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  • 1
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    Online Resource
    Metabolomics in advanced pancreatic cancer (PC) patients (pts) achieving weight stability on enteral feeding for cachexia.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. e16291-e16291
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e16291-e16291
    Abstract: e16291 Background: We previously showed that enteral feeding was associated with weight stability and compositional changes in the gut microbiome with increased abundance of the gram-negative genera Veillonella over time. Here, we evaluated the potential of plasma metabolites as predictors of weight stability and high Veillonella abundance in enteral fed pts. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for standard chemotherapy. In preplanned exploratory analyses, serial blood samples were collected over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. Pts were stratified by weight stable (WS, defined as weight change 〈 0.1 kg/baseline BMI-unit over 12 wks of enteral feeding) vs. weight unstable (WU) and high (HV) vs. low Veillonella (LV) abundance (defined by dichotomizing at the mean relative abundance in WS pts). Results: Of 31 cachectic pts enrolled into PANCAX-1, a total of 55 blood samples were collected from 28 pts for plasma metabolomics. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. Plasma metabolomics in 10 pts showed that WU pts (n = 4) had significantly decreased levels of essential amino acids (AAs, L-histidine, L-phenylalanine) and non-essential AAs (L-citrulline, L-tyrosine, all p 〈 0.05) than WS pts (n = 6) at the end of 12 wks of enteral feeding. In 7 WS pts with complete serial sets of blood samples available, enteral feeding over 12 wks was associated with increases in markers of muscle mass (creatinine) but decreases in nucleotide precursors (all p 〈 0.05) compared to baseline. Comparison of baseline metabolites between 6 WS pts with HV and 4 WU pts with LV showed that HV was associated with increases in the nucleotide dCDP and essential AA L-isoleucine but decreased TCA cycle metabolite alpha-ketoglutarate (all p 〈 0.05). Decreases in lactic acid was observed at 12 wks of enteral feeding in HV pts when compared to baseline (p 〈 0.05). Conclusions: Our findings are hypothesis-generating in that metabolites unique to weight stability and Veillonella abundance may inform future studies of anti-cachexia therapies involving enteral feeding or microbial modulation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.e16291
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Abstract 431: Mitochondrial Fission in the Heart is an Adaptation to Increased Energetic Demands: The Role of Physiologic Fragmentation
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation Research Vol. 119, No. suppl_1 ( 2016-07-22)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 119, No. suppl_1 ( 2016-07-22)
    Abstract: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Current paradigms hold that mitochondrial fission and fragmentation are the result of pathologic stresses such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in cardiac impairment, suggesting that fission is important for maintaining normal mitochondrial function. In this study, we identify a novel role for mitochondrial fragmentation as a normal physiological adaptation to increased energetic demand. Using two models of exercise, we demonstrate that “physiologic” mitochondrial fragmentation occurs, results in enhanced mitochondrial function, and is mediated through beta 1-adrenergic receptor signaling. Similar to pathologic fragmentation, physiologic fragmentation is induced by activation of Drp1; however, unlike pathologic fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. To confirm the role of fragmentation as a physiological adaptation to exercise, we inhibited the pro-fission mediator Drp1 in mice using the peptide inhibitor P110 and had mice undergo exercise. Mice treated with P110 had significantly decreased exercise capacity, decreased fragmentation and inactive Drp1 vs controls. To further confirm these findings, we generated cardiac-specific Drp1 KO mice and had them undergo exercise. Mice with cardiac specific Drp1 KO had significantly decreased exercise capacity and abnormally large mitochondria compared to controls. These findings indicate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise and support the still evolving conceptual framework, where fragmentation plays a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.119.suppl_1.431
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467838-X
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  • 3
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    Abstract 83: β1 Vs β2 Adrenergic Signaling Differentially Regulates Mitochondrial Dynamics Through Alterations In Calcineurin And Drp1
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Circulation Research Vol. 115, No. suppl_1 ( 2014-07-18)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 115, No. suppl_1 ( 2014-07-18)
    Abstract: Signal transduction through β1 and β2-adrenergic receptors (ARs) is considered a primary mechanism for regulating cardiovascular function and remodeling. Upon β-AR activation (i.e., physical activity, cardiac pathology) inotropy and chonotropy increase and mitochondria must quickly meet increased energy demand. This suggests that βARs and mitochondria are coupled mechanistically to rapidly respond to the functional and energetic needs of the heart. To investigate the role of β1 vs. β2-AR signaling on mitochondrial dynamics, we compared β1-/- and β2-/- to WT controls. β2-/- had increased mitochondrial fragmentation (increased number and decreased size) by electron microscopy vs. both WT and β1-/-. β2-/- showed altered regulation of mitochondrial fission: increased Drp1 translocation to the mitochondria vs. WT, whereas β1-/- had lower Drp1 translocation. These data suggest differential regulation of fission by βAR signaling, β1 activating and β2 suppressing fission. Since Ca2+-dependent calcineurin is known to activate Drp1 and [Ca2+]i is differentially regulated by β-AR signaling, we examined calcineurin as the bridge between β-AR signaling and Drp1 activation. In β2-/-, both Ca2+ transients and calcineurin activity were increased, suggesting β1-AR/Ca2+/calcinurin-mediated fission. To quantify mitochondrial fragmentation and biogenesis, mitotimer-transfected C2C12 cells were treated with the non-specific β-AR agonist isoproterenol resulting in mitochondrial fragmentation that was inhibited by the β1-antagonist CGP 12177 but not by the ß2-antagonist ICI 118551. Taken together, our data indicate that β1 and β2-AR signaling differentially regulate mitochondrial dynamics in the heart through alterations in [Ca2+] i, leading to calcineurin-induced translocation of Drp1.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.115.suppl_1.83
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467838-X
