tbuckley/cabot-search huggingface dataset:
Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR-T therapies in autoimmunity
Authors: Aaron Bodansky, David Jl Yu, Alysa Rallistan, Muge Kalaycioglu, Jim Boonyaratanakornkit, Damian J Green, Jordan Gauthier, Cameron J Turtle, Kelsey Zorn, Brian O'Donovan, Caleigh Mandel-Brehm, James Asaki, Hannah Kortbawi, Andrew F Kung, Elze Rackaityte, Chung-Yu Wang, Aditi Saxena, Kimberly de Dios, Gianvito Masi, Richard J Nowak, Kevin C O'Connor, Hao Li, Valentina E Diaz, Rowan Saloner, Kaitlin B Casaletto, Eva Q Gontrum, Brandon Chan, Joel H Kramer, Michael R Wilson, Paul J Utz, Joshua A Hill, Shaun W Jackson, Mark S Anderson, Joseph L DeRisi
Journal: Journal of Clinical Investigation (2024)

Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.
The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells
Authors: Juan Carlos López-Gil, Susana García-Silva, Laura Ruiz-Cañas, Diego Navarro, Adrián Palencia-Campos, Antonio Giráldez-Trujillo, Julie Earl, Jorge Dorado, Gonzalo Gómez-López, Ana Monfort-Vengut, Sonia Alcalá, Matthias M Gaida, Sandra García-Mulero, Pablo Cabezas-Sáinz, Sandra Batres-Ramos, Emma Barreto, Patricia Sánchez-Tomero, Mireia Vallespinós, Leah Ambler, Meng-Lay Lin, Alexandra Aicher, Ana García García de Paredes, Carolina de la Pinta, Alfonso Sanjuanbenito, Ignacio Ruz-Caracuel, Mercedes Rodríguez-Garrote, Carmen Guerra, Alfredo Carrato, Guillermo de Cárcer, Laura Sánchez, César Nombela-Arrieta, Elisa Espinet, Víctor Javier Sanchez-Arevalo Lobo, Christopher Heeschen, Bruno Sainz
Journal: Gut (2024)

Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies.
Softening the tumor matrix through cholesterol depletion breaks the physical barrier for enhanced antitumor therapy
Authors: Zhangwen Peng, Yunfei Yi, Yichu Nie, Tianqi Wang, Jia Tang, Sheng Hong, Yuanqi Liu, Wenxin Huang, Shengjie Sun, Hui Tan, Meiying Wu
Journal: Journal of Controlled Release (2024)
Meningeal lymphatic CGRP signaling governs pain via cerebrospinal fluid efflux and neuroinflammation in migraine models
Authors: Nathan P Nelson-Maney, Laszlo Balint, Anna Ls Beeson, D Stephen Serafin, Bryan M Kistner, Elizabeth S Douglas, Aisha H Siddiqui, Alyssa M Tauro, Kathleen M Caron
Journal: Journal of Clinical Investigation (2024)

Recently developed antimigraine therapeutics targeting calcitonin gene-related peptide (CGRP) signaling are effective, though their sites of activity remain elusive. Notably, the lymphatic vasculature is responsive to CGRP signaling, but whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology is unknown. Mice with lymphatic vasculature deficient in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin-mediated (NTG-mediated) chronic migraine exhibit reduced pain and light avoidance compared with NTG-treated littermate controls. Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG revealed increased MLV-immune interactions compared with cells from untreated mice. Interestingly, the relative abundance of mucosal vascular addressin cell adhesion molecule 1-interacting (MAdCAM1-interacting) CD4+ T cells was increased in the deep cervical lymph nodes of NTG-treated control mice but not in NTG-treated CalcrliLEC mice. Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial-cadherin (VE-cadherin) rearrangement and reduced functional permeability. Likewise, intra cisterna magna injection of CGRP caused rearrangement of VE-cadherin, decreased MLV uptake of cerebrospinal fluid (CSF), and impaired CSF drainage in control mice but not in CalcrliLEC mice. Collectively, these findings reveal a previously unrecognized role for lymphatics in chronic migraine, whereby CGRP signaling primes MLV-immune interactions and reduces CSF efflux.
Conditional knockdown of OsMLH1 to improve plant prime editing systems without disturbing fertility in rice
Authors: Xiaoshuang Liu, Dongfang Gu, Yiru Zhang, Yingli Jiang, Zhi Xiao, Rongfang Xu, Ruiying Qin, Juan Li, Pengcheng Wei
Journal: Genome biology (2024)

