829 results on '"Billiar TR"'
Search Results
2. Abstract 91
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Wang, Dan, primary, Gilbert, JR, additional, Shakir, S, additional, Shaw, MA, additional, Kubala, AA, additional, Losee, JE, additional, Billiar, TR, additional, and Cooper, GM, additional
- Published
- 2013
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3. Abstract 61
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Shaw, Melissa A, primary, Wang, D, additional, Gilbert, JR, additional, Kubala, AA, additional, Shakir, S, additional, Losee, JE, additional, Billiar, TR, additional, and Cooper, GM, additional
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- 2013
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4. The Acute Inflammatory Response in Trauma / Hemorrhage and Traumatic Brain Injury: Current State and Emerging Prospects
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Namas, R, primary, Ghuma, A, additional, Hermus, L, additional, Zamora, R, additional, Okonkwo, DO, additional, Billiar, TR, additional, and Vodovotz, Y, additional
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- 2009
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5. Parenteral calcium for intensive care unit patients
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Rosengart, M, primary, Angus, DC, additional, Billiar, TR, additional, and Forsythe, RM, additional
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- 2006
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6. Effects of molecular and functional intestinal adaptation to chronic LPS administration
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Schwarz, NT, primary, Kalff, JC, additional, Billiar, TR, additional, Simmons, RL, additional, Hirner, A, additional, and Bauer, AJ, additional
- Published
- 2001
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7. Resolving the nitric oxide paradox in acute tissue damage
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Billiar, TR, primary and Harbrecht, BG, additional
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- 1997
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8. TRANSCRIPTIONAL REGULATION OF THE HUMAN INDUCIBLE NITRIC OXIDE SYNTHASE (iNOS) GENE
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Geller, DA, primary, Mellott, J, additional, Taylor, BS, additional, Nick, HS, additional, Billiar, TR, additional, and Chesrown, SE, additional
- Published
- 1997
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- View/download PDF
9. ADENOVIRUS-MEDIATED HUMAN iNOS GENE THERAPY AS A METHOD FOR LOCAL NO DELIVERY
- Author
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Shears, LL, primary, Tzeng, E, additional, Kawaharada, N, additional, Lizonova, A, additional, Kovesdi, I, additional, Miyagishima, M, additional, Pham, S, additional, and Billiar, TR, additional
- Published
- 1997
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10. NITRIC OXIDE PREVENTS APOPTOSIS BY INHIBITION OF BOTH CASPASE-3-LIKE PROTEASE ACTIVATION AND ACTIVITY
- Author
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Kim, YM, primary, Talanian, RV, additional, and Billiar, TR, additional
- Published
- 1997
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11. Characterization of acute coagulopathy and sexual dimorphism after injury: females and coagulopathy just do not mix.
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Brown JB, Cohen MJ, Minei JP, Maier RV, West MA, Billiar TR, Peitzman AB, Moore EE, Cuschieri J, Sperry JL, Inflammation and the Host Response to Injury Investigators, Brown, Joshua B, Cohen, Mitchell J, Minei, Joseph P, Maier, Ronald V, West, Michael A, Billiar, Timothy R, Peitzman, Andrew B, Moore, Ernest E, and Cuschieri, Joseph
- Published
- 2012
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12. Debunking the survival bias myth: characterization of mortality during the initial 24 hours for patients requiring massive transfusion.
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Brown JB, Cohen MJ, Minei JP, Maier RV, West MA, Billiar TR, Peitzman AB, Moore EE, Cushieri J, Sperry JL, and Inflammation and Host Response to Injury Investigators
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- 2012
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13. Crystalloid to packed red blood cell transfusion ratio in the massively transfused patient: when a little goes a long way.
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Neal MD, Hoffman MK, Cuschieri J, Minei JP, Maier RV, Harbrecht BG, Billiar TR, Peitzman AB, Moore EE, Cohen MJ, Sperry JL, Neal, Matthew D, Hoffman, Marcus K, Cuschieri, Joseph, Minei, Joseph P, Maier, Ronald V, Harbrecht, Brian G, Billiar, Timothy R, Peitzman, Andrew B, and Moore, Ernest E
- Published
- 2012
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14. Changes in massive transfusion over time: an early shift in the right direction?
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Kautza BC, Cohen MJ, Cuschieri J, Minei JP, Brackenridge SC, Maier RV, Harbrecht BG, Moore EE, Billiar TR, Peitzman AB, Sperry JL, Inflammation and the Host Response to Injury Investigators, Kautza, Benjamin C, Cohen, Mitchell J, Cuschieri, Joseph, Minei, Joseph P, Brackenridge, Scott C, Maier, Ronald V, Harbrecht, Brian G, and Moore, Ernest E
- Published
- 2012
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15. Evolving role of endovascular techniques for traumatic vascular injury: A changing landscape?
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Avery LE, Stahlfeld KR, Corcos AC, Scifres AM, Ziembicki JA, Varcelotti J, Peitzman AB, Billiar TR, and Sperry JL
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- 2012
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16. Preinjury statin use is associated with a higher risk of multiple organ failure after injury: a propensity score adjusted analysis.
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Neal MD, Cushieri J, Rosengart MR, Alarcon LH, Moore EE, Maier RV, Minei JP, Billiar TR, Peitzman AB, Sperry JL, and Inflammation and Host Response to Injury Investigators
- Published
- 2009
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17. Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome.
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Watson GA, Sperry JL, Rosengart MR, Minei JP, Harbrecht BG, Moore EE, Cuschieri J, Maier RV, Billiar TR, Peitzman AB, and Inflammation and Host Response to Injury Investigators
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- 2009
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18. Activation of latent transforming growth factor-beta1 by nitric oxide in macrophages: role of soluble guanylate cyclase and MAP kinases.
