025 270 patients with AD between 2013 and 2020, 164 809 cases (mean [SD] age, 39.4 [14.8]; 56.9% women) were matched with 328 303 controls (mean [SD] age, 39.3 [14.7]; 56.9% women) for sex, age, cohort entry date, follow-up duration, and severity of AD, where the balance of most baseline characteristics was achieved. A total of 5533 cases (3.4%) and 10 561 controls (3.2%) were exposed to oral corticosteroids for more than 30 days, while 684 cases (0.4%) and 1153 controls (0.4%) were exposed to oral corticosteroids for more than 90 days. Overall, there was no increased risk of AEs with use of oral corticosteroids for more than 30 days (adjusted odds ratio [AOR], 1.00; 95% CI, 0.97-1.04), whereas the risk was slightly higher with use of oral corticosteroids for more than 90 days (AOR, 1.11; 95% CI, 1.01-1.23). The small elevation in experiencing an AE was observed with each cumulative or consecutive year of ever long-term use. Conclusions and Relevance This case-control study found a slightly increased risk of AEs associated with use of oral corticosteroids for more than 90 days per year, which warrants future research to fully elucidate the observed findings.
Efficacy of the FIFA cooling break heat policy during an intermittent treadmill football simulation in hot conditions in trained males
Authors: Harry A Brown, Samuel Chalmers, Thomas H Topham, Brad Clark, Andrew Jowett, Tim Meyer, Ollie Jay, Julien D Périard
Journal: British Journal of Sports Medicine (2024)

Objective To evaluate the efficacy of the Fédération Internationale de Football Association (FIFA) cooling break policy against alternative cooling configurations in attenuating thermal strain during simulated football in the heat. Methods 12 males (age: 27±6 years, V̇O 2peak : 61±7 mL/kg/min) completed five 90 min intermittent treadmill football match simulations in 40°C and 41% relative humidity (32°C wet-bulb globe temperature) with different cooling configurations: regular match without cooling breaks (REG), 3 min breaks without cooling (BRK no-cool ), 3 min breaks with cooling (BRK cool : current FIFA policy; chilled fluid ingestion and ice towel across neck and shoulders), 5 min extended half-time without cooling breaks (ExtHT only ) and 3 min cooling breaks with 5 min ExtHT (ExtHT cool ). Rectal temperature (T re ), heart rate, whole-body sweat rate (WBSR) and rating of perceived exertion (RPE) were recorded. Data are presented as mean (95% CIs). Results Final T re was lower in BRK no-cool (0.20°C (0.01, 0.39), p=0.038), BRK cool (0.39°C (0.21, 0.57), p&lt;0.001) and ExtHT cool (0.40°C (0.22, 0.58), p&lt;0.001) than REG (39.1°C (38.8, 39.3)). Mean T re was lower in ExtHT cool (38.2°C (38.0, 38.4)) than BRK cool (38.3°C (38.1, 38.5), p=0.018), BRK no-cool and ExtHT only (38.4°C (38.2, 38.6), p&lt;0.001) and REG (38.5°C (38.3, 38.7), p&lt;0.001). Mean heart rate was lower during BRK cool (6 beats/min (4, 7), p&lt;0.001) and ExtHT cool (7 beats/min (6, 8), p&lt;0.001) compared with REG. WBSR was comparable across trials (p ≥ 0.07) and RPE was attenuated during BRK cool (0.4 (0.1, 0.7), p=0.004) and ExtHT cool (0.5 (0.2, 0.7), p=0.002), compared with REG. Conclusion BRK cool and ExtHT cool attenuated thermal, cardiovascular and perceptual strain during a simulated football match in the heat. Additional strategies may be required in field settings or under harsher conditions.