Abstract Background High-efficiency prime editing (PE) is desirable for precise genome manipulation. The activity of mammalian PE systems can be largely improved by inhibiting DNA mismatch repair by coexpressing a dominant-negative variant of MLH1. However, this strategy has not been widely used for PE optimization in plants, possibly because of its less conspicuous effects and inconsistent performance at different sites. Results We show that direct RNAi knockdown of OsMLH1 in an ePE5c system increases the efficiency of our most recently updated PE tool by 1.30- to 2.11-fold in stably transformed rice cells, resulting in as many as 85.42% homozygous mutants in the T 0 generation. The high specificity of ePE5c is revealed by whole-genome sequencing. To overcome the partial sterility induced by OsMLH1 knockdown of ePE5c, a conditional excision system is introduced to remove the RNAi module by Cre-mediated site-specific recombination. Using a simple approach of enriching excision events, we generate 100% RNAi module-free plants in the T 0 generation. The increase in efficiency due to OsMLH1 knockdown is maintained in the excised plants, whose fertility is not impaired. Conclusions This study provides a safe and reliable plant PE optimization strategy for improving editing efficiency without disturbing plant development via transient MMR inhibition with an excisable RNAi module of MLH1.
HATCHet2: clone- and haplotype-specific copy number inference from bulk tumor sequencing data
Authors: Matthew A. Myers, Brian J. Arnold, Vineet Bansal, Metin Balaban, Katelyn M. Mullen, Simone Zaccaria, Benjamin J. Raphael
Journal: Genome biology (2024)

Bulk DNA sequencing of multiple samples from the same tumor is becoming common, yet most methods to infer copy-number aberrations (CNAs) from this data analyze individual samples independently. We introduce HATCHet2, an algorithm to identify haplotype- and clone-specific CNAs simultaneously from multiple bulk samples. HATCHet2 extends the earlier HATCHet method by improving identification of focal CNAs and introducing a novel statistic, the minor haplotype B-allele frequency (mhBAF), that enables identification of mirrored-subclonal CNAs. We demonstrate HATCHet2's improved accuracy using simulations and a single-cell sequencing dataset. HATCHet2 analysis of 10 prostate cancer patients reveals previously unreported mirrored-subclonal CNAs affecting cancer genes.
High-flow nasal oxygen for children's airway surgery to reduce hypoxaemic events: a randomised controlled trial
Authors: Susan Humphreys, Britta S von Ungern-Sternberg, Fiona Taverner, Andrew Davidson, Justin Skowno, Ben Hallett, David Sommerfield, Neil Hauser, Tara Williams, Susan Spall, Trang Pham, Tiffany Atkins, Mark Jones, Emma King, Laura Burgoyne, Philip Stephens, Shyan Vijayasekaran, Nicola Slee, Hannah Burns, Donna Franklin, Judith Hough, Andreas Schibler
Journal: The Lancet Respiratory Medicine (2024)
Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (D2EFT): an open-label, randomised, phase 3b/4 trial
Authors: Gail Matthews, Simone Jacoby, Margaret Borok, Nnakelu Eriobu, Richard Kaplan, Nagalingeswaran Kumarasamy, Jaclyn Ann Bennet, Anchalee Avihingsanon, Ploenchan Chetchotisakd, Sandra Wagner Cardoso, Iskandar Azwa, Marcelo Losso, Dannae Brown, Dona Arlinda, Jolie Hutchinson, Anthony Kelleher, Mohamed Cisse, Sounkalo Dao, Mark Polizzotto, Sean Emery, Matthew Law, Emmanuelle Papot, Muhammad Karyana, Sergio Lupo, Ana Melisa Solari, Beatriz Grinsztejn, Marcello Wolff, Jaime Andrade-Villanueva, Juan Luis Mosqueda Gómez, Ting Soo Chow, Lerato Mohapi, Evy Yunihastuti, Usman Hadi, Sudirman Katu, Yanri Wijayanti Subronto, H. Clifford Lane, Leonardo Perelis
Journal: The Lancet HIV (2024)
Dual‐Site Biomacromolecule Doped Poly(3, 4‐ethylenedioxythiophene) for Bosting Both Anticoagulant and Electrochemical Performances
Authors: Xiangya Wang, Jianzhou Niu, Mohammed Kamal Hadi, Dongli Guo, Yuxia Zhang, Meimei Yu, Qi Zhou, Fen Ran
Journal: Advanced Healthcare Materials (2024)

