tbuckley/cabot-search huggingface dataset:
Polymerized Salicylic Acid Microparticles Reduce the Progression and Formation of Human Neutrophil Extracellular Traps (NET)s
Authors: Emma R. Brannon, Logan D. Piegols, Gillian Cady, Daniel Kupor, Xueqi Chu, M. Valentina Guevara, Mariana R.N. Lima, Yogendra Kanthi, David J. Pinsky, Kathryn E. Uhrich, Omolola Eniola‐Adefeso
Journal: Advanced Healthcare Materials (2024)

Abstract Neutrophils can contribute to inflammatory disease propagation via innate mechanisms intended for inflammation resolution. For example, neutrophil extracellular traps (NETs) are necessary for trapping pathogens but can contribute to clot formation and blood flow restriction, that is, ischemia. Currently, no therapeutics in the clinic directly target NETs despite the known involvement of NETs contributing to mortality and increased disease severity. Vascular‐deployed particle‐based therapeutics are a novel and robust alternative to traditional small‐molecule drugs by enhancing drug delivery to cells of interest. This work designs a high‐throughput assay to investigate the immunomodulatory behavior and functionality of salicylic acid‐based polymer‐based particle therapeutics against NETosis in human neutrophils. Briefly, this work finds that polymeric composition plays a role, and particle size can also influence rates of NETosis. Salicylate‐based polymeric (Poly‐SA) particles are found to functionally inhibit NETosis depending on the particle size and concentration exposed to neutrophils. This work demonstrates the high throughput method can help fast‐track particle‐based therapeutic optimization and design, more efficiently preparing this innovative therapeutics for the clinic.
Network analysis reveals age‐ and virus‐specific circuits in nasal epithelial cells of extremely premature infants
Authors: Lukas Wisgrill, Anke Martens, Rajmund Kasbauer, Michael Eigenschink, Linda Pummer, Monika Redlberger‐Fritz, Ákos Végvári, Benedikt Warth, Angelika Berger, Nanna Fyhrquist, Harri Alenius
Journal: Allergy (2024)

Abstract Background and objectives Viral respiratory infections significantly affect young children, particularly extremely premature infants, resulting in high hospitalization rates and increased health‐care burdens. Nasal epithelial cells, the primary defense against respiratory infections, are vital for understanding nasal immune responses and serve as a promising target for uncovering underlying molecular and cellular mechanisms. Methods Using a trans‐well pseudostratified nasal epithelial cell system, we examined age‐dependent developmental differences and antiviral responses to influenza A and respiratory syncytial virus through systems biology approaches. Results Our studies revealed differences in innate‐receptor repertoires, distinct developmental pathways, and differentially connected antiviral network circuits between neonatal and adult nasal epithelial cells. Consensus network analysis identified unique and shared cellular‐viral networks, emphasizing highly relevant virus‐specific pathways, independent of viral replication kinetics. Conclusion This research highlights the importance of nasal epithelial cells in innate antiviral immune responses and offers crucial insights that allow for a deeper understanding of age‐related differences in nasal epithelial cell immunity following respiratory virus infections.
Letter to the Editor: MAFLD versus MASLD criteria debate- Certainly not for children!
Authors: Mortada H. F. El-Shabrawi, Abdelaziz Elamin, Naglaa M. Kamal
Journal: Hepatology (2024)