- Author
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Metukuri MR, Namas R, Gladstone C, Clermont T, Jefferson B, Barclay D, Hermus L, Billiar TR, Zamora R, and Vodovotz Y
- Abstract
The inducible nitric oxide (NO) synthase and the cytokine transforming growth factor-[beta]1 (TGF-[beta]1), both central modulators of wound healing, interact reciprocally: TGF-[beta]1 generally suppresses iNOS expression, while NO can induce and activate latent TGF-[beta]1. We have shown that chemical NO activates recombinant human latent TGF-[beta]1 by S-nitrosation of the latency-associated peptide (LAP), a cleaved portion of pro-TGF-[beta]1 that maintains TGF-[beta]1 in a biologically-inactive state. We hypothesized that cell-associated TGF-[beta]1 could be activated by NO via known NO-inducible signaling pathways (soluble guanylate cyclase [sGC] and mitogen-activated protein [MAP] kinases). Treatment of mouse RAW 264.7 macrophage-like cells with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) led to a dose- and time-dependent increase in cell-associated active and latent TGF-[beta]1, as assessed by quantitative immunocytochemistry for active TGF-[beta]1 vs. LAP and partially validated by western blot analysis. Treatment with the sGC inhibitor 1,H-[1,2,4]oxadiazole[4,3-a]quinoxalon-1-one (ODQ) reduced both active and latent TGF-[beta]1 dose-dependently. SNAP, in the presence or absence of ODQ or the MAP kinase inhibitors, did not affect steady-state TGF-[beta]1 mRNA levels. Treatment with inhibitors specific for JNK1/2, ERK1/2, and p38 MAP kinases suppressed SNAP-induced active and latent TGF-[beta]1. Treatment with the cell-permeable cGMP analog 8-Br-cGMP increased both active and latent TGF-[beta]1. However, TGF-[beta]1 activation induced by 8-Br-cGMP was not blocked by MAP kinase inhibitors. Our findings suggest that NO activates latent TGF-[beta]1 via activation of sGC and generation of cGMP and separately via MAP kinase activation, and may shed insight into the mechanisms by which both cGMP production and MAP kinase activation enhance wound healing. [ABSTRACT FROM AUTHOR]
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- 2009
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19. An FFP:PRBC transfusion ratio <GT>=1:1.5 is associated with a lower risk of mortality after massive transfusion.
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Sperry JL, Ochoa JB, Gunn SR, Alarcon LH, Minei JP, Cuschieri J, Rosengart MR, Maier RV, Billiar TR, Peitzman AB, Moore EE, and The Inflammation the Host Response to Injury Investigators
- Published
- 2008
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20. The role of fracture-associated soft tissue injury in the induction of systemic inflammation and remote organ dysfunction after bilateral femur fracture.
- Author
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Kobbe P, Vodovotz Y, Kaczorowski DJ, Billiar TR, and Pape H
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- 2008
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21. Biliverdin administration prevents the formation of intimal hyperplasia induced by vascular injury.
- Author
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Nakao A, Murase N, Ho C, Toyokawa H, Billiar TR, and Kanno S
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- 2005
22. A brief episode of hypotension increases mortality in critically ill trauma patients.
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Zenati MS, Billiar TR, Townsend RN, Peitzman AB, Harbrecht BG, and Shapiro MB
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- 2002
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23. TRISS unexpected survivors: an outdated standard?
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Norris R, Woods R, Harbrecht B, Fabian T, Rhodes M, Morris J, Billiar TR, Courcoulas AP, Udekwu AO, Stinson C, and Peitzman AB
- Published
- 2002
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24. Effects of hemodilution on long-term survival in an uncontrolled hemorrhagic shock model in rats.
- Author
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Marshall HP Jr., Capone A, Courcoulas AP, Harbrecht BG, Billiar TR, Udekwu AO, and Peitzman AB
- Published
- 1997
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25. Nitric oxide, sepsis, and arginine metabolism.
- Author
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Kelly E, Morris SM Jr., Billiar TR, Kelly, E, Morris, S M Jr, and Billiar, T R
- Published
- 1995
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26. An L-arginine-dependent mechanism mediates kupffer cell inhibition of hepatocyte protein synthesis in vitro
- Author
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Billiar, TR, Curran, RD, Stuehr, DJ, West, MA, Bentz, BG, and Simmons, RL
- Abstract
The hepatic failure associated with severe sepsis is characterized by specific, progressive, and often irreversible defects in hepatocellular metabolism (1). Although the etiologic microbe can often be identified, the direct causes and mechanisms of the hepatocellular dysfunction are poorly understood. We have hypothesized that Kupffer cells (KC), which interact with ambient septic stimuli, respond by providing signals to adjacent hepatocytes (HC) in sepsis . Furthermore, we have provided evidence (2, 3) that KC activated by LPS from Gram-negative bacteria can induce profound changes in the function of neighboring HC in coculture. In our model, coculture of either KC (2) or peritoneal macrophages (Mφ)(3) with HC normally promotes HC protein synthesis ([(3)H]leucine incorporation). The addition of LPS or killed Escherichia colt' to such cocultures induces a profound decrease in HC protein synthesis, as well as qualitative changes ([(35)S]methionine, SDS-gel electrophoresis) in protein synthesis without inducing HC death (2, 3) . In this report we show that the inhibition in protein synthesis is mediated via an L-arginine-dependent mechanism. The metabolism of L-arginine by activated Mφ to substances with cytostatic and even lethal effects on target cells is a relatively recent discovery. After the description by Stuehr and Marletta (4, 5) that LPS- triggered Mφ produced nitrite/nitrate (NO(2)(-)/NO(3)(-)), Hibbs et al. (6, 7) and Iyengar et al. (8) demonstrated that L-arginine was the substrate for the formation of both these nitrogen end products and citrulline. A role for the arginine-dependent mechanism in Mφ tumor cytotoxicity (6, 7) and microbiostatic activity (9) has been suggested. However, the in vivo functions of this novel Mφ mechanism have not yet been defined, but it is possible that there are both physiologic as well as pathologic roles. Our in vitro results raise the possibility that some metabolic responses to microbial invasion maybe partially mediated by the L-arginine-dependent mechanism. What other metabolic responses are affected and the possible pathologic consequences remain to be studied.
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- 1989
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27. Nitric oxide: a clinical primer.
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Levy RM, Prince JM, Billiar TR, Levy, Ryan M, Prince, Jose M, and Billiar, Timothy R
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- 2005
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28. P-291 - NITRIC OXIDE PREVENTS APOPTOSIS BY INHIBITION OF BOTH CASPASE-3-LIKE PROTEASE ACTIVATION AND ACTIVITY
- Author
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Kim, YM, Talanian, RV, and Billiar, TR
- Published
- 1997
- Full Text
- View/download PDF
29. 62 - ADENOVIRUS-MEDIATED HUMAN iNOS GENE THERAPY AS A METHOD FOR LOCAL NO DELIVERY
- Author
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Shears, LL, Tzeng, E, Kawaharada, N, Lizonova, A, Kovesdi, I, Miyagishima, M, Pham, S, and Billiar, TR
- Published
- 1997
- Full Text
- View/download PDF
30. 14 - TRANSCRIPTIONAL REGULATION OF THE HUMAN INDUCIBLE NITRIC OXIDE SYNTHASE (iNOS) GENE
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Geller, DA, Mellott, J, Taylor, BS, Nick, HS, Billiar, TR, and Chesrown, SE
- Published
- 1997
- Full Text
- View/download PDF
31. Correction: Caspase 1 activation is protective against hepatocyte cell death by up-regulating beclin 1 protein and mitochondrial autophagy in the setting of redox stress.
