tbuckley/cabot-search huggingface dataset:
Low-Dose Ionizing γ-Radiation Elicits the Extrusion of Neutrophil Extracellular Traps
Authors: Alvaro Teijeira, Saray Garasa, Maria C. Ochoa, Sandra Sanchez-Gregorio, Gabriel Gomis, Carlos Luri-Rey, Rafael Martinez-Monge, Beatrice Pinci, Karmele Valencia, Belen Palencia, Benigno Barbés, Elixabet Bolaños, Arantza Azpilikueta, Marina García-Cardosa, Javier Burguete, Iñaki Eguren-Santamaría, Eneko Garate-Soraluze, Pedro Berraondo, Jose L. Perez-Gracia, Carlos E. de Andrea, Maria E. Rodriguez-Ruiz, Ignacio Melero
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Patients with cancer frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NET), we have investigated the mechanisms, consequences, and occurrence of such phenomena in patients undergoing radiotherapy. Experimental Design: NETosis was analyzed in cultures of neutrophils isolated from healthy donors, patients with cancer, and cancer-bearing mice under confocal microscopy. Cocultures of radiation-induced NETs, immune effector lymphocytes, and tumor cells were used to study the effects of irradiation-induced NETs on immune cytotoxicity. Radiation-induced NETs were intravenously injected to mice for assessing their effects on metastasis. Circulating NETs in irradiated patients with cancer were measured using ELISA methods for detecting MPO–DNA complexes and citrullinated histone 3. Results: Irradiation of neutrophils with very low γ-radiation doses (0.5–1 Gy) elicits NET formation in a manner dependent on oxidative stress, NADPH oxidase activity, and autocrine IL8. Radiation-induced NETs interfere with NK cell and T-cell cytotoxicity. As a consequence, preinjection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs were readily detected in two prospective series of patients following the first fraction of their radiotherapy courses. Conclusions: NETosis is induced by low-dose ionizing irradiation in a neutrophil-intrinsic fashion, and radiation-induced NETs are able to interfere with immune-mediated cytotoxicity. Radiation-induced NETs foster metastasis in mouse models and can be detected in the circulation of patients undergoing conventional radiotherapy treatments. See related commentary by Mowery and Luke, p. 3965
Facts and Hopes on Cancer Immunotherapy for Small Cell Lung Cancer
Authors: Jon Zugazagoitia, Handerson Osma, Javier Baena, Alvaro C. Ucero, Luis Paz-Ares
Journal: Clinical Cancer Research (2024)

Platinum-based chemotherapy plus PD1 axis blockade is the standard of care in the first-line treatment of extensive-stage small cell lung cancer (SCLC). Despite the robust and consistent increase in long-term survival with PD1 axis inhibition, the magnitude of the benefit from immunotherapy seems lower than that for other solid tumors. Several immune evasive mechanisms have been shown to be prominently altered in human SCLC, including T-cell exclusion, downregulation of components of the MHC class I antigen processing and presentation machinery, or upregulation of macrophage inhibitory checkpoints, among others. New immunotherapies aiming to target some of these dominant immune suppressive features are being intensively evaluated preclinically and clinically in SCLC. They include strategies to enhance the efficacy and/or reverse features that promote intrinsic resistance to PD1 axis inhibition (e.g., restoring MHC class I deficiency and targeting DNA damage response) and novel immunomodulatory agents beyond T-cell checkpoint blockers (e.g., T cell-redirecting strategies, antibody-drug conjugates, or macrophage checkpoint blockers). Among them, delta-like ligand 3-targeted bispecific T-cell engagers have shown the most compelling preliminary evidence of clinical efficacy and hold promise as therapies that might contribute to further improve patient outcomes in this disease. In this study, we first provide a brief overview of key tumor microenvironment features of human SCLC. Then, we update the current clinical evidence with immune checkpoint blockade and review other emerging immunotherapy strategies that are gaining increasing attention in SCLC. We finally summarize our future perspective on immunotherapy and precision oncology for this disease.
Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity from a Phase I Study of Simlukafusp Alfa (FAP-IL2v) in Advanced/Metastatic Solid Tumors
Authors: Neeltje Steeghs, Carlos Gomez-Roca, Kristoffer S. Rohrberg, Morten Mau-Sørensen, Debbie Robbrecht, Josep Tabernero, Samreen Ahmed, Maria E. Rodríguez-Ruiz, Caroline Ardeshir, Daniela Schmid, Nassim Sleiman, Carl Watson, Hanna Piper-Lepoutre, David Dejardin, Stefan Evers, Christophe Boetsch, Jehad Charo, Volker Teichgräber, Ignacio Melero
Journal: Clinical Cancer Research (2024)

