20 results on '"Adams, Taylor"'
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2. Constrictive physiology is not present in all dogs with idiopathic chylothorax
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Adams, Taylor E., primary, Marvel, Sarah J., additional, and Monnet, Eric, additional
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- 2024
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3. Identification of complex co-occurring symptom burden in persons with cancer through multisite implementation of health-related social needs assessment in community oncology settings.
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Indurlal, Puneeth, Garey, Jody S., Traul, Abigail, Chicchirichi, Misty Dawn, Adams, Taylor, Wilfong, Lalan S., Weber, Dana, Neeb, Jessica louise, Osborne, Evan, and Subbiah, Ishwaria M.
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- 2024
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4. Perceived changes in trait attributions to others and the self.
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Sanbonmatsu, David M., Adams, Taylor, and White, Paul H.
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INTERPERSONAL relations , *SELF-evaluation , *SELF , *DESIRE , *MOTIVATION (Psychology) - Abstract
A study was conducted to examine the perceived changes in the impressions of others or self on 133 trait dimensions. Attributions to others were reportedly more negative over time whereas attributions to self were more positive over time. Perceived changes in others' traits appear to be guided by basic behavioral inference processes. Trait beliefs about others tend to be revised when the traits are common and disconfirming behavior is infrequent and more diagnostic. Positive trait impressions of others change more frequently because they are more prevalent and because negative behaviors (that disconfirm positive attributions) are less frequent and more diagnostic than positive behaviors. In contrast, revisions of trait impressions of the self appear to be driven heavily by self-evaluation motivations such as the desire to see self-improvement. The favorableness of changes in trait self-concepts were positively correlated with self-esteem. The consequences of the observed patterns of attributional change for interpersonal relations are discussed. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Dendritic Cell – Fibroblast Crosstalk via TLR9 and AHR Signaling Drives Lung Fibrogenesis
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Carter, Hannah, primary, Costa, Rita Medina, additional, Adams, Taylor S., additional, Gilchrist, Talon, additional, Emch, Claire E., additional, Bame, Monica, additional, Oldham, Justin M., additional, Linderholm, Angela L., additional, Noth, Imre, additional, Kaminski, Naftali, additional, Moore, Bethany B., additional, and Gurczynski, Stephen J., additional
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- 2024
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6. Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ-dependent manner
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Perrot, Carole Y., primary, Karampitsakos, Theodoros, additional, Unterman, Avraham, additional, Adams, Taylor, additional, Marlin, Krystin, additional, Arsenault, Alyssa, additional, Zhao, Amy, additional, Kaminski, Naftali, additional, Katlaps, Gundars, additional, Patel, Kapilkumar, additional, Bandyopadhyay, Debabrata, additional, and Herazo-Maya, Jose D., additional
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- 2024
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7. Noninvasive assessment of the lung inflammation-fibrosis axis by targeted imaging of CMKLR1.
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Mannes, Philip Z., Adams, Taylor S., Farsijani, Samaneh, Barnes, Clayton E., Latoche, Joseph D., Day, Kathryn E., Nedrow, Jessie R., Ahangari, Farida, Kaminski, Naftali, Lee, Janet S., and Tavakoli, Sina
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LUNGS , *IDIOPATHIC pulmonary fibrosis , *PULMONARY fibrosis , *POSITRON emission tomography , *LUNG diseases , *GENE expression - Abstract
Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and therapeutic monitoring. Here, we validated the accuracy of CMKLR1 as an imaging biomarker of the lung inflammation-fibrosis axis. By analyzing single-cell RNA sequencing datasets, we demonstrated CMKLR1 expression as a transient signature of monocyte-derived macrophages (MDMf) enriched in patients with idiopathic pulmonary fibrosis (IPF). Consistently, we identified MDMf as the major driver of the uptake of CMKLR1-targeting peptides in a murine model of bleomycin-induced lung fibrosis. Furthermore, CMKLR1- targeted positron emission tomography in the murine model enabled quantification and spatial mapping of inflamed lung regions infiltrated by CMKLR1-expressing macrophages and emerged as a robust predictor of subsequent lung fibrosis. Last, high CMKLR1 expression by bronchoalveolar lavage cells identified an inflammatory endotype of IPF with poor survival. Our investigation supports the potential of CMKLR1 as an imaging biomarker for endotyping and risk stratification of fibrotic lung diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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8. The use of a minimally invasive integrated endoscopic system to perform hemilaminectomies in chondrodystrophic dogs with thoracolumbar intervertebral disc extrusions.