- Author
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Sun Q, Gao W, Loughran P, Shapiro R, Fan J, Billiar TR, and Scott MJ
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- 2024
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32. NETWORK ANALYSIS OF SINGLE-NUCLEOTIDE POLYMORPHISMS ASSOCIATED WITH ABERRANT INFLAMMATION IN TRAUMA PATIENTS SUGGESTS A ROLE FOR VESICLE-ASSOCIATED INFLAMMATORY PROGRAMS INVOLVING CD55.
- Author
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El-Dehaibi F, Zamora R, Yin J, Namas RA, Billiar TR, and Vodovotz Y
- Abstract
Background: Critical illness stemming from severe traumatic injury is a leading cause of morbidity and mortality worldwide, and involves the dysfunction of multiple organ systems, driven, at least in part, by dysregulated inflammation. We and others have shown a key role for genetic predisposition to dysregulated inflammation and downstream adverse critical illness outcomes. Recently, we demonstrated an association among genotypes at the single-nucleotide polymorphism (SNP) rs10404939 in LYPD4, dysregulated systemic inflammation, and adverse clinical outcomes in a broad sample of ~1000 critically ill patients., Methods: We sought to gain mechanistic insights into the role of LYPD4 in critical illness by bioinformatically analyzing potential interactions among rs10404939 and other SNPs. We analyzed a dataset of common (i.e., not rare) SNPs previously defined to be associated with genotype-specific, significantly dysregulated systemic inflammation trajectories in trauma patients, in comparison to a control dataset of common SNPs determined to exhibit an absence of genotype-specific inflammatory responses., Results: In the control dataset, this analysis implicated SNPs associated with phosphatidylinositol and various membrane transport proteins, but not LYPD4. In the patient subset with genotypically dysregulated inflammation, our analysis suggested the co-localization to lipid rafts of LYPD4 and the complement receptor CD55, as well as the neurally related CNTNAP2 and RIMS4. Segregation of trauma patients based on genotype of the CD55 SNP rs11117564 showed distinct trajectories of organ dysfunction and systemic inflammation despite similar demographics and injury characteristics., Conclusion: These analyses define novel interactions among SNPs that could enhance our understanding of the response to traumatic injury and critical illness., (Copyright © 2024 by the Shock Society.)
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- 2024
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33. Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia.
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Tang Y, Wu J, Sun X, Tan S, Li W, Yin S, Liu L, Chen Y, Liu Y, Tan Q, Jiang Y, Yang W, Huang W, Weng C, Wu Q, Lu Y, Yuan H, Xiao Q, Chen AF, Xu Q, Billiar TR, and Cai J
- Subjects
- Animals, Mice, Humans, Mice, Inbred C57BL, Male, Apoptosis, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Mitochondria metabolism, Gasdermins, Cardiolipins metabolism, Reactive Oxygen Species metabolism, Endotoxemia metabolism, Endotoxemia pathology, Phosphate-Binding Proteins metabolism, Intracellular Signaling Peptides and Proteins metabolism, Oxidation-Reduction, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology
- Abstract
Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this cardiac dysfunction. Here, we show that the N-terminal gasdermin D (GSDMD-N) initiates mitochondrial apoptotic pore and cardiac dysfunction by directly interacting with cardiolipin oxidized by complex II-generated reactive oxygen species (ROS) during endotoxemia. Caspase-4/11 initiates GSDMD-N pores that are subsequently amplified by the upregulation and activation of NLRP3 inflammation through further generation of ROS. GSDMD-N pores form prior to BAX and VDAC1 apoptotic pores and further incorporate into BAX and VDAC1 oligomers within mitochondria membranes to exacerbate the apoptotic process. Our findings identify oxidized cardiolipin as the definitive target of GSDMD-N in mitochondria of cardiomyocytes during endotoxin-induced myocardial dysfunction (EIMD), and modulation of cardiolipin oxidation could be a therapeutic target early in the disease process to prevent EIMD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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34. Activation of TLR9 signaling suppresses the immunomodulating functions of CD55 lo fibroblastic reticular cells during bacterial peritonitis.
- Author
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Jiang T, Li Y, Huang X, Jayakumar P, Billiar TR, and Deng M
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- Animals, Humans, Male, Mice, Disease Models, Animal, Immunomodulation, Mice, Inbred C57BL, Mice, Knockout, Fibroblasts metabolism, Fibroblasts immunology, Peritonitis immunology, Peritonitis metabolism, Signal Transduction, Toll-Like Receptor 9 metabolism, Toll-Like Receptor 9 genetics
- Abstract
Fibroblastic reticular cells (FRCs) are a subpopulation of stromal cells modulating the immune environments in health and disease. We have previously shown that activation of TLR9 signaling in FRC in fat-associated lymphoid clusters (FALC) regulate peritoneal immunity via suppressing immune cell recruitment and peritoneal resident macrophage (PRM) retention. However, FRCs are heterogeneous across tissues and organs. The functions of each FRC subset and the regulation of TLR9 in distinct FRC subsets are unknown. Here, we confirmed that specific deletion of TLR9 in FRC improved bacterial clearance and survival during peritoneal infection. Furthermore, using single-cell RNA sequencing, we found two subsets of FRCs (CD55
hi and CD55lo ) in the mesenteric FALC. The CD55hi FRCs were enriched in gene expression related to extracellular matrix formation. The CD55lo FRCs were enriched in gene expression related to immune response. Interestingly, we found that TLR9 is dominantly expressed in the CD55lo subset. Activation of TLR9 signaling suppressed proliferation, cytokine production, and retinoid metabolism in the CD55lo FRC, but not CD55hi FRC. Notably, we found that adoptive transfer of Tlr9-/- CD55lo FRC from mesenteric FALC more effectively improved the survival during peritonitis compared with WT-FRC or Tlr9-/- CD55hi FRC. Furthermore, we identified CD55hi and CD55lo subsets in human adipose tissue-derived FRC and confirmed the suppressive effect of TLR9 on the proliferation and cytokine production in the CD55lo subset. Therefore, inhibition of TLR9 in the CD55lo FRCs from adipose tissue could be a useful strategy to improve the therapeutic efficacy of FRC-based therapy for peritonitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Jiang, Li, Huang, Jayakumar, Billiar and Deng.)- Published
- 2024
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35. IRG1/ACOD1 Promotes Neutrophil Reverse Migration and Alleviates Local Inflammation.
