tbuckley/cabot-search huggingface dataset:
Monoclonal antibodies against the spike protein alter the endogenous humoral response to SARS-CoV-2 vaccination and infection
Authors: Christopher D. Petro, Andrea T. Hooper, Avery Peace, Kusha Mohammadi, Will Eagan, Sayda M. Elbashir, Anthony DiPiazza, Daniel Makrinos, Kristen Pascal, Pooja Bandawane, Mauricio Durand, Ranu Basu, Alida Coppi, Bei Wang, Jacquelynn Golubov, Seblewongel Asrat, Samit Ganguly, Ellen-Marie Koehler-Stec, Matthew F. Wipperman, George Ehrlich, Ana M. Gonzalez Ortiz, Flonza Isa, Mark G. Lewis, Hanne Andersen, Bret J. Musser, Marcela Torres, Wen-Yi Lee, Darin Edwards, Dimitris Skokos, Jamie Orengo, Matthew Sleeman, Thomas Norton, Meagan O’Brien, Eduardo Forleo-Neto, Gary A. Herman, Jennifer D. Hamilton, Andrew J. Murphy, Christos A. Kyratsous, Alina Baum
Journal: Science Translational Medicine (2024)

Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen. Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice. The presence of CAS+IMD at the time of vaccination led to a specific diminishment of vaccine-elicited pseudovirus neutralizing antibody titers without overall dampening of spike protein–directed immune responses, including antibody, B cell, and T cell responses. The impact on pseudovirus neutralizing titers extended to other therapeutic anti–spike protein antibodies when used as either monotherapy or combination therapy. The specific reduction in pseudovirus neutralizing titers was the result of epitope masking, a phenomenon where specific epitopes are bound by high-affinity antibodies and blocked from B cell recognition. Encouragingly, this reduction in pseudovirus neutralizing titers was reversible with additional booster vaccination. Moreover, by assessing the antiviral immune response in SARS-CoV-2–infected individuals treated therapeutically with CAS+IMD, we demonstrated alteration of antiviral humoral immunity in those who had received mAb therapy, but only in those individuals who had yet to start mounting their natural immune response at the time of mAb treatment. Together, these data demonstrate that antiviral mAbs can alter endogenous humoral immunity during vaccination or infection.
Transient anti-interferon autoantibodies in the airways are associated with recovery from COVID-19
Authors: Benjamin R. Babcock, Astrid Kosters, Devon J. Eddins, Maria Sophia Baluyot Donaire, Sannidhi Sarvadhavabhatla, Vivian Pae, Fiona Beltran, Victoria W. Murray, Gurjot Gill, Guorui Xie, Brian S. Dobosh, Vincent D. Giacalone, Rabindra M. Tirouvanziam, Richard P. Ramonell, Scott A. Jenks, Ignacio Sanz, F. Eun-Hyung Lee, Nadia R. Roan, Sulggi A. Lee, Eliver E. B. Ghosn
Journal: Science Translational Medicine (2024)

Preexisting anti–interferon-α (anti–IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti–IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti–IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti–IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti–SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti–IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti–IFN-α response. In contrast, systemic IgG1 anti–IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti–IFN-α in the immunopathology of COVID-19 and suggest that anti–IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa.
Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice
Authors: Victor Fattori, Tiago H. Zaninelli, Fernanda S. Rasquel-Oliveira, Olivia K. Heintz, Ashish Jain, Liang Sun, Maya L. Seshan, Daniëlle Peterse, Anne E. Lindholm, Raymond M. Anchan, Waldiceu A. Verri, Michael S. Rogers
Journal: Science Translational Medicine (2024)