Poly(3, 4-ethylenedioxythiophene) (PEDOT) as a new generation of intelligent conductive polymers, is attracting much attention in the field of tissue engineering. However, its water dispersibility, conductivity, and biocompatibility are incompatible, which limit its further development. In this work, biocompatible electrode material of PEDOT doped with sodium sulfonated alginate (SS) which contains two functional groups of sulfonic acid and carboxylic acid per repeat unit of the macromolecule. The as dual-site doping strategy simultaneously boosts anticoagulant and electrochemical performances, for example, good hydrophilicity (water contact angle of 59.40°), well dispersibility (dispersion solution unstratified in 30 days), high conductivity (4.45 S m
Anti-EGFR antibody-drug conjugate carrying an inhibitor targeting CDK restricts triple-negative breast cancer growth
Authors: Anthony Cheung, Alicia M. Chenoweth, Annelie Johansson, Roman Laddach, Naomi Guppy, Jennifer Trendell, Benjamina Esapa, Antranik Mavousian, Blanca Navarro-Llinas, Syed Haider, Pablo Romero-Clavijo, Ricarda M. Hoffmann, Paolo Andriollo, Khondaker M. Rahman, Paul Jackson, Sophia Tsoka, Sheeba Irshad, Ioannis Roxanis, Anita Grigoriadis, David E. Thurston, Christopher J. Lord, Andrew N. J. Tutt, Sophia N. Karagiannis
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Anti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite the clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors in hormone receptor–positive tumors, aggressive triple-negative breast cancers (TNBC) are largely resistant due to CDK2/cyclin E expression, whereas free CDK2 inhibitors display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK inhibitor selected based on oncogene dysregulation, alongside patient subgroup stratification, may provide EGFR-targeted delivery. Experimental Design: Expressions of G1/S-phase cell cycle regulators were evaluated alongside EGFR in breast cancer. We conjugated cetuximab with CDK inhibitor SNS-032, for specific delivery to EGFR-expressing cells. We assessed ADC internalization and its antitumor functions in vitro and in orthotopically grown basal-like/TNBC xenografts. Results: Transcriptomic (6,173 primary, 27 baseline, and matched post-chemotherapy residual tumors), single-cell RNA sequencing (150,290 cells, 27 treatment-naïve tumors), and spatial transcriptomic (43 tumor sections, 22 TNBCs) analyses confirmed expression of CDK2 and its cyclin partners in basal-like/TNBCs, associated with EGFR. Spatiotemporal live-cell imaging and super-resolution confocal microscopy demonstrated ADC colocalization with late lysosomal clusters. The ADC inhibited cell cycle progression, induced cytotoxicity against high EGFR-expressing tumor cells, and bystander killing of neighboring EGFR-low tumor cells, but minimal effects on immune cells. Despite carrying a small molar fraction (1.65%) of the SNS-032 inhibitor, the ADC restricted EGFR-expressing spheroid and cell line/patient-derived xenograft tumor growth. Conclusions: Exploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab–CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle–targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease.
Reprogramming exosomes for immunity-remodeled photodynamic therapy against non-small cell lung cancer
Authors: Jiao Guo, Wei Zhao, Xinyu Xiao, Shanshan Liu, Liang Liu, La Zhang, Lu Li, Zhenghang Li, Zhi Li, Mengxia Xu, Qiling Peng, Jianwei Wang, Yuxian Wei, Ning Jiang
Journal: Bioactive Materials (2024)