To the editor,The concept of metabolic dysfunction–associated fatty liver disease (MAFLD) was the first to introduce positive criteria for the diagnosis of the disease and acknowledge that it is a continuum across the lifespan.1,2 Recently, a new nomenclature was suggested: metabolic dysfunction–associated steatotic liver disease (MASLD). This was accompanied by a set of diagnostic criteria that were largely adopted from the MAFLD definition for both adults and children.3 However, while there may be a rationale for the debate about the appropriateness of each criterion among adults, it seems that this is not the case in pediatrics, as the MASLD definition falls short in this context and needs serious reconsideration. To elaborate, the MAFLD definition provides a conceptual framework for pediatric fatty liver disease. Type 1 denotes fatty liver with an identifiable systemic disorder; type 2 denotes fatty liver associated with metabolic dysfunction (MAFLD); and type 3 denotes fatty liver without a clear underlying defect (but a defect that might become apparent with time).2 This classification is crucial to avoid misclassification and not miss serious inherited metabolic disorders on the one hand and avoid excessive testing that can lead to unintended patient anxiety and harm, including physical, psychological, or economic risks on the other hand.4 The MASLD concept does not consider this aspect at all. Second, while the MAFLD definition applies age-specific criteria for children and adolescents, the MASLD criteria do not. This is another critical point, as it is well known that the change in body composition contributes to the differential risk of metabolic dysfunction. Third, some of the used cutoffs of obesity and metabolic factors in MASLD are factually incorrect, such as BMI, for example. Therefore, it is not surprising that a recent study demonstrated the superiority of the MAFLD definition over the MASLD in pediatrics.5 In conclusion, the flaws of the MASLD definition for children are more profound. The points raised above, including those in a recent work5, go to the heart of the current debate on what is the most appropriate definition for this chronic liver disease and suggest that, at least for children, the answer hands down is MAFLD (Table 1)! TABLE 1 - Comparison of the MAFLD and MASLD concepts in pediatrics MAFLD MASLD Provides a conceptual framework of pediatric fatty liver disease to minimize misclassification and over testing. Do not Apply age-specific criteria for children and adolescents One size fit all Appropriately capture fibrosis Overlook cases with advanced fibrosis Abbreviations: MAFLD, metabolic dysfunction–associated fatty liver disease; MASLD, metabolic dysfunction–associated steatotic liver disease.
Exosomal miR-17-5p derived from epithelial cells is involved in aberrant epithelium-fibroblast crosstalk and induces the development of oral submucosal fibrosis
Authors: Changqing Xie, Liang Zhong, Hui Feng, Rifu Wang, Yuxin Shi, Yonglin Lv, Yanjia Hu, Jing Li, Desheng Xiao, Shuang Liu, Qianming Chen, Yongguang Tao
Journal: International Journal of Oral Science (2024)

Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development. The epithelium, which is the first line of defense against the external environment, can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment. However, the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear. In this study, we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes. MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts, where it promoted cell secretion, contraction, migration and fibrogenic marker (α-SMA and collagen type I) expression. The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-β receptor 1 (TGFBR1) through the E3 ubiquitination ligase WWP1, thus facilitating downstream TGF-β pathway signaling. Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes. Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts. In conclusion, we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-β fibrotic pathway, which provided a new perspective and strategy for the diagnosis and treatment of OSF.
Cancer-preventing vaccination programs in prison: promoting health equity in Europe
Authors: Nicola Cocco, Maria Paola Tramonti Fantozzi, Josephine Njeri Ihuthia, Babak Moazen, Fadi Meroueh, Irina Barbîroș, Josephina Mavrou, Angela Bardelli, Erica De Vita, Emma Plugge, Lara Tavoschi
Journal: The Lancet Regional Health - Europe (2024)
Outcomes of acute myeloid leukemia patients who responded to venetoclax and azacitidine and stopped treatment
Authors: Sylvain Garciaz, Pierre‐Yves Dumas, Sarah Bertoli, David A. Sallman, Justine Decroocq, Amine Belhabri, Corentin Orvain, Gaspar Aspas Requena, Celestine Simand, Kamel Laribi, Martin Carré, Alberto Santagostino, Chantal Himberlin, Pierre Peterlin, Sarah Bonnet, Onyee Chan, Jeffrey Lancet, Rami Komrokji, François Vergez, Nicolas Chapuis, Tatiana Raskovalova, Adriana Plesa, Anne‐Catherine Lhoumeau, Ariane Mineur, Marie Anne Hospital, Arnaud Pigneux, Norbert Vey, Christian Récher
Journal: American Journal of Hematology (2024)