Endometriosis is a debilitating and painful gynecological inflammatory disease affecting up to 15% of women and transgender men. Current treatments are ineffective for a substantial proportion of patients, underscoring the need for additional therapies with long-term benefits. Nociceptors release neuropeptides, such as calcitonin gene–related peptide (CGRP), which are known to shape immunity through neuroimmune communication. Given the comorbidity between endometriosis and migraine and the integral role of immune cells and inflammation in endometriosis, we investigated the role of CGRP-mediated neuroimmune communication in endometriosis. Using samples from eight patients with endometriosis and a nonsurgical mouse model of the disease, we found that mouse and human endometriosis lesions contain both CGRP and its coreceptor, receptor activity modifying protein 1 (RAMP1). In mice, nociceptor ablation reduced pain, monocyte recruitment, and lesion size, suggesting that nociceptor activation and neuropeptide release contribute to endometriosis lesion growth and pain. Mechanistically, CGRP changed the phenotype of macrophages to a pro-endometriosis phenotype. CGRP-stimulated macrophages demonstrated impaired efferocytosis and supported increased endometrial cell growth in a RAMP1-dependent manner. Treatment of lesion-bearing mice with US Food and Drug Administration–approved drugs that block CGRP-RAMP1 signaling reduced mechanical hyperalgesia, spontaneous pain, and lesion size. Together, our data demonstrated the effectiveness and underlying cellular mechanisms of nonhormonal and nonopioid CGRP/RAMP1 blockade in a mouse model of endometriosis, suggesting that targeting this axis may lead to clinical benefit for patients with endometriosis.
Cutting-edge nanotechnology transforming cancer surgery and recovery
Authors: Vimalraj Selvaraj, Swathi Sudhakar, Saravanan Sekaran, Neelamegam Rameshkumar, Muthukaligan Khrishnan, Suresh Kumar Rajamani Sekar
Journal: International Journal of Surgery (2024)

Selvaraj, Vimalraj; Sudhakar, Swathi; Sekaran, Saravanan; Rameshkumar, Neelamegam; Khrishnan, Muthukaligan; Rajamani Sekar, Suresh Kumar Author Information
Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients
Authors: Luke C. Bartelt, Pawel M. Switonski, Grażyna Adamek, Fabiana Longo, Juliana Carvalho, Lisa A. Duvick, Sabrina I. Jarrah, Hayley S. McLoughlin, Daniel R. Scoles, Stefan M. Pulst, Harry T. Orr, Court Hull, Craig B. Lowe, Albert R. La Spada
Journal: Science Translational Medicine (2024)

Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias.
Enhancing postoperative care with telemedicine and remote monitoring for improved recovery and patient safety
Authors: Jeyanthi P, Gulothungan G, Vinoth Kumar V, Hitesh Chopra, Talha Bin Emran
Journal: International Journal of Surgery (2024)

P, Jeyanthi; G, Gulothungan; V, Vinoth Kumar; Chopra, Hitesh; Bin Emran, Talha Author Information
Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population
Authors: Jingjing Ding, Huaizheng Liu, Xiaoxun Zhang, Nan Zhao, Ying Peng, Junping Shi, Jinjun Chen, Xiaoling Chi, Ling Li, Mengni Zhang, Wen-Yue Liu, Liangjun Zhang, Jiafeng Ouyang, Qian Yuan, Min Liao, Ya Tan, Mingqiao Li, Ziqian Xu, Wan Tang, Chuanming Xie, Yi Li, Qiong Pan, Ying Xu, Shi-Ying Cai, Christopher D. Byrne, Giovanni Targher, Xinshou Ouyang, Liqun Zhang, Zhongyong Jiang, Ming-Hua Zheng, Fengjun Sun, Jin Chai
Journal: Science Translational Medicine (2024)

Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid–mTOR–FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.
Letter to the editor regarding ‘Using computed tomography to evaluate anatomic landmarks in taiwanese trauma patients for insertion of resuscitative endovascular balloon occlusion of the aorta: A retrospective cohort study’ – liberating REBOA from imaging
Authors: Jan C. van de Voort, Boudewijn L.S. Borger van der Burg, Rigo Hoencamp
Journal: International Journal of Surgery (2024)

van de Voort, Jan C. MD; Borger van der Burg, Boudewijn L.S. MD PhD; Hoencamp, Rigo MD PhD Author Information
The <i>R1441C-Lrrk2</i> mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice
Authors: Rebecca L. Wallings, Karen McFarland, Hannah A. Staley, Noelle Neighbarger, Susen Schaake, Norbert Brüggemann, Simone Zittel, Tatiana Usnich, Christine Klein, Esther M. Sammler, Malú Gámez Tansey
Journal: Science Translational Medicine (2024)

Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the LRRK2 gene affects risk for both familial and sporadic Parkinson’s disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear. We analyzed peritoneal macrophages from R1441C-Lrrk2 knock-in mice and observed a biphasic, age-dependent effect of the R1441C-Lrrk2 mutation on peritoneal macrophage function. We report increases in antigen presentation, anti-inflammatory cytokine production, lysosomal activity, and pathogen uptake in peritoneal macrophages from young (2- to 3-month-old) female R1441C-Lrrk2 mice. Conversely, macrophages from aged (18- to 21-month-old) female R1441C-Lrrk2 mice exhibited decreased antigen presentation after inflammatory insult, decreased lysosomal function, and pathogen uptake, with a concomitant increase in DNA fragmentation in the presence of pathogens. This immune cell exhaustion phenotype was not observed in male R1441C-Lrrk2 mice and was driven by increased LRRK2 protein kinase activity. This phenotype was also observed in human peripheral myeloid cells, with monocyte-derived macrophages from patients with PD who had either the R1441C- or Y1699C-LRRK2 mutation exhibiting decreased pathogen uptake and increased PDL1 expression, consistent with immune cell exhaustion. Our findings that LRRK2 mutations conferred an immunological advantage at a young age but could predispose the carrier to age-acquired immune cell exhaustion have implications for the therapeutic development of LRRK2 inhibitors.
The Diverse Aspects of Uterine Serous Cancer: <i>An NCI workshop on the status of and opportunities for advancement of research</i>
Authors: Naveena B Janakiram, Megan A Clarke, Mihoko Kai, Tiffany A Wallace, Sandra Russo, Toby T Hecht, Elise C Kohn, Brandy Heckman-Stoddard
Journal: JNCI Journal of the National Cancer Institute (2024)

The marked increase in incidence and mortality in endometrial cancer over the last two decades is driven in part by rising rates of higher grade, more aggressive endometrial cancers with mutations in TP53, uterine serous cancers and their dedifferentiated component, uterine carcinosarcomas (collectively USC). USC rates have been increasing among all racial and ethnic groups, with higher rates of this aggressive uterine cancer in Black women. The National Cancer Institute (NCI) hosted a workshop in June 2023 to examine the diverse aspects of USC across epidemiology, biology, and molecular genetics, and to advance knowledge from basic to preclinical and translational efforts. Key stakeholders came together including basic scientists, clinical investigators, and patient advocates to identify critical research gaps that, when addressed, would facilitate more comprehensive and rapid progress in understanding and ultimately treating USC across all patients. NCI released a supplemental funding opportunity (NOT-CA-24-044) in Spring 2024 to facilitate rapid translation of these recommendations.
Transplantation of peripheral nerve tissueoid based on a decellularized optic nerve scaffold to restore rat hindlimb sensory and movement functions
Authors: Zhao-Wei Zhu, Ge Li, Guang-Geng Wu, Yu-Jing Zhang, Yu-Rong Bai, Bi-Qin Lai, Ying Ding, Xiang Zeng, Yuan-Huan Ma, Shu Liu, Rui Wang, Jing-Hua Liang, Yang-Bin Xu, Bo He, Yuan-Shan Zeng
Journal: Biomaterials (2024)
Engineered VNP20009 expressing IL-15&amp;15Rα augments anti-tumor immunity for bladder cancer treatment
Authors: Bo Liu, Kaiwei Wang, Qiaofeng Li, Zhisheng Xiao, Zihao Chen, Yuting Zhang, Yuzhe Wu, Yuchun Xu, Yumin Wu, Zhuang Liu
Journal: Biomaterials (2024)
Device-Measured 24-Hour Movement Behaviors and Blood Pressure: A 6-Part Compositional Individual Participant Data Analysis in the ProPASS Consortium
Authors: Joanna M. Blodgett, Matthew N. Ahmadi, Andrew J. Atkin, Richard M. Pulsford, Vegar Rangul, Sebastien Chastin, Hsiu-Wen Chan, Kristin Suorsa, Esmée A. Bakker, Nidhi Gupta, Pasan Hettiarachchi, Peter J. Johansson, Lauren B. Sherar, Borja del Pozo Cruz, Nicholas Koemel, Gita D. Mishra, Thijs M.H. Eijsvogels, Sari Stenholm, Alun D. Hughes, Armando Teixeira-Pinto, Ulf Ekelund, I-Min Lee, Andreas Holtermann, Annemarie Koster, Emmanuel Stamatakis, Mark Hamer, Hans Savelberg, Bastiaan de Galan, Carla van de Kallen, Dick H.J. Thijssen
Journal: Circulation (2024)