Traditional treatments against advanced non-small cell lung cancer (NSCLC) with high morbidity and mortality continue to be dissatisfactory. Given this situation, there is an urgent requirement for alternative modalities that provide lower invasiveness, superior clinical effectiveness, and minimal adverse effects. The combination of photodynamic therapy (PDT) and immunotherapy gradually become a promising approach for high-grade malignant NSCLC. Nevertheless, owing to the absence of precise drug delivery techniques as well as the hypoxic and immunosuppressive characteristics of the tumor microenvironment (TME), the efficacy of this combination therapy approach is less than ideal. In this study, we construct a novel nanoplatform that indocyanine green (ICG), a photosensitizer, loads into hollow manganese dioxide (MnO
Hemoglobin A1c Trajectories During Pregnancy and Adverse Outcomes in Women With Type 2 Diabetes: A Danish National Population-Based Cohort Study
Authors: Anna S. Koefoed, Sine Knorr, Jens Fuglsang, Magnus Leth-Møller, Adam Hulman, Dorte M. Jensen, Lise Lotte T. Andersen, A. Emilie Rosbach, Peter Damm, Elisabeth R. Mathiesen, Anne Sørensen, Trine T. Christensen, H. David McIntyre, Per Ovesen, Ulla Kampmann
Journal: Diabetes Care (2024)

OBJECTIVE To identify and characterize groups of pregnant women with type 2 diabetes with distinct hemoglobin A1c (HbA1c) trajectories across gestation and to examine the association with adverse obstetric and perinatal outcomes. RESEARCH DESIGN AND METHODS This was a retrospective Danish national cohort study including all singleton pregnancies in women with type 2 diabetes, giving birth to a liveborn infant, between 2004 and 2019. HbA1c trajectories were identified using latent class linear mixed-model analysis. Associations with adverse outcomes were examined with logistic regression models. RESULTS A total of 1,129 pregnancies were included. Three HbA1c trajectory groups were identified and named according to the glycemic control in early pregnancy (good, 59%; moderate, 32%; and poor, 9%). According to the model, all groups attained an estimated HbA1c &amp;lt;6.5% (48 mmol/mol) during pregnancy, with no differences between groups in the 3rd trimester. Women with poor glycemic control in early pregnancy had lower odds of having an infant with large-for-gestational-age (LGA) birth weight (adjusted odds ratio [aOR] 0.57, 95% CI 0.40–0.83), and higher odds of having an infant with small-for-gestational age (SGA) birth weight (aOR 2.49, 95% CI 2.00–3.10) and congenital malformation (CM) (aOR 4.60 95% CI 3.39–6.26) compared with women with good glycemic control. There was no evidence of a difference in odds of preeclampsia, preterm birth, and caesarean section between groups. CONCLUSIONS Women with poor glycemic control in early pregnancy have lower odds of having an infant with LGA birth weight, but higher odds of having an infant with SGA birth weight and CM.
Identifying key health system components associated with improved outcomes to inform the re-configuration of services for adults with rare autoimmune rheumatic diseases: a mixed-methods study
Authors: Rosemary J Hollick, Warren R G James, Avril Nicoll, Louise Locock, Corri Black, Neeraj Dhaun, Allyson C Egan, Nicholas Fluck, Lynn Laidlaw, Peter C Lanyon, Mark A Little, Raashid Ahmed Luqmani, Laura Moir, Maureen McBain, Neil Basu
Journal: The Lancet Rheumatology (2024)

Adults with rare autoimmune rheumatic diseases face unique challenges and struggles to navigate health-care systems designed to manage common conditions. Evidence to inform an optimal service framework for their care is scarce. Using systemic vasculitis as an exemplar, we aimed to identify and explain the key service components underpinning effective care for rare diseases.
Geospatial disparities in survival of patients with breast cancer in sub-Saharan Africa from the African Breast Cancer-Disparities in Outcomes cohort (ABC-DO): a prospective cohort study
Authors: Joanne Kim, Peter M Macharia, Valerie McCormack, Milena Foerster, Moses Galukande, Maureen Joffe, Herbert Cubasch, Annelle Zietsman, Angelica Anele, Shadrach Offiah, Groesbeck Parham, Leeya F Pinder, Benjamin O Anderson, Joachim Schüz, Isabel dos Santos-Silva, Kayo Togawa
Journal: The Lancet Global Health (2024)