Purpose: Simlukafusp alfa [fibroblast activation protein α–targeted IL2 variant (FAP-IL2v)], a tumor-targeted immunocytokine, comprising an IL2 variant moiety with abolished CD25 binding fused to human IgG1, is directed against fibroblast activation protein α. This phase I, open-label, multicenter, dose-escalation, and extension study (NCT02627274) evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of FAP-IL2v in patients with advanced/metastatic solid tumors. Patients and Methods: Participants received FAP-IL2v intravenously once weekly. Dose escalation started at 5 mg; flat dosing (≤25 mg) and intraparticipant uptitration regimens (15/20, 20/25, 20/20/35, and 20/35/35 mg) were evaluated. Primary objectives were dose-limiting toxicities, maximum tolerated dose, recommended expansion dose, and pharmacokinetics. Results: Sixty-one participants were enrolled. Dose-limiting toxicities included fatigue (flat dose 20 mg: n = 1), asthenia (25 mg: n = 1), drug-induced liver injury (uptitration regimen 20/25 mg: n = 1), transaminase increase (20/25 mg: n = 1), and pneumonia (20/35/35 mg: n = 1). The uptitration regimen 15/20 mg was determined as the maximum tolerated dose and was selected as the recommended expansion dose. Increases in peripheral blood absolute immune cell counts were seen for all tested doses [NK cells, 13-fold; CD4+ T cells (including regulatory T cells), 2-fold; CD8+ T cells, 3.5-fold] but without any percentage change in regulatory T cells. Clinical activity was observed from 5 mg [objective response rate, 5.1% (n = 3); disease control rate, 27.1% (n = 16)]. Responses were durable [n = 3, 2.8 (censored), 6.3, and 43.4 months]. Conclusions: FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors.
Population-based deep image prior for dynamic PET denoising: A data-driven approach to improve parametric quantification
Authors: Qiong Liu, Yu-Jung Tsai, Jean-Dominique Gallezot, Xueqi Guo, Ming-Kai Chen, Darko Pucar, Colin Young, Vladimir Panin, Michael Casey, Tianshun Miao, Huidong Xie, Xiongchao Chen, Bo Zhou, Richard Carson, Chi Liu
Journal: Medical Image Analysis (2024)
The potential value of a quantitative PCR assay for assessing respiratory samples in approaching a laboratory diagnosis of pulmonary mucormycosis
Authors: Ya-Ping Chen, Cong-Tat Cia, Ya-Ting Hsu, Po-Lin Chen, Tsai-Yun Chen, Jen-Chieh Lee, Sin-Syue Li, Ming-I Hsieh, Hsuan-Chen Wang, Chi-Jung Wu
Journal: Journal of Infection (2024)

•Mucorales qPCR aids in the aetiological diagnosis of breakthrough invasive fungal infections not responding to Aspergillus-targeted therapy.•Narrow hyphal widths (3−7 μm) were observed on histology of mucormycosis caused by Cunninghamella bertholletiae, which could be differentiated from aspergillosis by Mucorales qPCR using fresh lung tissue.•Further refinement of Mucorales qPCR assays for specific detection of C. bertholletiae aids in pathogen-tailored management.
Overcoming Osimertinib Resistance with AKT Inhibition in EGFRm-Driven Non–Small Cell Lung Cancer with PIK3CA/PTEN Alterations
Authors: Ursula Grazini, Aleksandra Markovets, Lucy Ireland, Daniel O’Neill, Benjamin Phillips, Man Xu, Matthias Pfeifer, Tereza Vaclova, Matthew J. Martin, Ludovic Bigot, Luc Friboulet, Ryan Hartmaier, Maria E. Cuomo, Simon T. Barry, Paul D. Smith, Nicolas Floc’h
Journal: Clinical Cancer Research (2024)