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MacQuiddy, Brittany, Bartner, Lisa, Marolf, Angela, Rao, Sangeeta, Dupont, Emily, Adams, Taylor, and Monnet, Eric
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INTERVERTEBRAL disk ,DOGS ,LAMINECTOMY ,NERVE tissue ,VETERINARY hospitals ,VETERINARY medicine - Abstract
Introduction: The objective was to evaluate the use of a minimally invasive surgical (MIS) approach to perform hemilaminectomies in chondrodystrophic dogs with thoracolumbar intervertebral disc extrusions (IVDE). Additionally, we aimed to evaluate the degree of soft tissue trauma using the endoscopic procedure compared to the standard open approach. Methods: Eight client-owned dogs presented to the Colorado State University Veterinary Teaching Hospital with acute onset thoracolumbar IVDE were included in this study. This was a prospective, randomized case-series. Patients were assigned to undergo an endoscopic (group 1; n = 4) or a standard open approach (group 2; n = 4) for a hemilaminectomy. A post-operative MRI was performed in all cases. Results: Conversion to an open approach was not necessary for any case in group 1. All cases had adequate spinal cord decompression on post-operative MRI. There was no significant difference in soft tissue changes noted on post-operative MRI between the two groups. Discussion: The MIS approach to hemilaminectomies in chondrodystrophic dogs with thoracolumbar IVDE can successfully be performed to decompress the neural tissue and appears to lead to similar clinical outcomes in the early postoperative period compared to the standard open approach. Larger studies are needed to determine the potential advantages of the MIS technique compared to the standard open approach in veterinary medicine. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Organ Boundary Circuits Regulate Sox9+ Alveolar Tuft Cells During Post-Pneumonectomy Lung Regeneration
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Obata, Tomohiro, primary, Mizoguchi, Satoshi, additional, Greaney, Allison M., additional, Adams, Taylor Sterling, additional, Yuan, Yifan, additional, Edelstein, Sophie, additional, Leiby, Katherine L., additional, Rivero, Rachel, additional, Wang, Nuoya, additional, Kim, Hahram, additional, Yang, Junchen, additional, Schupp, Jonas Christian, additional, Stitelman, David, additional, Tsuchiya, Tomoshi, additional, Levchenko, Andre, additional, Kaminski, Naftali, additional, Niklason, Laura E., additional, and Raredon, Micha Sam Brickman, additional
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- 2024
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10. Dedifferentiated early postnatal lung myofibroblasts redifferentiate in adult disease.
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Chandran, Rachana R., Adams, Taylor S., Kabir, Inamul, Gallardo-Vara, Eunate, Kaminski, Naftali, Gomperts, Brigitte N., and Greif, Daniel M.