Venetoclax-azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE-A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax-azacitidine due to poor tolerance. Sixty-two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort (n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow-up of 23 months (IQR, 20-32), median overall survival and treatment-free survival were 44 (IQR, 16-NR) and 16 (IQR, 8-27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2-year treatment-free survival of 80%. In the RR cohort (n = 22), median overall survival and treatment-free survival were 19 (IQR, 17-31) and 10 (IQR, 5-NR) months, respectively. Prior number of venetoclax-azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment-free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials.
Five million nights: temporal dynamics in human sleep phenotypes
Authors: Varun K. Viswanath, Wendy Hartogenesis, Stephan Dilchert, Leena Pandya, Frederick M. Hecht, Ashley E. Mason, Edward J. Wang, Benjamin L. Smarr
Journal: npj Digital Medicine (2024)

Abstract Sleep monitoring has become widespread with the rise of affordable wearable devices. However, converting sleep data into actionable change remains challenging as diverse factors can cause combinations of sleep parameters to differ both between people and within people over time. Researchers have attempted to combine sleep parameters to improve detecting similarities between nights of sleep. The cluster of similar combinations of sleep parameters from a night of sleep defines that night’s sleep phenotype. To date, quantitative models of sleep phenotype made from data collected from large populations have used cross-sectional data, which preclude longitudinal analyses that could better quantify differences within individuals over time. In analyses reported here, we used five million nights of wearable sleep data to test (a) whether an individual’s sleep phenotype changes over time and (b) whether these changes elucidate new information about acute periods of illness (e.g., flu, fever, COVID-19). We found evidence for 13 sleep phenotypes associated with sleep quality and that individuals transition between these phenotypes over time. Patterns of transitions significantly differ (i) between individuals (with vs. without a chronic health condition; chi-square test; p -value &lt; 1e−100) and (ii) within individuals over time (before vs. during an acute condition; Chi-Square test; p -value &lt; 1e−100). Finally, we found that the patterns of transitions carried more information about chronic and acute health conditions than did phenotype membership alone (longitudinal analyses yielded 2–10× as much information as cross-sectional analyses). These results support the use of temporal dynamics in the future development of longitudinal sleep analyses.
Gut mycobiome alterations in obesity in geographically different regions
Authors: Hui Zhan, Yating Wan, Yang Sun, Zhilu Xu, Fen Zhang, Keli Yang, Wenyi Zhu, Chun Pan Cheung, Whitney Tang, Enders Kw Ng, Simon Kh Wong, Yun Kit Yeoh, Francis Kl Chan, Yinglei Miao, Tao Zuo, Zhong Zeng, Siew C Ng
Journal: Gut Microbes (2024)

The gut fungi play important roles in human health and are involved in energy metabolism. This study aimed to examine gut mycobiome composition in obese subjects in two geographically different regions in China and to identify specific gut fungi associated with obesity. A total of 217 subjects from two regions with different urbanization levels [Hong Kong (HK): obese,
Differences in tumor-associated T-cell receptor repertoires between early-onset and average-onset colorectal cancer
Authors: Ya-Yu Tsai, Kanika G Nair, Shimoli V Barot, Shao Xiang, Suneel Kamath, Marilena Melas, Christopher P Walker, Raghvendra M Srivastava, Nicole Osborne, Timothy A Chan, Jonathan B Mitchem, Joseph D Bonner, Kevin J McDonnell, Gregory E Idos, Rebeca Sanz-Pamplona, Joel K Greenson, Hedy S Rennert, Gad Rennert, Victor Moreno, Stephen B Gruber, Alok A Khorana, David Liska, Stephanie L Schmit
Journal: JNCI Journal of the National Cancer Institute (2024)

