9 results on '"Billiar TR"'
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2. NETWORK ANALYSIS OF SINGLE-NUCLEOTIDE POLYMORPHISMS ASSOCIATED WITH ABERRANT INFLAMMATION IN TRAUMA PATIENTS SUGGESTS A ROLE FOR VESICLE-ASSOCIATED INFLAMMATORY PROGRAMS INVOLVING CD55.
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El-Dehaibi F, Zamora R, Yin J, Namas RA, Billiar TR, and Vodovotz Y
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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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3. 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
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- 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
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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.)
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- 2024
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4. Activation of TLR9 signaling suppresses the immunomodulating functions of CD55 lo fibroblastic reticular cells during bacterial peritonitis.
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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
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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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5. IRG1/ACOD1 Promotes Neutrophil Reverse Migration and Alleviates Local Inflammation.
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Ji J, Zhong H, Li Y, Billiar TR, Wilson MA, Scott MJ, and Fan J
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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.)
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- 2024
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6. Transcriptomic and Proteomic Characterization of the Immune Response to Elective Spinal Reconstructive Surgery: Impact of Aging and Comparison with Traumatic Injury Response.
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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
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- Humans, Aged, Adolescent, Young Adult, Adult, Transcriptome, Leukocytes, Mononuclear, Proteomics, Aging, Gene Expression Profiling, Immunity, Inflammation, Surgery, Plastic, Multiple Trauma surgery
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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.)
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- 2024
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7. Fibroblastic reticular cell-derived exosomes are a promising therapeutic approach for septic acute kidney injury.
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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
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- 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
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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.)
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- 2024
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8. Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials.
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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
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- Humans, Proportional Hazards Models, Endothelial Cells, Retrospective Studies, Wounds, Penetrating complications, Wounds, Nonpenetrating complications, Emergency Medical Services
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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).)
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- 2024
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9. Transforming the Future of Surgeon-Scientists.
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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
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- Humans, United States, Mentors, Faculty, Academic Medical Centers, Career Mobility, National Institutes of Health (U.S.), Surgeons, Biomedical Research
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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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