- Author
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Ji J, Zhong H, Li Y, Billiar TR, Wilson MA, Scott MJ, and Fan J
- Abstract
Polymorphonuclear neutrophil (PMN) infiltration at inflammatory site plays a critical role in inflammation. PMN reverse migration (rM) describes the phenomenon that PMNs migrate away from inflammatory site back into the vasculature, and its role within inflammatory scenarios remains to be fully determined. This study aimed to investigate the mechanism underlying PMN rM and its role in inflammation. First, we demonstrated PMN rM in a mouse model of LPS-induced acute lung inflammation. By single-cell RNA sequencing (scRNA-seq), we demonstrated that reverse migrated (rM-ed) PMNs in blood expressed high level of immuneresponsive gene 1 (Irg1), the encoding gene of cis-aconitate decarboxylase (ACOD1). Using a mouse air pouch model, which enables us to directly track rM-ed PMNs in vivo, we detected higher expression of ACOD1 in the rM-ed PMNs in circulation. Furthermore, mice with Irg1 knockout exhibited decreased PMN rM and higher levels of inflammatory cytokine in inflammatory site. Mechanistically, we found that itaconate, the product of ACOD1 catalyzation, decreased PMN ICAM-1 expression at the inflammation site. Furthermore, inflammatory site showed a high level of shed CD11a, the ligand of ICAM-1. Neutralization of either ICAM-1 or CD11a leading to increased PMN rM. These findings suggest that the binding of ICAM-1 and shed CD11a serves as a retaining force to hold PMNs in the site of inflammation, and ACOD1-decreased PMN surface expression of ICAM-1 weakens the retaining force, so promoting PMNs to leave the inflammatory site. These results indicate a regulatory role of IRG1 in PMN rM and subsequent contributions to inflammation resolution., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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36. Transcriptomic and Proteomic Characterization of the Immune Response to Elective Spinal Reconstructive Surgery: Impact of Aging and Comparison with Traumatic Injury Response.
- Author
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Bonaroti JW, Ozel M, Chen T, Darby JL, Sun X, Moheimani H, Reitz KM, Kar UK, Zuckerbraun BS, Das J, Okonkwo DO, and Billiar TR
- Subjects
- Humans, Aged, Adolescent, Young Adult, Adult, Transcriptome, Leukocytes, Mononuclear, Proteomics, Aging, Gene Expression Profiling, Immunity, Inflammation, Surgery, Plastic, Multiple Trauma surgery
- Abstract
Background: Major surgery triggers trauma-like stress responses linked to age, surgery duration, and blood loss, resembling polytrauma. This similarity suggests elective surgery as a surrogate model for studying polytrauma immune responses. We investigated stress responses across age groups and compared them with those of polytrauma patients., Study Design: Patients undergoing major spinal reconstruction surgery were divided into older (age >65 years, n = 5) and young (age 18 to 39 years, n = 6) groups. A comparison group consisted of matched trauma patients (n = 8). Blood samples were collected before, during, and after surgery. Bone marrow mononuclear cells and peripheral blood mononuclear cells were analyzed using cellular indexing of transcriptomes and epitopes sequencing or single-cell RNA sequencing. Plasma was subjected to dual-platform proteomic analysis (SomaLogic and O-link)., Results: Response to polytrauma was highest within 4 hours. By comparison, the response to surgery was highest at 24 hours. Both insults triggered significant changes in cluster of differentiation 14 monocytes, with increased inflammation and lower major histocompatibility complex-class 2 expression. Older patient's cluster of differentiation 14 monocytes displayed higher inflammation and less major histocompatibility complex-class 2 suppression; a trend was also seen in bone marrow mononuclear cells. Although natural killer cells were markedly activated after polytrauma, they were suppressed after surgery, especially in older patients. In plasma, innate immunity proteins dominated at 24 hours, shifting to adaptive immunity proteins by 6 weeks with heightened inflammation in older patients. Senescence-associated secretory phenotype proteins were higher in older patients at baseline and further elevated during and after surgery., Conclusions: Although both major surgery and polytrauma initiate immune and stress responses, substantial differences exist in timing and cellular profiles, suggesting major elective surgery is not a suitable surrogate for the polytrauma response. Nonetheless, distinct responses in young vs older patients highlight the utility of elective spinal in studying patient-specific factors affecting outcomes after major elective surgery., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Surgeons.)
- Published
- 2024
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37. Fibroblastic reticular cell-derived exosomes are a promising therapeutic approach for septic acute kidney injury.
- Author
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Li Y, Hu C, Zhai P, Zhang J, Jiang J, Suo J, Hu B, Wang J, Weng X, Zhou X, Billiar TR, Kellum JA, Deng M, and Peng Z
- Subjects
- Mice, Animals, Inflammasomes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Lipopolysaccharides, Mice, Inbred C57BL, Exosomes metabolism, Acute Kidney Injury metabolism, Sepsis complications, Sepsis metabolism
- Abstract
Sepsis-induced acute kidney injury (S-AKI) is highly lethal, and effective drugs for treatment are scarce. Previously, we reported the robust therapeutic efficacy of fibroblastic reticular cells (FRCs) in sepsis. Here, we demonstrate the ability of FRC-derived exosomes (FRC-Exos) to improve C57BL/6 mouse kidney function following cecal ligation and puncture-induced sepsis. In vivo imaging confirmed that FRC-Exos homed to injured kidneys. RNA-Seq analysis of FRC-Exo-treated primary kidney tubular cells (PKTCs) revealed that FRC-Exos influenced PKTC fate in the presence of lipopolysaccharide (LPS). FRC-Exos promoted kinase PINK1-dependent mitophagy and inhibited NLRP3 inflammasome activation in LPS-stimulated PKTCs. To dissect the mechanism underlying the protective role of Exos in S-AKI, we examined the proteins within Exos by mass spectrometry and found that CD5L was the most upregulated protein in FRC-Exos compared to macrophage-derived Exos. Recombinant CD5L treatment in vitro attenuated kidney cell swelling and surface bubble formation after LPS stimulation. FRCs were infected with a CD5L lentivirus to increase CD5L levels in FRC-Exos, which were then modified in vitro with the kidney tubular cell targeting peptide LTH, a peptide that binds to the biomarker protein kidney injury molecule-1 expressed on injured tubule cells, to enhance binding specificity. Compared with an equivalent dose of recombinant CD5L, the modified CD5L-enriched FRC-Exos selectively bound PKTCs, promoted kinase PINK-ubiquitin ligase Parkin-mediated mitophagy, inhibiting pyroptosis and improved kidney function by hindering NLRP3 inflammasome activation, thereby improving the sepsis survival rate. Thus, strategies to modify FRC-Exos could be a new avenue in developing therapeutics against kidney injury., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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38. Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials.