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MYOFIBROBLASTS ,LUNGS ,GENE expression profiling ,TISSUE remodeling ,MUSCLE cells - Abstract
Alveolarization ensures sufficient lung surface area for gas exchange, and during bulk alveolarization in mice (postnatal day [P] 4.5-14.5), alpha-smooth muscle actin (SMA)+ myofibroblasts accumulate, secrete elastin, and lay down alveolar septum. Herein, we delineate the dynamics of the lineage of early postnatal SMA+ myofibroblasts during and after bulk alveolarization and in response to lung injury. SMA+ lung myofibroblasts first appear at ~ P2.5 and proliferate robustly. Lineage tracing shows that, at P14.5 and over the next few days, the vast majority of SMA+ myofibroblasts downregulate smooth muscle cell markers and undergo apoptosis. Of note, ~8% of these dedifferentiated cells and another ~1% of SMA+ myofibroblasts persist to adulthood. Single cell RNA sequencing analysis of the persistent SMA-cells and SMA+ myofibroblasts in the adult lung reveals distinct gene expression profiles. For instance, dedifferentiated SMA-cells exhibit higher levels of tissue remodeling genes. Most interestingly, these dedifferentiated early postnatal myofibroblasts re-express SMA upon exposure of the adult lung to hypoxia or the pro-fibrotic drug bleomycin. However, unlike during alveolarization, these cells that re-express SMA do not proliferate with hypoxia. In sum, dedifferentiated early postnatal myofibroblasts are a previously undescribed cell type in the adult lung and redifferentiate in response to injury. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Surgical interventions and outcome in a population of canine trauma patients.
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Fisher, Corey J., Adams, Taylor, Liss, David, Cavanagh, Amanda A., Marvel, Sarah J., and Hall, Kelly E.
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SURGERY , *ELECTRONIC health records , *LENGTH of stay in hospitals , *TRAUMA registries , *TEACHING hospitals , *ARACHNOID cysts - Abstract
Objective: To determine signalment, injury type, trauma severity score, and outcome of canine trauma patients undergoing surgical (emergency room [ER] or operating room [OR]) and nonsurgical treatment in addition to time to surgery, specialty services involved, and cost in the OR surgery population. Design: Retrospective evaluation of medical record and hospital trauma registry data on canine trauma cases. Setting: University teaching hospital. Animals: One thousand six hundred and thirty dogs presenting for traumatic injury between May 2017 and July 2020. Interventions: None. Measurements and Main Results: Demographics and outcome were compared for canine trauma patients undergoing OR surgery (12.8%, 208/1630), ER surgery (39.1%, 637/1630), or no surgical intervention (48.2%, 785/1630). Among the 2 surgical groups, 98.9% (836/845) survived to discharge compared with 92.2% (724/785) of the nonsurgical group (P < 0.0001). The OR surgical group had significantly higher median Animal Trauma Triage scores (2 vs 1, P < 0.0001) and median days in hospital (2 vs < 1, P < 0.0001) compared with the other groups. For the OR surgical cohort, electronic medical records were reviewed to determine the specialty surgery service involved, time to and duration of anesthesia and surgery, and visit cost. The most common surgery services involved were orthopedics (45.2%, 94/208) and general surgery (26.9%, 56/208). Neurology and general surgery cases required the longest median length of stay in hospital, and ophthalmology and dentistry cases required the shortest. The median cost of visit was highest in neurology ($10,032) and lowest in ophthalmology ($2305) and dentistry ($2404). Conclusions: Surgical intervention in canine trauma patients appears to be associated with higher survival rates, and among the surgery groups, mortality was highest in the ER and general surgery groups. OR surgical intervention, in particular general surgery and neurology, was associated with increased length of hospitalization, increased cost, and higher Animal Trauma Triage scores. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Identification of FGFR4 as a regulator of myofibroblast differentiation in Pulmonary Fibrosis.
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Ghanem M, Justet A, Jaillet M, Vasarmidi E, Boghanim T, Hachem M, Vadel A, Joannes A, Mordant P, Balayev A, Adams T, Mal H, Cazes A, Poté N, Mailleux A, and Crestani B
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Introduction IPF is a devastating lung disease with limited therapeutic options. FGFR4 is a known receptor for several paracrine Fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have anti-fibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. Methods We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of TGF-b, Endothelin-1 and PDGF on FGFR4 expression in human lung fibroblasts. We determined the effect FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-b-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in Fgfr4 -deficient ( Fgfr4 -/-) mice compared to Wild Type littermates (WT), and after FGF401 treatment in WT mice compared to a control group receiving the solvent only. Results FGFR4 was decreased in IPF lungs as compared to control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment by TGF- β, Endothelin-1 and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-b1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in Fgfr4 -/- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Conclusion Our data suggest that FGFR4 exerts pro-fibrotic properties by enhancing TGF- β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo.