Osimertinib is an EGFR tyrosine kinase inhibitor indicated for the treatment of EGFR-mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line-treated patients with EGFRm advanced non-small cell lung cancer (NSCLC). Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. ctDNA profiling analysis of on-progression plasma samples from patients treated with osimertinib in both first- (phase III, FLAURA trial) and second-line trials (phase III, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR-engineered NSCLC cell lines and patient-derived xenograft (PDX) models supports a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance. These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be resensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alterations, and in these double-mutant models, capivasertib and osimertinib combination elicits an improved antitumor effect versus osimertinib alone. Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC who have a suboptimal response or develop resistance to osimertinib through PIK3CA/AKT/PTEN alterations. See related commentary by Vokes et al., p. 3968.
Monitoring Hepatocellular Carcinoma Using Tumor Content in Circulating Cell-Free DNA
Authors: Shifeng Lian, Chenyu Lu, Fugui Li, Xia Yu, Limei Ai, Biaohua Wu, Xueyi Gong, Wenjing Zhou, Xuejun Liang, Jiyun Zhan, Yong Yuan, Fang Fang, Zhiwei Liu, Mingfang Ji, Zongli Zheng
Journal: Clinical Cancer Research (2024)

The objective of the study was to evaluate the use of tumor content in circulating cell-free DNA (ccfDNA) for monitoring hepatocellular carcinoma (HCC) throughout its natural history.
Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol
Authors: Birgit S. Geurts, Laurien J. Zeverijn, Lindsay V.M. Leek, Jade M. van Berge Henegouwen, Louisa R. Hoes, Hanneke van der Wijngaart, Vincent van der Noort, Joris van de Haar, Annemiek van Ommen-Nijhof, Marleen Kok, Paul Roepman, Anne M.L. Jansen, Wendy W.J. de Leng, Maja J.A. de Jonge, Ann Hoeben, Carla M.L. van Herpen, Hans M. Westgeest, Lodewyk F.A. Wessels, Henk M.W. Verheul, Hans Gelderblom, Emile E. Voest
Journal: Clinical Cancer Research (2024)

To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing-based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234).
Allopolyploid subgenome identification and implications for evolutionary analysis
Authors: Adam M. Session
Journal: Trends in Genetics (2024)

Whole-genome duplications (WGDs) are widespread genomic events in eukaryotes that are hypothesized to contribute to the evolutionary success of many lineages, including flowering plants, Saccharomyces yeast, and vertebrates. WGDs generally can be classified into autopolyploids (ploidy increase descended from one species) or allopolyploids (ploidy increase descended from multiple species). Assignment of allopolyploid progenitor species (called subgenomes in the polyploid) is important to understanding the biology and evolution of polyploids, including the asymmetric subgenome evolution following hybridization (biased fractionation). Here, I review the different methodologies used to identify the ancestors of allopolyploid subgenomes, discuss the advantages and disadvantages of these methods, and outline the implications of how these methods affect the subsequent evolutionary analysis of these genomes.
Patient outcomes, efficiency, and adverse events for elective hip and knee replacement in private and NHS hospitals: a population-based cohort study in England
Authors: Michael Anderson, Rocco Friebel, Laia Maynou, Ilias Kyriopoulos, Alistair McGuire, Elias Mossialos
Journal: The Lancet Regional Health - Europe (2024)

Since the early 2000s, the National Health Service (NHS) in England has expanded provision of publicly funded care in private hospitals as a strategy to meet growing demand for elective care. This study aims to compare patient outcomes, efficiency and adverse events in private and NHS hospitals when providing elective hip and knee replacement.
National and regional prevalence of interpersonal violence from others’ alcohol use: a systematic review and modelling study
Authors: Carolin Kilian, Sinja Klinger, Jakob Manthey, Jürgen Rehm, Taisia Huckle, Charlotte Probst
Journal: The Lancet Regional Health - Europe (2024)