There is an urgent need to improve breast cancer survival in sub-Saharan Africa. Geospatial barriers delay diagnosis and treatment, but their effect on survival in these settings is not well understood. We examined geospatial disparities in 4-year survival in the African Breast Cancer-Disparities in Outcomes cohort. In this prospective cohort study, women (aged ≥18 years) newly diagnosed with breast cancer were recruited from eight hospitals in Namibia, Nigeria, South Africa, Uganda, and Zambia. They reported sociodemographic information in interviewer-administered questionnaires, and their clinical and treatment data were collected from medical records. Vital status was ascertained by contacting participants or their next of kin every 3 months. The primary outcome was all-cause mortality in relation to rural versus urban residence, straight-line distance, and modelled travel time to hospital, analysed using restricted mean survival time, Cox proportional hazards, and flexible parametric survival models. 2228 women with breast cancer were recruited between Sept 8, 2014, and Dec 31, 2017. 127 were excluded from analysis (58 had potentially recurrent cancer, had previously received treatment, or had no follow-up; 14 from minority ethnic groups with small sample sizes; and 55 with missing geocoded home addresses). Among the 2101 women included in analysis, 928 (44%) lived in a rural area. 1042 patients had died within 4 years of diagnosis; 4-year survival was 39% (95% CI 36–42) in women in rural areas versus 49% (46–52) in urban areas (unadjusted hazard ratio [HR] 1·24 [95% CI 1·09–1·40]). Among the 734 women living more than 1 h from the hospital, the crude 4-year survival was 37% (95% CI 32–42) in women in rural areas versus 54% (46–62) in women in urban areas (HR 1·35 [95% CI 1·07–1·71] after adjustment for age, stage, and treatment status). Among women in rural areas, mortality rates increased with distance (adjusted HR per 50 km 1·04, 1·01–1·07) and travel time (adjusted HR per h 1·06, 1·02–1·10). Among women with early-stage breast cancer receiving treatment, women in rural areas had a strong survival disadvantage (overall HR 1·54, 1·14–2·07 adjusted for age and stage; >1 h distance adjusted HR 2·14, 1·21–3·78). Geospatial barriers reduce survival of patients with breast cancer in sub-Saharan Africa. Specific attention is needed to support patients with early-stage breast cancer living in rural areas far from cancer treatment facilities. US National Institutes of Health (National Cancer Institute), Susan G Komen for the Cure, and the International Agency for Research on Cancer.
Phase I Trial of GD2.CART Cells Augmented With Constitutive Interleukin-7 Receptor for Treatment of High-Grade Pediatric CNS Tumors
Authors: Frank Y. Lin, Austin Stuckert, Candise Tat, Mark White, Lucia Ruggieri, Huimin Zhang, Birju Mehta, Natalia Lapteva, Zhuyong Mei, Angela Major, Sachin Thakkar, Thomas Shum, Kathan Parikh, Meng-Fen Wu, Holly B. Lindsay, Lauren Scherer, Meghan Shekar, Patricia Baxter, Tao Wang, Bambi Grilley, Karen Moeller, John Hicks, Angshumoy Roy, Jamie Anastas, Fatema Malbari, Guillermo Aldave, Murali Chintagumpala, Susan Blaney, D. Williams Parsons, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney, Bilal Omer
Journal: Journal of Clinical Oncology (2024)

T cells modified with chimeric antigen receptors (CARTs) have demonstrated efficacy for hematologic malignancies; however, benefit for patients with CNS tumors has been limited. To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 receptor (C7R-GD2.CARTs).
Virtual fitness buddy ecosystem: a mixed reality precision health physical activity intervention for children
Authors: Sun Joo Ahn, Michael D. Schmidt, Allan D. Tate, Stephen Rathbun, James J. Annesi, Lindsay Hahn, Eric Novotny, Christian Okitondo, Rebecca N. Grimsley, Kyle Johnsen
Journal: npj Digital Medicine (2024)

Abstract 6–11-year-old children provide a critical window for physical activity (PA) interventions. The Virtual Fitness Buddy ecosystem is a precision health PA intervention for children integrating mixed reality technology to connect people and devices. A cluster randomized, controlled trial was conducted across 19 afterschool sites over two 6-month cohorts to test its efficacy in increasing PA and decreasing sedentary behavior. In the treatment group, a custom virtual dog via a mixed reality kiosk helped children set PA goals while sharing progress with parents to receive feedback and support. Children in the control group set PA goals using a computer without support from the virtual dog or parents. 303 children had 8+ hours of PA data on at least one day of each of the 3 intervention time intervals. Conversion of sedentary time was primarily to light-intensity PA and was strongest for children with low baseline moderate-to-vigorous PA than children above 45 min of baseline moderate-to-vigorous PA. Findings suggest that the VFB ecosystem can promote sustainable PA in children and may be rapidly diffused for widespread public health impact.