The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early-onset CRC [EOCRC]) has substantially increased, and yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T-cell repertoires between EOCRC and average-onset CRC (AOCRC) to uncover potentially unique immune microenvironment-related features by age of onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 to 2020. EOCRC was defined as younger than age 50 years at diagnosis (N = 126) and AOCRC as 60 years of age or older (N = 116). T-cell receptor (TCR) abundance and clonality were measured by immunosequencing of tumors. Logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 EOCRC and 1984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study. EOCRC tumors had significantly higher TCR diversity compared with AOCRC tumors in the discovery cohort (odds ratio [OR] = 0.44, 95% confidence interval [CI] = 0.32 to 0.61, P < .0001). This association was also observed in the replication cohort (OR = 0.74, 95% CI = 0.62 to 0.89, P = .0013). No significant differences in TCR abundance were observed between EOCRC and AOCRC in either cohort. Higher TCR diversity, suggesting a more diverse intratumoral T-cell response, is more frequently observed in EOCRC than AOCRC. Further studies are warranted to investigate the role of T-cell diversity and the adaptive immune response more broadly in the etiology and outcomes of EOCRC.
Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis
Authors: Tobias Poch, Jonas Bahn, Christian Casar, Jenny Krause, Ioannis Evangelakos, Hilla Gilladi, Lilly K. Kunzmann, Alena Laschtowitz, Nicola Iuso, Anne-Marie Schäfer, Laura A. Liebig, Silja Steinmann, Marcial Sebode, Trine Folseraas, Lise K. Engesæter, Tom H. Karlsen, Andre Franke, Norbert Hubner, Christian Schlein, Eithan Galun, Samuel Huber, Ansgar W. Lohse, Nicola Gagliani, Dorothee Schwinge, Christoph Schramm
Journal: Cell Reports Medicine (2024)

Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4+ T (CD4+ TN) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4+ TN is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases.
Congenital Vascular and Lymphatic Diseases
Authors: Roy Jung, Chinmay M. Trivedi
Journal: Circulation Research (2024)

Over the past several centuries, the integration of contemporary medical techniques and innovative technologies, like genetic sequencing, have played a pivotal role in enhancing our comprehension of congenital vascular and lymphatic disorders. Nonetheless, the uncommon and complex characteristics of these disorders, especially considering their formation during the intrauterine stage, present significant obstacles in diagnosis and treatment. Here, we review the intricacies of these congenital abnormalities, offering an in-depth examination of key diagnostic approaches, genetic factors, and therapeutic methods.
Soluble Glycoprotein VI Predicts Abdominal Aortic Aneurysm Growth Rate and is a Novel Therapeutic Target
Authors: Tyler W. Benson, Mindy M. Pike, Anthony Spuzzillo, Sarah M. Hicks, Sidra Ali, Michael Pham, Doran S. Mix, Seth I. Brunner, Caris Wadding-Lee, Kelsey A. Conrad, Hannah M. Russell, Courtney Jennings, Taylor M. Coughlin, Anu Aggarwal, Sean Lyden, Kevin Mani, Martin Björck, Anders Wanhainen, Rohan Bhandari, Loren Lipworth-Elliot, Cassianne Robinson-Cohen, Francis J. Caputo, Sharon Shim, Odayme Quesada, Benjamin Tourdot, Todd L. Edwards, Michael Tranter, Elizabeth E. Gardiner, Nigel Mackman, Scott J. Cameron, A. Phillip Owens
Journal: Blood (2024)
Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma
Authors: Omid Hamid, Karl D. Lewis, Amy Weise, Meredith McKean, Kyriakos P. Papadopoulos, John Crown, Tae Min Kim, Dae Ho Lee, Sajeve S. Thomas, Janice Mehnert, John Kaczmar, Nehal J. Lakhani, Kevin B. Kim, Mark R. Middleton, Guilherme Rabinowits, Alexander I. Spira, Melinda Yushak, Inderjit Mehmi, Fang Fang, Shuquan Chen, Jayakumar Mani, Vladimir Jankovic, Fang Wang, Nathalie Fiaschi, Laura Brennan, Anne Paccaly, Sheila Masinde, Mark Salvati, Matthew G. Fury, Glenn Kroog, Israel Lowy, Giuseppe Gullo
Journal: Journal of Clinical Oncology (2024)

PURPOSE Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. METHODS Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti–PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. RESULTS ORRs were 63% for patients with anti–PD-1–naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment–naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti–PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti–PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. CONCLUSION The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti–PD-1 therapy in the adjuvant, but not advanced, setting.