BackgroundWhile alcohol use is an established risk factor for interpersonal violence, the extent to which people are affected by interpersonal violence from others' drinking has not yet been quantified for different world regions. This modelling study aims to provide the first estimates of the national and regional prevalence of interpersonal violence from others' drinking.MethodsAn international systematic literature search (02/28/2023, Prospero: CRD42022337364) was conducted to identify general adult population studies assessing the prevalence of interpersonal violence from others' drinking with no restrictions to publication date or language. Reports that did not provide data on interpersonal violence from others' drinking (primary outcome), were no original research studies, or captured a selected group of people only, were excluded. Observed prevalence data were extracted and used to build fractional response regression models to predict past-year prevalence of emotional and physical violence from others' drinking in 2019. Random-effects meta-regression models were used to aggregate the observed prevalence of sexual and intimate partner violence. Study risk of bias (ROB) was assessed using a modified version of the Newcastle–Ottawa Scale.FindingsOut of 13,835 identified reports, 50 were included covering just under 830,000 individuals (women: 347,112; men: 322,331; men/women combined: 160,057) from 61 countries. With an average prevalence of 16·8% (95% CI: 15·2–18·3%) and 28·3% (95% CI: 23·9–32·4%) in men and women combined in the GBD super regions High Income and Central Europe, Eastern Europe, & Central Asia, respectively, emotional violence was the most common form of interpersonal violence from others' drinking. Physical violence averaged around 3% (women) and 5% (men) in both regions. The pooled prevalence of sexual violence from others' drinking in men and women was 1·3% (95% CI: 0·5–3·3%, 95% PI: 0·1–16·9%) and 3·4% (95% CI: 1·4–8·3%, 95% PI: 0·2–35·3%), respectively, and ranged between 0·4% (95% CI: 0·1–1·6%, 95% PI: 0·0–7·3%) and 2·7% (95% CI: 1·1–6·3%, 95% PI: 0·2–30·0%) for different forms of intimate partner violence. ROB was moderate or critical for most reports; accounting for critical ROB did not substantially alter our results.InterpretationThe share of the population experiencing harms from others' drinking is significant and should be an integral part of public health strategies.FundingResearch reported in this publication was supported by the Canadian Institutes of Health Research (CIHR; grant: CIHR FRN 477887).
PU.1 and BCL11B sequentially cooperate with RUNX1 to anchor mSWI/SNF to poise the T cell effector landscape
Authors: Noah Gamble, Alexandra Bradu, Jason A. Caldwell, Joshua McKeever, Olubusayo Bolonduro, Ebru Ermis, Caroline Kaiser, YeEun Kim, Benjamin Parks, Sandy Klemm, William J. Greenleaf, Gerald R. Crabtree, Andrew S. Koh
Journal: Nature Immunology (2024)
The fasciola cinereum of the hippocampal tail as an interventional target in epilepsy
Authors: Ryan M. Jamiolkowski, Quynh-Anh Nguyen, Jordan S. Farrell, Ryan J. McGinn, David A. Hartmann, Jeff J. Nirschl, Mateo I. Sanchez, Vivek P. Buch, Ivan Soltesz
Journal: Nature Medicine (2024)

Abstract Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of six patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.
Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes
Authors: Sylvanus Toikumo, Mariela V. Jennings, Benjamin K. Pham, Hyunjoon Lee, Travis T. Mallard, Sevim B. Bianchi, John J. Meredith, Laura Vilar-Ribó, Heng Xu, Alexander S. Hatoum, Emma C. Johnson, Vanessa K. Pazdernik, Zeal Jinwala, Shreya R. Pakala, Brittany S. Leger, Maria Niarchou, Michael Ehinmowo, Greg D. Jenkins, Anthony Batzler, Richard Pendegraft, Abraham A. Palmer, Hang Zhou, Joanna M. Biernacka, Brandon J. Coombes, Joel Gelernter, Ke Xu, Dana B. Hancock, Nancy J. Cox, Jordan W. Smoller, Lea K. Davis, Amy C. Justice, Henry R. Kranzler, Rachel L. Kember, Sandra Sanchez-Roige
Journal: Nature Human Behaviour (2024)
Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis
Authors: Jonas Ghouse, Gardar Sveinbjörnsson, Marijana Vujkovic, Anne-Sofie Seidelin, Helene Gellert-Kristensen, Gustav Ahlberg, Vinicius Tragante, Søren A. Rand, Joseph Brancale, Silvia Vilarinho, Pia Rengtved Lundegaard, Erik Sørensen, Christian Erikstrup, Mie Topholm Bruun, Bitten Aagaard Jensen, Søren Brunak, Karina Banasik, Henrik Ullum, Niek Verweij, Luca Lotta, Aris Baras, Luca A. Lotta, Tooraj Mirshahi, David J. Carey, David E. Kaplan, Julie Lynch, Timothy Morgan, Tae-Hwi Schwantes-An, Daniel R. Dochtermann, Saiju Pyarajan, Philip S. Tsao, Triin Laisk, Reedik Mägi, Julia Kozlitina, Anne Tybjærg-Hansen, David Jones, Kirk U. Knowlton, Lincoln Nadauld, Egil Ferkingstad, Einar S. Björnsson, Magnus O. Ulfarsson, Árni Sturluson, Patrick Sulem, Ole B. Pedersen, Sisse R. Ostrowski, Daniel F. Gudbjartsson, Kari Stefansson, Morten Salling Olesen, Kyong-Mi Chang, Hilma Holm, Henning Bundgaard, Stefan Stender
Journal: Nature Genetics (2024)