BACKGROUND: Blood pressure (BP)–lowering effects of structured exercise are well-established. Effects of 24-hour movement behaviors captured in free-living settings have received less attention. This cross-sectional study investigated associations between a 24-hour behavior composition comprising 6 parts (sleeping, sedentary behavior, standing, slow walking, fast walking, and combined exercise-like activity [eg, running and cycling]) and systolic BP (SBP) and diastolic BP (DBP). METHODS: Data from thigh-worn accelerometers and BP measurements were collected from 6 cohorts in the Prospective Physical Activity, Sitting and Sleep consortium (ProPASS) (n=14 761; mean±SD, 54.2±9.6 years). Individual participant analysis using compositional data analysis was conducted with adjustments for relevant harmonized covariates. Based on the average sample composition, reallocation plots examined estimated BP reductions through behavioral replacement; the theoretical benefits of optimal (ie, clinically meaningful improvement in SBP [2 mm Hg] or DBP [1 mm Hg]) and minimal (ie, 5-minute reallocation) behavioral replacements were identified. RESULTS: The average 24-hour composition consisted of sleeping (7.13±1.19 hours), sedentary behavior (10.7±1.9 hours), standing (3.2±1.1 hours), slow walking (1.6±0.6 hours), fast walking (1.1±0.5 hours), and exercise-like activity (16.0±16.3 minutes). More time spent exercising or sleeping, relative to other behaviors, was associated with lower BP. An additional 5 minutes of exercise-like activity was associated with estimated reductions of –0.68 mm Hg (95% CI, –0.15, –1.21) SBP and –0.54 mm Hg (95% CI, –0.19, 0.89) DBP. Clinically meaningful improvements in SBP and DBP were estimated after 20 to 27 minutes and 10 to 15 minutes of reallocation of time in other behaviors into additional exercise. Although more time spent being sedentary was adversely associated with SBP and DBP, there was minimal impact of standing or walking. CONCLUSIONS: Study findings reiterate the importance of exercise for BP control, suggesting that small additional amounts of exercise are associated with lower BP in a free-living setting.
Virological characteristics of the SARS-CoV-2 XEC variant
Authors: Yu Kaku, Kaho Okumura, Shusuke Kawakubo, Keiya Uriu, Luo Chen, Yusuke Kosugi, Yoshifumi Uwamino, MST Monira Begum, Sharee Leong, Terumasa Ikeda, Kenji Sadamasu, Hiroyuki Asakura, Mami Nagashima, Kazuhisa Yoshimura, Jumpei Ito, Kei Sato
Journal: The Lancet Infectious Diseases (2024)

