tbuckley/cabot-search huggingface dataset:
Age-related epithelial defects limit thymic function and regeneration
Authors: Anastasia I. Kousa, Lorenz Jahn, Kelin Zhao, Angel E. Flores, Dante Acenas, Emma Lederer, Kimon V. Argyropoulos, Andri L. Lemarquis, David Granadier, Kirsten Cooper, Michael D’Andrea, Julie M. Sheridan, Jennifer Tsai, Lisa Sikkema, Amina Lazrak, Katherine Nichols, Nichole Lee, Romina Ghale, Florent Malard, Hana Andrlova, Enrico Velardi, Salma Youssef, Marina Burgos da Silva, Melissa Docampo, Roshan Sharma, Linas Mazutis, Verena C. Wimmer, Kelly L. Rogers, Susan DeWolf, Brianna Gipson, Antonio L. C. Gomes, Manu Setty, Dana Pe’er, Laura Hale, Nancy R. Manley, Daniel H. D. Gray, Marcel R. M. van den Brink, Jarrod A. Dudakov
Journal: Nature Immunology (2024)

Abstract The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.
Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity
Authors: Luciano Santollani, Laura Maiorino, Yiming J. Zhang, Joseph R. Palmeri, Jordan A. Stinson, Lauren R. Duhamel, Kashif Qureshi, Jack R. Suggs, Owen T. Porth, William Pinney, Riyam Al Msari, Agnes A. Walsh, K. Dane Wittrup, Darrell J. Irvine
Journal: Nature Immunology (2024)

Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8
AI-based automation of enrollment criteria and endpoint assessment in clinical trials in liver diseases
Authors: Janani S. Iyer, Dinkar Juyal, Quang Le, Zahil Shanis, Harsha Pokkalla, Maryam Pouryahya, Aryan Pedawi, S. Adam Stanford-Moore, Charles Biddle-Snead, Oscar Carrasco-Zevallos, Mary Lin, Robert Egger, Sara Hoffman, Hunter Elliott, Kenneth Leidal, Robert P. Myers, Chuhan Chung, Andrew N. Billin, Timothy R. Watkins, Scott D. Patterson, Murray Resnick, Katy Wack, Jon Glickman, Alastair D. Burt, Rohit Loomba, Arun J. Sanyal, Ben Glass, Michael C. Montalto, Amaro Taylor-Weiner, Ilan Wapinski, Andrew H. Beck
Journal: Nature Medicine (2024)

Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P < 0.0001) and stage 4 (P = 0.03) fibrosis. In a retrospective analysis of the ATLAS trial (NCT03449446), responders receiving study treatment showed a greater continuous change in fibrosis compared with placebo (P = 0.02). Overall, these results suggest that AIM-MASH may assist pathologists in histologic review of MASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient responses.
Evaluating multimodal AI in medical diagnostics
Authors: Robert Kaczmarczyk, Theresa Isabelle Wilhelm, Ron Martin, Jonas Roos
Journal: npj Digital Medicine (2024)

This study evaluates multimodal AI models' accuracy and responsiveness in answering NEJM Image Challenge questions, juxtaposed with human collective intelligence, underscoring AI's potential and current limitations in clinical diagnostics. Anthropic's Claude 3 family demonstrated the highest accuracy among the evaluated AI models, surpassing the average human accuracy, while collective human decision-making outperformed all AI models. GPT-4 Vision Preview exhibited selectivity, responding more to easier questions with smaller images and longer questions.
Race and Sex Differences in the Association of Bystander CPR for Cardiac Arrest
Authors: Paul S. Chan, Saket Girotra, Audrey Blewer, Kevin F. Kennedy, Bryan F. McNally, Justin L. Benoit, Monique A. Starks
Journal: Circulation (2024)

Bystander cardiopulmonary resuscitation (CPR) is associated with higher survival for out-of-hospital cardiac arrest, but whether its association with survival differs by patients' sex and race and ethnicity is less clear.
PD‐L1<sup>+</sup> macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B‐cell lymphoma microenvironment impact CD19 CAR‐T cell immunotherapy efficacy
Authors: Alexandre V. Hirayama, Jocelyn H. Wright, Kimberly S. Smythe, Salvatore Fiorenza, Akira N. Shaw, Jordan Gauthier, David G. Maloney, Kikkeri N. Naresh, Cecilia C. S. Yeung, Cameron J. Turtle
Journal: HemaSphere (2024)