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- 2024
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13. Implicit Race Bias in Pediatric Patients: Understanding Patient Perspectives.
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Adams TM, Guzek R, and Brar R
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Introduction: Implicit racial bias has been well studied in adults, including among orthopaedic surgeons, through the Implicit Association Test (IAT). Recent studies suggest implicit race bias is also present among children. Explicit racial preference has been studied in children through The Clark Doll Test since the 1930s. The purpose of this study was to determine whether implicit and explicit racial biases are present among pediatric orthopaedic patients., Methods: A prospective, cross-sectional survey was administered to pediatric orthopaedic patients aged 7 to 18 years at clinics in a tertiary pediatric hospital setting. The survey included a Clark Doll Test to determine whether pediatric patients expressed explicit bias, followed by a race IAT to determine whether pediatric patients expressed implicit bias. Preference and magnitude of implicit bias as demonstrated on the IAT was calculated using standard D-scores., Results: A total of 96 patients were consented and included in this study. Overall, pediatric patients demonstrated a slight pro-White implicit bias (M = 0.22) on IAT testing. Pediatric patients who identified as White or European American and Hispanic or Latinx both had the strongest pro-White implicit bias (M = 0.35). Patients who identified as Black or African American demonstrated no implicit racial bias (M = -0.13) on IAT testing. No notable explicit bias was observed in participants of any racial background., Discussion: This study contributes evidence that pediatric orthopaedic patients express implicit racial bias on IAT testing, with an overall slight pro-White bias. It also provides insight into the dissociation of implicit and explicit racial bias in childhood and adolescence., Conclusion: We encourage future research on implicit bias among pediatric patients in the orthopaedic community to provide a better understanding and possible solutions to bias-related challenges in health care., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)
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- 2024
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14. Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts.
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Sand JMB, Jessen H, Leeming DJ, Yu S, Lee CJ, Hu B, Sun Y, Adams T, Pivarnik T, Liu A, Woo S, McGovern JR, Fiorini V, Saber T, Higuero-Sevilla JP, Gulati M, Kaminski N, Damsky W, Shaw AC, Mohanty S, Goobie G, Zhang Y, Herzog EL, and Ryu C
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Introduction: The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown., Methods: We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes., Results: Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts., Discussion: In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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15. Dendritic Cell - Fibroblast Crosstalk via TLR9 and AHR Signaling Drives Lung Fibrogenesis.
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Carter H, Costa RM, Adams TS, Gilchrist T, Emch CE, Bame M, Oldham JM, Linderholm AL, Noth I, Kaminski N, Moore BB, and Gurczynski SJ
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Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2-5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and IL-17, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHR
Δex2 ) with mice harboring a CD11c-Cre. Bleomycin was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2 mice treated with bleomycin developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2. Study of human samples corroborate the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.- Published
- 2024
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16. Single Cell Analysis Reveals Novel Immune Perturbations in Fibrotic Hypersensitivity Pneumonitis.