- Author
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Donohue JK, Gruen DS, Iyanna N, Lorence JM, Brown JB, Guyette FX, Daley BJ, Eastridge BJ, Miller RS, Nirula R, Harbrecht BG, Claridge JA, Phelan HA, Vercruysse GA, O'Keeffe T, Joseph B, Neal MD, Billiar TR, and Sperry JL
- Subjects
- Humans, Proportional Hazards Models, Endothelial Cells, Retrospective Studies, Wounds, Penetrating complications, Wounds, Nonpenetrating complications, Emergency Medical Services
- Abstract
Injury mechanism is an important consideration when conducting clinical trials in trauma. Mechanisms of injury may be associated with differences in mortality risk and immune response to injury, impacting the potential success of the trial. We sought to characterize clinical and endothelial cell damage marker differences across blunt and penetrating injured patients enrolled in three large, prehospital randomized trials which focused on hemorrhagic shock. In this secondary analysis, patients with systolic blood pressure < 70 or systolic blood pressure < 90 and heart rate > 108 were included. In addition, patients with both blunt and penetrating injuries were excluded. The primary outcome was 30-day mortality. Mortality was characterized using Kaplan-Meier and Cox proportional-hazards models. Generalized linear models were used to compare biomarkers. Chi squared tests and Wilcoxon rank-sum were used to compare secondary outcomes. We characterized data of 696 enrolled patients that met all secondary analysis inclusion criteria. Blunt injured patients had significantly greater 24-h (18.6% vs. 10.7%, log rank p = 0.048) and 30-day mortality rates (29.7% vs. 14.0%, log rank p = 0.001) relative to penetrating injured patients with a different time course. After adjusting for confounders, blunt mechanism of injury was independently predictive of mortality at 30-days (HR 1.84, 95% CI 1.06-3.20, p = 0.029), but not 24-h (HR 1.65, 95% CI 0.86-3.18, p = 0.133). Elevated admission levels of endothelial cell damage markers, VEGF, syndecan-1, TM, S100A10, suPAR and HcDNA were associated with blunt mechanism of injury. Although there was no difference in multiple organ failure (MOF) rates across injury mechanism (48.4% vs. 42.98%, p = 0.275), blunt injured patients had higher Denver MOF score (p < 0.01). The significant increase in 30-day mortality and endothelial cell damage markers in blunt injury relative to penetrating injured patients highlights the importance of considering mechanism of injury within the inclusion and exclusion criteria of future clinical trials., (© 2024. The Author(s).)
- Published
- 2024
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39. Transforming the Future of Surgeon-Scientists.
- Author
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Ladner DP, Goldstein AM, Billiar TR, Cameron AM, Carpizo DR, Chu DI, Coopersmith CM, DeMatteo RP, Feng S, Gallagher KA, Gillanders WE, Lal BK, Lipshutz GS, Liu A, Maier RV, Mittendorf EA, Morris AM, Sicklick JK, Velazquez OC, Whitson BA, Wilke LG, Yoon SS, Zeiger MA, Farmer DL, and Hwang ES
- Subjects
- Humans, United States, Mentors, Faculty, Academic Medical Centers, Career Mobility, National Institutes of Health (U.S.), Surgeons, Biomedical Research
- Abstract
Objective: To create a blueprint for surgical department leaders, academic institutions, and funding agencies to optimally support surgeon-scientists., Background: Scientific contributions by surgeons have been transformative across many medical disciplines. Surgeon-scientists provide a distinct approach and mindset toward key scientific questions. However, lack of institutional support, pressure for increased clinical productivity, and growing administrative burden are major challenges for the surgeon-scientist, as is the time-consuming nature of surgical training and practice., Methods: An American Surgical Association Research Sustainability Task Force was created to outline a blueprint for sustainable science in surgery. Leaders from top NIH-sponsored departments of surgery engaged in video and in-person meetings between January and April 2023. A strength, weakness, opportunities, threats analysis was performed, and workgroups focused on the roles of surgeons, the department and institutions, and funding agencies., Results: Taskforce recommendations: (1) SURGEONS: Growth mindset : identifying research focus, long-term planning, patience/tenacity, team science, collaborations with disparate experts; Skill set : align skills and research, fill critical skill gaps, develop team leadership skills; DEPARTMENT OF SURGERY (DOS): (2) MENTORSHIP: Chair : mentor-mentee matching/regular meetings/accountability, review of junior faculty progress, mentorship training requirement, recognition of mentorship (eg, relative value unit equivalent, awards; Mentor: dedicated time, relevant scientific expertise, extramural funding, experience and/or trained as mentor, trusted advisor; Mentee : enthusiastic/eager, proactive, open to feedback, clear about goals; (3) FINANCIAL SUSTAINABILITY: diversification of research portfolio, identification of matching funding sources, departmental resource awards (eg, T-/P-grants), leveraging of institutional resources, negotiation of formalized/formulaic funds flow investment from academic medical center toward science, philanthropy; (4) STRUCTURAL/STRATEGIC SUPPORT: Structural: grants administrative support, biostats/bioinformatics support, clinical trial and research support, regulatory support, shared departmental laboratory space/equipment; Strategic: hiring diverse surgeon-scientist/scientists faculty across DOS, strategic faculty retention/ recruitment, philanthropy, career development support, progress tracking, grant writing support, DOS-wide research meetings, regular DOS strategic research planning; (5) COMMUNITY AND CULTURE: Community: right mix of faculty, connection surgeon with broad scientific community; Culture: building research infrastructure, financial support for research, projecting importance of research (awards, grand rounds, shoutouts); (6) THE ROLE OF INSTITUTIONS: Foundation: research space co-location, flexible start-up packages, courses/mock study section, awards, diverse institutional mentorship teams; Nurture: institutional infrastructure, funding (eg, endowed chairs), promotion friendly toward surgeon-scientists, surgeon-scientists in institutional leadership positions; Expectations: RVU target relief, salary gap funding, competitive starting salaries, longitudinal salary strategy; (7) THE ROLE OF FUNDING AGENCIES: change surgeon research training paradigm, offer alternate awards to K-awards, increasing salary cap to reflect market reality, time extension for surgeon early-stage investigator status, surgeon representation on study section, focused award strategies for professional societies/foundations., Conclusions: Authentic recommitment from surgeon leaders with intentional and ambitious actions from institutions, corporations, funders, and society is essential in order to reap the essential benefits of surgeon-scientists toward advancements of science., Competing Interests: S.H.F. reports past compensation to her institution from Novartis, Randox, and Transplant Genomics. S.H.F. also serves as an Editor-in-Chief for American Journal of Transplantation and a member of Editorial Board for New England Journal of Medicine . W.E.G. reports ongoing compensation to his institution from National Cancer Institute, Leidos Biomedical, and 1440 Foundation. E.A.M. reports compensated service on scientific advisory boards for Astra Zeneca, BioNTech and Merck; uncompensated service on steering committees for Bristol Myers Squibb and Roche/Genentech; and institutional research support from Roche/Genentech (via SU2C grant) and Gilead. E.A.M. also reports research funding from Susan Komen for the Cure for which she serves as a Scientific Advisor, and uncompensated participation as a member of the American Society of Clinical Oncology Board of Directors. J.K.S. receives consultant fees from Deciphera, Aadi and Grand Rounds, serves as a consultant for CureMatch, received speaker’s fees from Deciphera, La-Hoffman Roche, Foundation Medicine, Merck, QED, and Daiichi Sankyo; and owns stock in Personalis and CureMatch. L.G.W. reports ongoing compensation to her institution from Perimeter Medical and compensated services from Elucent Medical. D.L.F. reports compensated services from Briopryme and Artemis Cures; uncompensated services as a consultant for the National Institutes of Health; and research funding from California Institute for Regenerative Medicine (CIRM). The other authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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40. NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER- Breast Cancer.