The SARS-CoV-2 JN.1 (BA.2.86.1.1) variant, arising from BA.2.86.1 with spike protein (S) substitution S:L455S, outcompeted the previously predominant XBB lineages by the beginning of 2024.1 Subsequently, JN.1 subvariants including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which acquired additional S substitutions (eg, S:R346T, S:F456L, and S:Q493E), have emerged concurrently (appendix pp 19–20).2,3 As of October 2024, KP.3.1.1 (JN.1.11.1.3.1.1), which acquired S:31del, outcompeted other JN.1 subvariants including KP.2 and KP.3, and is the most predominant SARS-CoV-2 variant in the world.
Clinical outcomes of untreated adults living with chronic hepatitis B in The Gambia: an analysis of data from the prospective PROLIFICA cohort study
Authors: Gibril Ndow, Yusuke Shimakawa, Damien Leith, Sulayman Bah, Rohey Bangura, Isatou Mahmoud, Lamin Bojang, Amie Ceesay, Sainabou Drammeh, Queen Bola-Lawal, Gabriel Lambert, Perrine Hardy, Patrick Ingiliz, Yazan Haddadin, Erwan Vo-Quang, Stéphane Chevaliez, Gavin Cloherty, Sheikh Omar Bittaye, Gora Lo, Coumba Toure-Kane, Maimuna Mendy, Ramou Njie, Isabelle Chemin, Umberto D'Alessandro, Mark Thursz, Maud Lemoine
Journal: The Lancet. Gastroenterology & hepatology (2024)
Potential of ex vivo organotypic slice cultures in neuro-oncology
Authors: Ariane Steindl, Manuel Valiente
Journal: Neuro-Oncology (2024)

Abstract Over recent decades, in vitro and in vivo models have significantly advanced brain cancer research; however, each presents distinct challenges for accurately mimicking in situ conditions. In response, organotypic slice cultures have emerged as a promising model recapitulating precisely specific in vivo phenotypes through an ex vivo approach. Ex vivo organotypic brain slice models can integrate biological relevance and patient-specific variability early in drug discovery, thereby aiming for more precise treatment stratification. However, the challenges of obtaining representative fresh brain tissue, ensuring reproducibility, and maintaining essential central nervous system (CNS)-specific conditions reflecting the in situ situation over time have limited the direct application of ex vivo organotypic slice cultures in robust clinical trials. In this review, we explore the benefits and possible limitations of ex vivo organotypic brain slice cultures in neuro-oncological research. Additionally, we share insights from clinical experts in neuro-oncology on how to overcome these current limitations and improve the practical application of organotypic brain slice cultures beyond academic research.
Colonoscopy is associated with lower colorectal cancer occurrence and mortality in the older population: A population-based cohort study
Authors: Ji Young Lee, Jae Myung Cha, Jin Young Yoon, Min Seob Kwak, Hun Hee Lee
Journal: Endoscopy (2024)

Background and study aims: We aimed to evaluate the association between colonoscopy (CS) and colorectal cancer (CRC) occurrence and related mortality in an older population. Patients and methods: This retrospective, nationwide, population-based cohort study used data of adults aged ≥40 years from the Health Insurance Review and Assessment Service database. After excluding CS within 6 months of CRC diagnosis during enrollment, CRC occurrence and related mortality were compared between CS and non-CS groups using a time-dependent Cox proportional hazard model. Sub-group analysis was conducted among four age groups: young, middle age, old, and very old. Results Among 748,989 individuals followed for 9.64±0.99 years, the CS group had a 65% lower CRC occurrence (adjusted hazard ratio [HRa]: 0.35, 95% confidence interval [95%CI]: 0.32–0.38) and 76% lower CRC-related mortality (HRa: 0.24, 95%CI: 0.18–0.31) after 5 years than the non-CS group. CS was associated with the most significant reduction in CRC occurrence in the middle age group (HRa: 0.32, 95%CI: 0.29–0.35) and CRC-related mortality in the young age group (HRa: 0.04, 95%CI: 0.01–0.33); the very old age group had the least reduction in both CRC occurrence and CRC-related mortality (HRa: 0.44, 95%CI: 0.33–0.59 and HRa: 0.28, 95%CI: 0.15–0.53, respectively). Conclusion We found a significant association between colonoscopy and reduction in CRC occurrence and CRC-related mortality in adults aged ≥ 40 years after 5 years of follow-up; however, these associations were weaker in the very old group. Research is needed on the association between colonoscopy and older age.