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Zhao AY, Unterman A, Abu Hussein NS, Sharma P, Nekola F, Flint J, Yan X, Adams TS, Justet A, Sumida TS, Zhao J, Schupp JC, Raredon MSB, Ahangari F, Deluliis G, Zhang Y, Buendia-Roldan I, Adegunsoye A, Sperling AI, Prasse A, Ryu C, Herzog E, Selman M, Pardo A, and Kaminski N
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Rationale : Fibrotic hypersensitivity pneumonitis is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives : To elucidate immune aberrations in fibrotic hypersensitivity pneumonitis in single-cell resolution. Methods : Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and bronchoalveolar lavage cells obtained from 45 patients with fibrotic hypersensitivity pneumonitis, 63 idiopathic pulmonary fibrosis, 4 non-fibrotic hypersensitivity pneumonitis, and 36 healthy controls in the United States and Mexico. Analyses included differential gene expression (Seurat), transcription factor activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3/Velocyto-scVelo-CellRank). Measurements and Main Results : Overall, 501,534 peripheral blood mononuclear cells from 110 patients and controls and 88,336 bronchoalveolar lavage cells from 19 patients were profiled. Compared to controls, fibrotic hypersensitivity pneumonitis has elevated classical monocytes (adjusted-p=2.5e-3) and are enriched in CCL3
hi /CCL4hi and S100Ahi classical monocytes (adjusted-p<2.2e-16). Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. Compared to both controls and idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis patient cells are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit transcription factor activities indicative of TGFβ and TNFα/NFκB pathways. These results are publicly available at https://ildimmunecellatlas.org. Conclusions : Single-cell transcriptomics of fibrotic hypersensitivity pneumonitis patients uncovered novel immune perturbations, including previously undescribed increases in GZMhi cytotoxic CD4+ and CD8+ T cells - reflecting this disease's unique inflammatory T-cell driven nature - as well as increased S100Ahi and CCL3hi /CCL4hi classical monocytes also observed in idiopathic pulmonary fibrosis. Both cell populations may guide the development of new biomarkers and therapeutic interventions.- Published
- 2024
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17. Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ-dependent manner.
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Perrot CY, Karampitsakos T, Unterman A, Adams T, Marlin K, Arsenault A, Zhao A, Kaminski N, Katlaps G, Patel K, Bandyopadhyay D, and Herazo-Maya JD
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- Humans, Monocytes metabolism, Membrane Proteins metabolism, Chemotaxis, Mast Cells metabolism, Transforming Growth Factor beta metabolism, Macrophages, Alveolar metabolism, Idiopathic Pulmonary Fibrosis genetics, Idiopathic Pulmonary Fibrosis metabolism
- Abstract
Mast-cell expressed membrane protein-1 (MCEMP1) is higher in patients with idiopathic pulmonary fibrosis (IPF) with an increased risk of death. Here we aimed to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared with controls. MCEMP1 is upregulated by transforming growth factor beta (TGFβ) at the mRNA and protein levels in monocytic leukemia THP-1 cells. TGFβ-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1 cis- regulatory elements within the MCEMP1 promoter. We also found that MCEMP1 regulates TGFβ-mediated monocyte chemotaxis, adhesion, and migration. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression. NEW & NOTEWORTHY MCEMP1 is highly expressed in circulating classical monocytes and alveolar macrophages in IPF, is regulated by TGFβ, and participates in the chemotaxis, adhesion, and migration of circulating monocytes by modulating the effect of TGFβ in RHO activity.
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- 2024
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18. Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma.
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Obacz J, Valer JA, Nibhani R, Adams TS, Schupp JC, Veale N, Lewis-Wade A, Flint J, Hogan J, Aresu G, Coonar AS, Peryt A, Biffi G, Kaminski N, Francies H, Rassl DM, Garnett MJ, Rintoul RC, and Marciniak SJ
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- Humans, Pleura pathology, Gene Expression Profiling, Mesothelioma genetics, Mesothelioma pathology, Mesothelioma, Malignant pathology, Pleural Neoplasms genetics, Pleural Neoplasms pathology