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Ridnour LA, Heinz WF, Cheng RY, Wink AL, Kedei N, Pore M, Imtiaz F, Femino EL, Gonzalez AL, Coutinho L, Butcher D, Edmondson EF, Rangel MC, Kinders RJ, Lipkowitz S, Wong ST, Anderson SK, McVicar DW, Li X, Glynn SA, Billiar TR, Chang JC, Hewitt SM, Ambs S, Lockett SJ, and Wink DA
- Abstract
Estrogen receptor-negative (ER-) breast cancer is an aggressive breast cancer subtype with limited therapeutic options. Upregulated expression of both inducible nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) in breast tumors predicts poor clinical outcomes. Signaling molecules released by these enzymes activate oncogenic pathways, driving cancer stemness, metastasis, and immune suppression. The influence of tumor NOS2/COX2 expression on the landscape of immune markers using multiplex fluorescence imaging of 21 ER- breast tumors were stratified for survival. A powerful relationship between tumor NOS2/COX2 expression and distinct CD8+ T cell phenotypes was observed at 5 years post-diagnosis. These results were confirmed in a validation cohort using gene expression data showing that ratios of NOS2 to CD8 and COX2 to CD8 are strongly associated with poor outcomes in high NOS2/COX2-expressing tumors. Importantly, multiplex imaging identified distinct CD8+ T cell phenotypes relative to tumor NOS2/COX2 expression in Deceased vs Alive patient tumors at 5-year survival. CD8+NOS2-COX2- phenotypes defined fully inflamed tumors with significantly elevated CD8+ T cell infiltration in Alive tumors expressing low NOS2/COX2. In contrast, two distinct phenotypes including inflamed CD8+NOS2+COX2+ regions with stroma-restricted CD8+ T cells and CD8-NOS2-COX2+ immune desert regions with abated CD8+ T cell penetration, were significantly elevated in Deceased tumors with high NOS2/COX2 expression. These results were supported by applying an unsupervised nonlinear dimensionality-reduction technique, UMAP, correlating specific spatial CD8/NOS2/COX2 expression patterns with patient survival. Moreover, spatial analysis of the CD44v6 and EpCAM cancer stem cell (CSC) markers within the CD8/NOS2/COX2 expression landscape revealed positive correlations between EpCAM and inflamed stroma-restricted CD8+NOS2+COX2+ phenotypes at the tumor/stroma interface in deceased patients. Also, positive correlations between CD44v6 and COX2 were identified in immune desert regions in deceased patients. Furthermore, migrating tumor cells were shown to occur only in the CD8-NOS2+COX2+ regions, identifying a metastatic hot spot. Taken together, this study shows the strength of spatial localization analyses of the CD8/NOS2/COX2 landscape, how it shapes the tumor immune microenvironment and the selection of aggressive tumor phenotypes in distinct regions that lead to poor clinical outcomes. This technique could be beneficial for describing tumor niches with increased aggressiveness that may respond to clinically available NOS2/COX2 inhibitors or immune-modulatory agents.
- Published
- 2023
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41. Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients.
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Ridnour LA, Cheng RYS, Heinz WF, Pore M, Gonzalez AL, Femino EL, Moffat R, Wink AL, Imtiaz F, Coutinho L, Butcher D, Edmondson EF, Rangel MC, Wong STC, Lipkowitz S, Glynn S, Vitek MP, McVicar DW, Li X, Anderson SK, Paolocci N, Hewitt SM, Ambs S, Billiar TR, Chang JC, Lockett SJ, and Wink DA
- Abstract
Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER-breast cancers.
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- 2023
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42. Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis.
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Zhang R, Yu C, Zeh HJ, Wang H, Kroemer G, Klionsky DJ, Billiar TR, Kang R, and Tang D
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- Animals, Mice, DNA, Homeostasis, Intestines, Proteomics, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism
- Abstract
Extensive studies demonstrate the importance of the STING1 (also known as STING) protein as a signaling hub that coordinates immune and autophagic responses to ectopic DNA in the cytoplasm. Here, we report a nuclear function of STING1 in driving the activation of the transcription factor aryl hydrocarbon receptor (AHR) to control gut microbiota composition and homeostasis. This function was independent of DNA sensing and autophagy and showed competitive inhibition with cytoplasmic cyclic guanosine monophosphate (GMP)-AMP synthase (CGAS)-STING1 signaling. Structurally, the cyclic dinucleotide binding domain of STING1 interacted with the AHR N-terminal domain. Proteomic analyses revealed that STING1-mediated transcriptional activation of AHR required additional nuclear partners, including positive and negative regulatory proteins. Although AHR ligands could rescue colitis pathology and dysbiosis in wild-type mice, this protection was abrogated by mutational inactivation of STING1. These findings establish a key framework for understanding the nuclear molecular crosstalk between the microbiota and the immune system., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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43. Nitric oxide and thioredoxin modulate the activity of caspase 9 in HepG2 cells.