Abstract CD19‐targeted chimeric antigen receptor T‐cell (CAR‐T) immunotherapy has transformed the management of relapsed/refractory large B‐cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR‐T therapy outcomes. Using NanoString nCounter transcriptome profiling ( n = 24) and multiplex immunohistochemistry (mIHC, n = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR‐T therapy. Patients who achieved complete response (CR) after CAR‐T therapy demonstrated higher expression of genes associated with T‐cell trafficking and function, whereas those who did not achieve CR had higher expression of genes associated with macrophages and T‐cell dysfunction. Distinct patterns of immune infiltration and fibrosis in the TME were associated with CAR‐T therapy outcomes, and these findings were corroborated using artificial intelligence‐assisted image analyses. Patients who achieved CR had a lower proportion of the biopsy occupied by an interspersed immune infiltrate and a higher proportion of hypocellular/fibrotic regions. Furthermore, mIHC revealed lower density of CD4 + T cells and higher densities of both macrophages and tumor cells expressing PD‐L1 in non‐CR patients. Spatial analysis revealed that PD‐1 + T cells were in close proximity to PD‐L1 + macrophages or PD‐L1 + tumor cells in patients who did not compared to those who did achieve CR after CAR‐T therapy. These findings suggest that morphologic patterns in the TME and engagement of the PD‐1/PD‐L1 axis in pretreatment biopsies may impact CD19 CAR‐T immunotherapy response in patients with LBCL.
Transcriptomic profiles of well‐differentiated airway epithelial cells in response to environmental triggers of asthma exacerbation
Authors: Antonella Marrocco, Jennifer A. Mitchel, Margaret Parker, Maureen McGill, Robert P. Chase, Scott T. Weiss, Diane R. Gold, Peter J. Castaldi, Elliot Israel, Jin‐Ah Park, Joanne E. Sordillo
Journal: Allergy (2024)

The data that support the findings of this study are openly available in GEO at https://www.ncbi.nlm.nih.gov/geo/, reference number GSE261805. Figure S1. Data S1. Table S1. Table S2. Table S3. Table S4. Table S5. Table S6. Table S7. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Impact of a drug allergy education course for non‐specialists: Findings from <scp>ADAPT—</scp>A randomized crossover trial
Authors: Michaela Lucas, Hugo W. F. Mak, Jasmine T. Y. Lee, Rishabh Kulkarni, Sophia S. C. Chan, Philip H. Li
Journal: Allergy (2024)

The consequences of drug allergy remain a global health concern. Drug allergy is often a neglected topic and many non-specialists lack sufficient knowledge or confidence in evaluating or managing this common condition. Evidence-based interventions to better equip non-specialists to tackle drug allergy are needed. The aim of the study is to evaluate the effectiveness of an intensive educational course on drug allergy knowledge and practice of non-specialists. A randomized crossover trial (NCT06399601) was conducted among practicing physicians and nurses participating in an intensive drug allergy course-Advances in Drug Allergy & Penicillin Testing (ADAPT). Participants' baseline knowledge and self-reported practices were assessed with standardized questionnaires (scored from 0 to 100, with "satisfactory" defined as ≥60/100). Participants were randomized into two cohorts and attended ADAPT at different time points. Serial responses before and after the course were compared within and between cohorts. Seventy participants (25 physicians, 45 nurses) randomized into two groups completed the course. Baseline drug allergy knowledge (58.0 ± 19.9) and self-reported practice (36.9 ± 24.3) were unsatisfactory among non-specialists, with significantly lower scores from nurses than physicians in both domains (knowledge: 49.0 ± 17.4 vs. 74.0 ± 12.7; practice: 32.1 ± 21.3 vs. 53.3 ± 23.1; all p < 0.001). Following completion of ADAPT, participants demonstrated significant improvements in knowledge (58.0 ± 19.9 vs. 77.7 ± 15.9, p < 0.001) and self-reported practice (36.9 ± 24.3 vs. 71.0 ± 20.2, p < 0.001). All participants (100%) and 99% of participants agreed that the course improved their clinical knowledge and practice, respectively. ADAPT, an intensive drug allergy educational course was effective in improving drug allergy knowledge and practice for non-specialists. Further longitudinal studies are required to evaluate long-term impact.
Real‐world data show sustained therapeutic effects of dupilumab in chronic rhinosinusitis with nasal polyps (<scp>CRSwNP</scp>) over 3 years
Authors: Patrick Huber, Ulrike Förster‐Ruhrmann, Heidi Olze, Sven Becker, Friederike Bärhold, Mandy Cuevas, Nadine Gunder, Jan Hagemann, Christoph Matthias, Ludger Klimek, Moritz Gröger
Journal: Allergy (2024)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent chronic inflammatory condition affecting the nose and paranasal sinuses, posing a significant socio-economic impact with substantial challenges in management. Biologics targeting type 2 inflammation such as dupilumab, have emerged as promising options. This study addresses a critical knowledge gap by comprehensively evaluating the 3-year impact of sustained dupilumab therapy in CRSwNP.
rTMS as a Next Step in Antidepressant Nonresponders: A Randomized Comparison With Current Antidepressant Treatment Approaches
Authors: Iris Dalhuisen, Iris van Oostrom, Jan Spijker, Ben Wijnen, Eric van Exel, Hans van Mierlo, Dieuwertje de Waardt, Martijn Arns, Indira Tendolkar, Philip van Eijndhoven
Journal: American Journal of Psychiatry (2024)