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The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant, including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here, we present the first comprehensive single-cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple in vitro models of benign and malignant mesothelial cells, and characterise these through comparison with in vivo transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at the single-cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. It has already enabled us to shed light on the transdifferentiation of mesothelial cells, allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro ., Competing Interests: Conflicts of interest: In addition to the funding acknowledged in the support statement, the following conflicts are declared by the authors. J. Obacz reports grants from Victor Dahdaleh Charitable Foundation. A.S. Coonar reports grants from Innovate UK, consultancy for Viderigen, honoraria for lectures from AstraZeneca, book royalties from Springer Nature, payment for expert testimony from Medicolegal reports, leadership or fiduciary roles for Society for Cardiothoracic Surgery of GB and Ireland, and is Chair of the Thoracic Surgery Committee, NHS, National Clinical Lead for NHS England and a Governor of Royal Papworth Hospital. A. Peryt reports lecture honoraria from AstraZeneca, and travel support from Albyn Medical. N. Kaminski is a scientific founder at Thyron, served as a consultant to Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, AstraZeneca, RohBar, Veracyte, Augmanity, CSL Behring, Galapagos, Gilead, Chiesi, Arrowhead, Sofinnova and Thyron over the last 3 years, reports Equity in Pliant and Thyron, and grants from Veracyte, Boehringer Ingelheim, BMS and Three Lakes Foundation, and non-financial support from MiRagen and Astra Zeneca; N. Kaminski also has the following patents licensed to biotech: New therapies for IPF, New Therapies for ARDS and New Biomarkers in IPF. M.J. Garnett reports consultancy fees from and equity in Mosaic Therapeutics, and has a patent pending for describing suspension organoid cultures. R.C. Rintoul is chief investigator of Mesobank UK and is part funded by Asthma+Lung UK. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)
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- 2024
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19. Organ Boundary Circuits Regulate Sox9+ Alveolar Tuft Cells During Post-Pneumonectomy Lung Regeneration.
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Obata T, Mizoguchi S, Greaney AM, Adams T, Yuan Y, Edelstein S, Leiby KL, Rivero R, Wang N, Kim H, Yang J, Schupp JC, Stitelman D, Tsuchiya T, Levchenko A, Kaminski N, Niklason LE, and Brickman Raredon MS
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Tissue homeostasis is controlled by cellular circuits governing cell growth, organization, and differentation. In this study we identify previously undescribed cell-to-cell communication that mediates information flow from mechanosensitive pleural mesothelial cells to alveolar-resident stem-like tuft cells in the lung. We find mesothelial cells to express a combination of mechanotransduction genes and lineage-restricted ligands which makes them uniquely capable of responding to tissue tension and producing paracrine cues acting on parenchymal populations. In parallel, we describe a large population of stem-like alveolar tuft cells that express the endodermal stem cell markers Sox9 and Lgr5 and a receptor profile making them uniquely sensitive to cues produced by pleural Mesothelium. We hypothesized that crosstalk from mesothelial cells to alveolar tuft cells might be central to the regulation of post-penumonectomy lung regeneration. Following pneumonectomy, we find that mesothelial cells display radically altered phenotype and ligand expression, in a pattern that closely tracks with parenchymal epithelial proliferation and alveolar tissue growth. During an initial pro-inflammatory stage of tissue regeneration, Mesothelium promotes epithelial proliferation via WNT ligand secretion, orchestrates an increase in microvascular permeability, and encourages immune extravasation via chemokine secretion. This stage is followed first by a tissue remodeling period, characterized by angiogenesis and BMP pathway sensitization, and then a stable return to homeostasis. Coupled with key changes in parenchymal structure and matrix production, the cumulative effect is a now larger organ including newly-grown, fully-functional tissue parenchyma. This study paints Mesothelial cells as a key orchestrating cell type that defines the boundary of the lung and exerts critical influence over the tissue-level signaling state regulating resident stem cell populations. The cellular circuits unearthed here suggest that human lung regeneration might be inducible through well-engineered approaches targeting the induction of tissue regeneration and safe return to homeostasis., Competing Interests: Competing Interest Statement JCS received lecture honoraria from Böhringer Ingelheim and Kinevant. LEN is a founder and shareholder in Humacyte, Inc, which is a regenerative medicine company. Humacyte produces engineered blood vessels from allogeneic smooth muscle cells for vascular surgery. LEN’s spouse has equity in Humacyte, and LEN serves on Humacyte’s Board of Directors. LEN is an inventor on patents that are licensed to Humacyte and that produce royalties for LEN. Humacyte did not influence the conduct, description or interpretation of the findings in this report. NK reports personal fees from Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Numedii, Indalo, Theravance for consulting and non-financial support from Miragen, all outside the submitted work; In addition, NK has patents on new therapies in Pulmonary Fibrosis with royalties paid by biotech, and a patent on blood biomarkers in pulmonary fibrosis.