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Chakraborty S, Choudhuri A, Mishra A, Bhattacharyya C, Billiar TR, Stoyanovsky DA, and Sengupta R
- Subjects
- Humans, Caspase 9 metabolism, Hep G2 Cells, NADP metabolism, Thioredoxins metabolism, Thioredoxin-Disulfide Reductase, Nitric Oxide metabolism, Thioctic Acid
- Abstract
The interdependent and finely tuned balance between the well-established redox-based modification, S-nitrosylation, and its counteractive mechanism of S-nitrosothiol degradation, i.e., S-denitrosylation of biological protein or non-protein thiols defines the cellular fate in the context of redox homeostasis. S-nitrosylation of cysteine residues by S-nitrosoglutathione, S-nitroso-L-cysteine-like physiological and S-nitroso-L-cysteine ethyl ester-like synthetic NO donors inactivate Caspase-3, 8, and 9, thereby hindering their apoptotic activity. However, spontaneous restoration of their activity upon S-denitrosylation of S-nitrosocaspases into their reduced, free thiol active states, aided by the members of the ubiquitous cellular redoxin (thioredoxin/ thioredoxin reductase/ NADPH) and low molecular weight dithiol (lipoic acid/ lipoamide dehydrogenase/ dihydrolipoic acid/ NADPH) systems imply a direct relevance to their proteolytic activities and further downstream signaling cascades. Additionally, our previous and current findings offer crucial insight into the concept of redundancy between thioredoxin and lipoic acid systems, and the redox-modulated control of the apoptotic and proteolytic activity of caspases, triggering their cyto- and neurotoxic effects in response to nitro-oxidative stress. Thus, this might lay the foundation for the exogenous introduction of precise and efficient NO or related donor drug delivery systems that can directly participate in catering to the S-(de)-nitrosylation-mediated functional outcomes of the cysteinyl proteases in pathophysiological settings., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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44. A common single nucleotide polymorphism is associated with inflammation and critical illness outcomes.
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El-Dehaibi F, Zamora R, Radder J, Yin J, Shah AM, Namas RA, Situ M, Zhao Y, Bain W, Morris A, McVerry BJ, Barclay DA, Billiar TR, Zhang Y, Kitsios GD, and Vodovotz Y
- Abstract
Acute inflammation is heterogeneous in critical illness and predictive of outcome. We hypothesized that genetic variability in novel, yet common, gene variants contributes to this heterogeneity and could stratify patient outcomes. We searched algorithmically for significant differences in systemic inflammatory mediators associated with any of 551,839 SNPs in one derivation (n = 380 patients with blunt trauma) and two validation (n = 75 trauma and n = 537 non-trauma patients) cohorts. This analysis identified rs10404939 in the LYPD4 gene. Trauma patients homozygous for the A allele (rs10404939AA; 27%) had different trajectories of systemic inflammation along with persistently elevated multiple organ dysfunction (MOD) indices vs. patients homozygous for the G allele (rs10404939GG; 26%). rs10404939AA homozygotes in the trauma validation cohort had elevated MOD indices, and non-trauma patients displayed more complex inflammatory networks and worse 90-day survival compared to rs10404939GG homozygotes. Thus, rs10404939 emerged as a common, broadly prognostic SNP in critical illness., Competing Interests: The authors declare no competing interests associated with this article., (© 2023 The Authors.)
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- 2023
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45. A Prospective Cohort Protocol for the Remnant Investigation in Sepsis Study.
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Seymour CW, Urbanek KL, Nakayama A, Kennedy JN, Powell R, Robinson RAS, Kapp KL, Billiar TR, Vodovotz Y, Gelhaus SL, Cooper VS, Tang L, Mayr F, Reitz KM, Horvat C, Meyer NJ, Dickson RP, Angus D, and Palmer OP
- Abstract
Background: Sepsis is a common and deadly syndrome, accounting for more than 11 million deaths annually. To mature a deeper understanding of the host and pathogen mechanisms contributing to poor outcomes in sepsis, and thereby possibly inform new therapeutic targets, sophisticated, and expensive biorepositories are typically required. We propose that remnant biospecimens are an alternative for mechanistic sepsis research, although the viability and scientific value of such remnants are unknown., Methods and Results: The Remnant Biospecimen Investigation in Sepsis study is a prospective cohort study of 225 adults (age ≥ 18 yr) presenting to the emergency department with community sepsis, defined as sepsis-3 criteria within 6 hours of arrival. The primary objective was to determine the scientific value of a remnant biospecimen repository in sepsis linked to clinical phenotyping in the electronic health record. We will study candidate multiomic readouts of sepsis biology, governed by a conceptual model, and determine the precision, accuracy, integrity, and comparability of proteins, small molecules, lipids, and pathogen sequencing in remnant biospecimens compared with paired biospecimens obtained according to research protocols. Paired biospecimens will include plasma from sodium-heparin, EDTA, sodium fluoride, and citrate tubes., Conclusions: The study has received approval from the University of Pittsburgh Human Research Protection Office (Study 21120013). Recruitment began on October 25, 2022, with planned release of primary results anticipated in 2024. Results will be made available to the public, the funders, critical care societies, laboratory medicine scientists, and other researchers., Competing Interests: Dr. Seymour reports personal fees for consulting from Beckman Coulter Inc. and Inotrem, Inc., unrelated to the study. Dr. Meyer reports personal fees for consulting from Endpoint Health Inc and AstraZeneca BioPharmaceuticals Medical and payments to her institution by Quantum Leap Healthcare Collaborative for work unrelated to the study., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)
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- 2023
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46. Direct Trauma Center Access by Helicopter Emergency Medical Services is Associated With Improved Survival After Severe Injury.
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Deeb AP, Teng CY, Peitzman AB, Billiar TR, Sperry JL, Lu L, Beiriger J, and Brown JB
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- Humans, Retrospective Studies, Aircraft, Triage, Trauma Centers, Injury Severity Score, Air Ambulances, Emergency Medical Services, Wounds and Injuries therapy
- Abstract
Objective: Evaluate the association of survival with helicopter transport directly to a trauma center compared with ground transport to a non-trauma center (NTC) and subsequent transfer., Summary Background Data: Helicopter transport improves survival after injury. One potential mechanism is direct transport to a trauma center when the patient would otherwise be transported to an NTC for subsequent transfer., Methods: Scene patients 16 years and above with positive physiological or anatomic triage criteria within PTOS 2000-2017 were included. Patients transported directly to level I/II trauma centers by helicopter were compared with patients initially transported to an NTC by ground with a subsequent helicopter transfer to a level I/II trauma center. Propensity score matching was used to evaluate the association between direct helicopter transport and survival. Individual triage criteria were evaluated to identify patients most likely to benefit from direct helicopter transport., Results: In all, 36,830 patients were included. Direct helicopter transport was associated with a nearly 2-fold increase in odds of survival compared with NTC ground transport and subsequent transfer by helicopter (aOR 2.78; 95% CI 2.24-3.44, P <0.01). Triage criteria identifying patients with a survival benefit from direct helicopter transport included GCS≤13 (1.71; 1.22-2.41, P <0.01), hypotension (2.56; 1.39-4.71, P <0.01), abnormal respiratory rate (2.30; 1.36-3.89, P <0.01), paralysis (8.01; 2.03-31.69, P <0.01), hemothorax/pneumothorax (2.34; 1.36-4.05, P <0.01), and multisystem trauma (2.29; 1.08-4.84, P =0.03)., Conclusions: Direct trauma center access is a mechanism driving the survival benefit of helicopter transport. First responders should consider helicopter transport for patients meeting these criteria who would otherwise be transported to an NTC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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47. Targeting inflammation in traumatic injury: entering a new era.