Abstract We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.
Goal commitment is supported by vmPFC through selective attention
Authors: Eleanor Holton, Jan Grohn, Harry Ward, Sanjay G. Manohar, Jill X. O’Reilly, Nils Kolling
Journal: Nature Human Behaviour (2024)

When striking a balance between commitment to a goal and flexibility in the face of better options, people often demonstrate strong goal perseveration. Here, using functional MRI (n = 30) and lesion patient (n = 26) studies, we argue that the ventromedial prefrontal cortex (vmPFC) drives goal commitment linked to changes in goal-directed selective attention. Participants performed an incremental goal pursuit task involving sequential decisions between persisting with a goal versus abandoning progress for better alternative options. Individuals with stronger goal perseveration showed higher goal-directed attention in an interleaved attention task. Increasing goal-directed attention also affected abandonment decisions: while pursuing a goal, people lost their sensitivity to valuable alternative goals while remaining more sensitive to changes in the current goal. In a healthy population, individual differences in both commitment biases and goal-oriented attention were predicted by baseline goal-related activity in the vmPFC. Among lesion patients, vmPFC damage reduced goal commitment, leading to a performance benefit.
Neuropilin-1high monocytes protect against neonatal inflammation
Authors: Xiaoqing Zheng, Wen Lei, Yongmei Zhang, Han Jin, Cha Han, Fan Wu, Chonghong Jia, Ruihong Zeng, Zhanghua Chen, Yuxia Zhang, Haitao Wang, Qiang Liu, Zhi Yao, Ying Yu, Jie Zhou
Journal: Cellular and Molecular Immunology (2024)
Polymeric micellar nanoparticles for effective CRISPR/Cas9 genome editing in cancer
Authors: Yuzhen Li, Chun Li, Jiachang Yan, Ying Liao, Chengyuan Qin, Lingyin Wang, Yi Huang, Chuan Yang, Jianwei Wang, Xin Ding, Yi Yan Yang, Peiyan Yuan
Journal: Biomaterials (2024)
Novel‐Ink‐Based Direct Ink Writing of Ti6Al4V Scaffolds with Sub‐300 µm Structural Pores for Superior Cell Proliferation and Differentiation (Adv. Healthcare Mater. 10/2024)
Authors: Chao Xu, Yan Xu, Hao Chen, Qing Han, Wenzheng Wu, Lu Zhang, Qingping Liu, Jincheng Wang, Luquan Ren
Journal: Advanced Healthcare Materials (2024)
Amplified and Specific Staining of Protein Dimerization on Cell Membrane Catalyzed by Responsively Installed DNA Nanomachines for Cancer Diagnosis (Adv. Healthcare Mater. 10/2024)
Authors: Zhenqiang Wang, Xiyue Xie, Kaifei Jin, Daqing Xia, Jing Zhu, Jixi Zhang
Journal: Advanced Healthcare Materials (2024)
Material‐Intrinsic NIR‐Fluorescence Enables Image‐Guided Surgery for Ceramic Fracture Removal (Adv. Healthcare Mater. 10/2024)
Authors: Robert Nißler, Elena Totter, Sebastian G. Walter, Justus T. Metternich, Oscar Cipolato, Dimitri Nowack, Alexander Gogos, Inge K. Herrmann
Journal: Advanced Healthcare Materials (2024)