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- 2024
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20. Increased expression of CXCL6 in secretory cells drives fibroblast collagen synthesis and is associated with increased mortality in idiopathic pulmonary fibrosis.
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Bahudhanapati H, Tan J, Apel RM, Seeliger B, Schupp J, Li X, Sullivan DI, Sembrat J, Rojas M, Tabib T, Valenzi E, Lafyatis R, Mitash N, Hernandez Pineda R, Jawale C, Peroumal D, Biswas P, Tedrow J, Adams T, Kaminski N, Wuyts WA, McDyer JF, Gibson KF, Alder JK, Königshoff M, Zhang Y, Nouraie M, Prasse A, and Kass DJ
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- Animals, Humans, Mice, Bleomycin, Chemokine CXCL6 metabolism, Chemokines metabolism, Collagen metabolism, Fibroblasts metabolism, Lung pathology, Idiopathic Pulmonary Fibrosis genetics
- Abstract
Rationale: Recent data suggest that the localisation of airway epithelial cells in the distal lung in idiopathic pulmonary fibrosis (IPF) may drive pathology. We set out to discover whether chemokines expressed in these ectopic airway epithelial cells may contribute to the pathogenesis of IPF., Methods: We analysed whole lung and single-cell transcriptomic data obtained from patients with IPF. In addition, we measured chemokine levels in blood, bronchoalveolar lavage (BAL) of IPF patients and air-liquid interface cultures. We employed ex vivo donor and IPF lung fibroblasts and an animal model of pulmonary fibrosis to test the effects of chemokine signalling on fibroblast function., Results: By analysis of whole-lung transcriptomics, protein and BAL, we discovered that CXCL6 (a member of the interleukin-8 family) was increased in patients with IPF. Elevated CXCL6 levels in the BAL of two cohorts of patients with IPF were associated with poor survival (hazard ratio of death or progression 1.89, 95% CI 1.16-3.08; n=179, p=0.01). By immunostaining and single-cell RNA sequencing, CXCL6 was detected in secretory cells. Administration of mCXCL5 (LIX, murine CXCL6 homologue) to mice increased collagen synthesis with and without bleomycin. CXCL6 increased collagen I levels in donor and IPF fibroblasts 4.4-fold and 1.7-fold, respectively. Both silencing of and chemical inhibition of CXCR1/2 blocked the effects of CXCL6 on collagen, while overexpression of CXCR2 increased collagen I levels 4.5-fold in IPF fibroblasts., Conclusions: CXCL6 is expressed in ectopic airway epithelial cells. Elevated levels of CXCL6 are associated with IPF mortality. CXCL6-driven collagen synthesis represents a functional consequence of ectopic localisation of airway epithelial cells in IPF., Competing Interests: Conflict of interest: N. Kaminski is a scientific founder at Thyron, and served as a consultant to Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, AstraZeneca, RohBar, Veracyte, Augmanity, CSL Behring, Galapagos and Thyron over the last 3 years, reports equity in Pliant and Thyron, and grants from Veracyte, Boehringer Ingelheim and BMS, and non-financial support from MiRagen and AstraZeneca. R. Lafyatis reports grants from Bristol Meyer Squib, Corbus, Formation, Moderna, Regeneron, Pfizer and Kiniksa, outside the submitted work, and served as a consultant with Bristol Meyers Squibb, Formation, Sanofi, Boehringer Ingelheim, Merck and Genentech/Roche. A. Prasse reports personal fees and non-financial support from Boehringer Ingelheim and Roche, personal fees from Novartis, AstraZeneca, Amgen, Pliant and Nitto Denko, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)
- Published
- 2024
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