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Billiar TR, Hunt BJ, and Bailly S
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- Humans, Inflammation, Brain Injuries, Traumatic, Brain Injuries
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- 2023
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48. High-dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma.
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Li SR, Moheimani H, Herzig B, Kail M, Krishnamoorthi N, Wu J, Abdelhamid S, Scioscia J, Sung E, Rosengart A, Bonaroti J, Johansson PI, Stensballe J, Neal MD, Das J, Kar U, Sperry J, and Billiar TR
- Subjects
- Humans, Biomarkers, Critical Care, Injury Severity Score, Proteomics, Inflammation
- Abstract
Introduction: Severe traumatic injury with shock can lead to direct and indirect organ injury; however, tissue-specific biomarkers are limited in clinical panels. We used proteomic and metabolomic databases to identify organ injury patterns after severe injury in humans., Methods: Plasma samples (times 0, 24, and 72 hours after arrival to trauma center) from injured patients enrolled in two randomized prehospital trials were subjected to multiplexed proteomics (SomaLogic Inc., Boulder, CO). Patients were categorized by outcome: nonresolvers (died >72 hours or required ≥7 days of critical care), resolvers (survived to 30 days and required <7 days of critical care), and low Injury Severity Score (ISS) controls. Established tissue-specific biomarkers were identified through a literature review and cross-referenced with tissue specificity from the Human Protein Atlas. Untargeted plasma metabolomics (Metabolon Inc., Durham, NC), inflammatory mediators, and endothelial damage markers were correlated with injury biomarkers. Kruskal-Wallis/Mann-Whitney U tests with false discovery rate correction assessed differences in biomarker expression across outcome groups (significance; p < 0.1)., Results: Of 142 patients, 78 were nonresolvers (median ISS, 30), 34 were resolvers (median ISS, 22), and 30 were low ISS controls (median ISS, 1). A broad release of tissue-specific damage markers was observed at admission; this was greater in nonresolvers. By 72 hours, nine cardiac, three liver, eight neurologic, and three pulmonary proteins remained significantly elevated in nonresolvers compared with resolvers. Cardiac damage biomarkers showed the greatest elevations at 72 hours in nonresolvers and had significant positive correlations with proinflammatory mediators and endothelial damage markers. Nonresolvers had lower concentrations of fatty acid metabolites compared with resolvers, particularly acyl carnitines and cholines., Conclusion: We identified an immediate release of tissue-specific biomarkers with sustained elevation in the liver, pulmonary, neurologic, and especially cardiac injury biomarkers in patients with complex clinical courses after severe injury. The persistent myocardial injury in nonresolvers may be due to a combination of factors including metabolic stress, inflammation, and endotheliopathy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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49. Targeting Nitric Oxide: Say NO to Metastasis.
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Reddy TP, Glynn SA, Billiar TR, Wink DA, and Chang JC
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- Humans, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type II metabolism, Tumor Microenvironment, Nitric Oxide metabolism, Neoplasms drug therapy
- Abstract
Utilizing targeted therapies capable of reducing cancer metastasis, targeting chemoresistant and self-renewing cancer stem cells, and augmenting the efficacy of systemic chemo/radiotherapies is vital to minimize cancer-associated mortality. Targeting nitric oxide synthase (NOS), a protein within the tumor microenvironment, has gained interest as a promising therapeutic strategy to reduce metastatic capacity and augment the efficacy of chemo/radiotherapies in various solid malignancies. Our review highlights the influence of nitric oxide (NO) in tumor progression and cancer metastasis, as well as promising preclinical studies that evaluated NOS inhibitors as anticancer therapies. Lastly, we highlight the prospects and outstanding challenges of using NOS inhibitors in the clinical setting., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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50. Interferon-gamma is quintessential for NOS2 and COX2 expression in ER - breast tumors that lead to poor outcome.
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Cheng RYS, Ridnour LA, Wink AL, Gonzalez AL, Femino EL, Rittscher H, Somasundaram V, Heinz WF, Coutinho L, Rangel MC, Edmondson EF, Butcher D, Kinders RJ, Li X, Wong STC, McVicar DW, Anderson SK, Pore M, Hewitt SM, Billiar TR, Glynn SA, Chang JC, Lockett SJ, Ambs S, and Wink DA
- Subjects
- Female, Humans, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type II metabolism, Tumor Necrosis Factor-alpha metabolism, Interferon-gamma genetics, Interferon-gamma metabolism, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Tumor Microenvironment genetics, Tumor Microenvironment immunology
- Abstract
A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER breast cancer has been established. However, the mechanisms of tumor induction of these enzymes are unclear. Analysis of The Cancer Genome Atlas (TCGA) revealed correlations between NOS2 and COX2 expression and Th1 cytokines. Herein, single-cell RNAseq analysis of TNBC cells shows potent NOS2 and COX2 induction by IFNγ combined with IL1β or TNFα. Given that IFNγ is secreted by cytolytic lymphocytes, which improve clinical outcomes, this role of IFNγ presents a dichotomy. To explore this conundrum, tumor NOS2, COX2, and CD8
+ T cells were spatially analyzed in aggressive ER-, TNBC, and HER2 + breast tumors. High expression and clustering of NOS2-expressing tumor cells occurred at the tumor/stroma interface in the presence of stroma-restricted CD8+ T cells. High expression and clustering of COX2-expressing tumor cells extended into immune desert regions in the tumor core where CD8+ T cell penetration was limited or absent. Moreover, high NOS2-expressing tumor cells were proximal to areas with increased satellitosis, suggestive of cell clusters with a higher metastatic potential. Further in vitro experiments revealed that IFNγ + IL1β/TNFα increased the elongation and migration of treated tumor cells. This spatial analysis of the tumor microenvironment provides important insight into distinct neighborhoods where stroma-restricted CD8+ T cells exist proximal to NOS2-expressing tumor niches that could have increased metastatic potential., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
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