Although repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, little is known about the comparative effectiveness of rTMS and other treatment options, such as antidepressants. In this multicenter randomized controlled trial, rTMS was compared with the next pharmacological treatment step in patients with treatment-resistant depression.
Peer Social Genetic Effects and the Etiology of Substance Use Disorders, Major Depression, and Anxiety Disorder in a Swedish National Sample
Authors: Jessica E. Salvatore, Henrik Ohlsson, Jan Sundquist, Kristina Sundquist, Kenneth S. Kendler
Journal: American Journal of Psychiatry (2024)

There is growing interest in how peers' genotypes may influence health (i.e., peer social genetic effects). The authors sought to clarify the nature of peer social genetic effects on risk for drug use disorder, alcohol use disorder (AUD), major depression, and anxiety disorder.
Sensitive Colorimetric Lateral Flow Assays Enabled by Platinum‐Group Metal Nanoparticles with Peroxidase‐Like Activities
Authors: Shikuan Shao, Xiaochuan Wang, Caroline Sorial, Xiaohan Sun, Xiaohu Xia
Journal: Advanced Healthcare Materials (2024)

The last several decades have witnessed the success and popularity of colorimetric lateral flow assay (CLFA) in point-of-care testing. Driven by increasing demand, great efforts have been directed toward enhancing the detection sensitivity of CLFA. Recently, platinum-group metal nanoparticles (PGM NPs) with peroxidase-like activities have emerged as a type of promising colorimetric labels for enhancing the sensitivity of CLFA. By incorporating a simple and rapid post-treatment process, the PGM NP-based CLFAs are orders of magnitude more sensitive than conventional gold nanoparticle-based CLFAs. In this perspective, the study begins with introducing the design, synthesis, and characterization of PGM NPs with peroxidase-like activities. The current techniques for surface modification of PGM NPs are then discussed, followed by operation and optimization of PGM NP-based CLFAs. Afterward, opinions are provided on the social impact of PGM NP-based CLFAs. Lastly, this perspective is concluded with an outlook of future research directions in this emerging field, where the challenges and opportunities are discussed.
Inside Front Cover Image, Volume 44, Issue 5
Authors: Shuai‐Jiang Liu, Qian Zhao, Xiao‐Chen Liu, Allan B. Gamble, Wei Huang, Qian‐Qian Yang, Bo Han
Journal: Medicinal Research Reviews (2024)

The cover image is based on the article Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery by Shuai-Jiang Liu et al., https://doi.org/10.1002/med.22037.
Front Cover Image, Volume 44, Issue 5
Authors: Qian Zhao, Bo Han, Cheng Peng, Nan Zhang, Wei Huang, Gu He, Jun‐Long Li
Journal: Medicinal Research Reviews (2024)

The cover image is based on the article A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents by Qian Zhao et al., https://doi.org/10.1002/med.22039.
Physical activity and cognition: longitudinal findings from the Thinking and Living with Cancer Study
Authors: Ashley L Artese, Xingtao Zhou, Danielle B Tometich, Brent J Small, Tim A Ahles, Jaeil Ahn, Traci N Bethea, Elizabeth C Breen, Harvey J Cohen, Martine Extermann, Deena Graham, Claudine Isaacs, Heather S L Jim, Brenna C McDonald, Zev M Nakamura, Sunita K Patel, Kelly E Rentscher, James C Root, Andrew J Saykin, Kathleen Van Dyk, Wanting Zhai, Judith E Carroll, Jeanne Mandelblatt
Journal: JNCI Journal of the National Cancer Institute (2024)

Physical activity can improve cognition; however, little is known regarding the relationships between longitudinal objectively measured physical activity, cognition, and inflammation in older breast cancer survivors. Older (aged 60 years and older) breast cancer survivors (n = 216) and frequency-matched noncancer control participants (n = 216) were assessed at baseline (presystemic therapy for survivors) and annually for up to 5 years. Assessments included hip-worn actigraphs worn for 7 days, neuropsychological tests, the Functional Assessment of Cancer Therapy-Cognitive Function perceived cognitive impairment subscale, and circulating levels of C-reactive protein and interleukin-6. Data were analyzed using linear mixed-effect, random-effect contemporaneous fluctuation, and multilevel mediation models, considering covariates; a P value less than .05 (2-sided) was considered statistically significant. Survivors had fewer minutes of moderate-to-vigorous physical activity than controls at 36-, 48-, and 60-month time points (P < .03). Fewer survivors met aerobic physical activity guidelines at 36 months than control participants (17.7% vs 33.0%, P = .030). When guidelines were met (vs not), Functional Assessment of Cancer Therapy-Cognitive Function perceived cognitive impairment scores were 2.1 (1.0) (P = .034) points higher. Higher moderate-to-vigorous physical activity and meeting aerobic guidelines were not related to objective neuropsychological performance. Moderate-to-vigorous physical activity was inversely associated with C-reactive protein and interleukin-6 (P < .001), but inflammation did not mediate physical activity effects on perceived cognition. Older breast cancer survivors were less physically active than older noncancer controls, especially farther from baseline. Meeting aerobic guidelines was associated with better perceived cognition in survivors. Survivorship care should consider physical activity monitoring and referral to rehabilitation and supervised exercise programs to promote physical activity and improve recovery in older survivors.
Nuclear factor of activated T-cells 5 is indispensable for a balanced adaptive transcriptional response of lung endothelial cells to hypoxia
Authors: Hebatullah Laban, Sophia Siegmund, Katharina Schlereth, Felix A Trogisch, Alia Ablieh, Lennart Brandenburg, Andreas Weigert, Carolina De La Torre, Carolin Mogler, Markus Hecker, Wolfgang M Kuebler, Thomas Korff
Journal: Cardiovascular Research (2024)

Chronic hypoxia causes detrimental structural alterations in the lung, which may cause pulmonary hypertension and are partially mediated by the endothelium. While its relevance for the development of hypoxia-associated lung diseases is well known, determinants controlling the initial adaptation of the lung endothelium to hypoxia remain largely unexplored. We revealed that hypoxia activates the transcription factor nuclear factor of activated T-cells 5 (NFAT5) and studied its regulatory function in murine lung endothelial cells (MLECs). EC-specific knockout of Nfat5 (Nfat5(EC)-/-) in mice exposed to normobaric hypoxia (10% O2) for 21 days promoted vascular fibrosis and aggravated the increase in pulmonary right ventricular systolic pressure as well as right ventricular dysfunction as compared with control mice. Microarray- and single-cell RNA-sequencing-based analyses revealed an impaired growth factor-, energy-, and protein-metabolism-associated gene expression in Nfat5-deficient MLEC after exposure to hypoxia for 7 days. Specifically, loss of NFAT5 boosted the expression and release of platelet-derived growth factor B (Pdgfb)-a hypoxia-inducible factor 1 alpha (HIF1α)-regulated driver of vascular smooth muscle cell (VSMC) growth-in capillary MLEC of hypoxia-exposed Nfat5(EC)-/- mice, which was accompanied by intensified VSMC coverage of distal pulmonary arteries. Collectively, our study shows that early and transient subpopulation-specific responses of MLEC to hypoxia may determine the degree of organ dysfunction in later stages. In this context, NFAT5 acts as a protective transcription factor required to rapidly adjust the endothelial transcriptome to cope with hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb expression and consequently limits muscularization and resistance of the pulmonary vasculature.
Characterization of Cancer Stem Cells in Laryngeal Squamous Cell Carcinoma by Single-cell RNA Sequencing
Authors: Yanguo Li, Chen Lin, Yidian Chu, Zhengyu Wei, Qi Ding, Shanshan Gu, Hongxia Deng, Qi Liao, Zhisen Shen
Journal: Genomics Proteomics & Bioinformatics (2024)

Cancer stem cells (CSCs) constitute a pivotal element within the tumor microenvironment (TME), driving the initiation and progression of cancer. However, the identification of CSCs and their underlying molecular mechanisms in laryngeal squamous cell carcinoma (LSCC) remains a formidable challenge. Here, we employed single-cell RNA sequencing of matched primary tumor tissues, paracancerous tissues, and local lymph nodes from three LSCC patients to comprehensively characterize the CSCs in LSCC. Two distinct clusters of stem cells originating from epithelial populations were delineated and verified as CSCs and normal stem cells (NSCs), respectively. CSCs were abundant in the paracancerous tissues compared to those in the tumor tissues. CSCs showed high expression of stem cell marker genes such as PROM1, ALDH1A1, and SOX4, and increased the activity of tumor-related hypoxia, Wnt/β-catenin, and Notch signaling pathways. We then explored the intricate crosstalk between CSCs and the TME cells and identified targets within the TME that related with CSCs. We also found eight marker genes of CSCs that were correlated significantly with the prognosis of LSCC patients. Furthermore, bioinformatics analyses showed that drugs such as erlotinib, OSI-027, and ibrutinib selectively targeted the CSC-specifically expressed genes. In conclusion, our results represent the first comprehensive characterization of CSC properties in LSCC at the single-cell level.