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  • 4
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    α‐Ketoglutarate –Dependent KDM6 Histone Demethylases and Interferon‐Stimulated Gene Expression in Lupus
    Wiley ; 2024
    In:  Arthritis & Rheumatology
    Details
    In: Arthritis & Rheumatology, Wiley
    Abstract: We aimed to investigate the hypothesis that interferon (IFN)–stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression. Methods Monocytes from healthy volunteers and patients with SLE at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation, and gene expression. The histone demethylases KDM6A/B were inhibited using glycogen synthase kinase J4 (GSK‐J4). GSK‐J4 was tested in pristane and resiquimod (R848) models of IFN‐driven SLE. Results SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control monocytes, as well as increased levels of isocitrate dehydrogenase and its product, α‐ketoglutarate (α‐KG). Because α‐KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving “trained immune” responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly, decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK‐J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression, and kidney pathology in R848‐treated BALB/c mice. Conclusion Our study suggests long‐term IFNα exposure alters the epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone‐modifying enzymes, such as KDM6A/B, may reduce IFN responses in SLE. image
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Article
    DOI: 10.1002/art.42724
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2754614-7
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  • 5
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    Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Research Vol. 122, No. 2 ( 2018-01-19), p. 282-295
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 122, No. 2 ( 2018-01-19), p. 282-295
    Abstract: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis. Objective: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise. Methods and Results: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity. Conclusions: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.117.310725
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1467838-X
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  • 6
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    Distinct regulation of autoreactive CD4 T cell expansion by interleukin-4 under conditions of lymphopenia
    Oxford University Press (OUP) ; 2007
    In:  Journal of Leukocyte Biology Vol. 81, No. 3 ( 2007-03-01), p. 757-765
    Details
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 81, No. 3 ( 2007-03-01), p. 757-765
    Abstract: IL-4 is protective against Type 1 diabetes in the NOD mouse. IL-4 promotes T cell survival in vitro, but little is known about the effect of IL-4 on clonal expansion in vivo. Here, we show that IL-4 only enhances the expansion of autoreactive CD4 T cells during lymphopenia and that neither the presence of islet IL-4 nor IL-4 deficiency affects T cell expansion significantly under conditions of immunosufficiency. The accumulation of proliferating cells induced by IL-4 in a lymphopenic host is inhibited incrementally by increasing the number of bystander cells and is prevented by cell numbers well below that of unmanipulated NOD mice. The ability of IL-4 to promote autoreactive CD4 T cell expansion is therefore sensitive to the degree of host immunodeficiency. Paradoxically, IL-4 receptor-deficient, autoreactive CD4 T cells proliferate more extensively than wild-type T cells in immunodeficient hosts, suggesting that the growth-promoting effect of islet IL-4 acts indirectly. These results suggest that IL-4-mediated protection against autoimmunity and diabetes may be outweighed during immunodeficiency by a pathogenic, IL-4-induced expansion of autoreactive T cells.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
    URL: Article
    DOI: 10.1189/jlb.0406252
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2007
    detail.hit.zdb_id: 2026833-6
    SSG: 12
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  • 7
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    The evolution of TNF-induced apoptosis reveals 550 million years of functional conservation (P6345)
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 190, No. 1_Supplement ( 2013-05-01), p. 184.34-184.34
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 190, No. 1_Supplement ( 2013-05-01), p. 184.34-184.34
    Abstract: Coral reef health is in rapid decline worldwide yet the molecular mechanisms behind coral death remain poorly understood. The Tumor Necrosis Factor (TNF) receptor-ligand superfamily (TNFRSF/TNFSF) is a central mediator of apoptosis and it is hypothesized that the expansion of the TNFRSF/TNFSF occurred following the divergence of invertebrates and vertebrates. Here we challenge this hypothesis and identify more putative coral TNFRSF members than any organism described thus far, including humans. We then predicted Human TNFα (HuTNFα), a known inducer of apoptosis in humans, would also cause apoptosis in coral. Upon HuTNFα stimulation the coral proteome underwent an acidic shift, suggesting the induction signaling cascades. Stimulation of coral with HuTNFα also induced apoptotic blebbing, caspase activation and coral bleaching. This work identifies the first ligand/receptor system to be directly involved with apoptosis and bleaching in coral, and provides evidence for an ancient origin of the TNFRSF/TNFSF that has been functionally maintained for over 550 million years.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.190.Supp.184.34
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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  • 8
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    Bacteriophage adhered to mucus provide a novel mucosal immune system (P3166)
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 190, No. 1_Supplement ( 2013-05-01), p. 61.8-61.8
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 190, No. 1_Supplement ( 2013-05-01), p. 61.8-61.8
    Abstract: Mucosal surfaces serve as a primary entry point for multiple pathogens and are therefore principal sites of immune defense. Here we demonstrate through in vitro and in silico studies that increased phage adherence to the host mucosal layer, provides a novel immune defense mechanism. We show that compared to the surrounding environment, phage-to-bacteria ratios were increased on all mucosal surfaces sampled ranging from cnidarians to humans. This increased phage abundance protects the underlying epithelium from bacterial infection. Enrichment of phage on mucus occurs via interactions between host mucin glycoproteins and phage immunoglobulin-like protein domains exposed on phage capsids. Metagenomic analysis found these immunoglobulin-like proteins present in many environments, particularly those adjacent to mucosal surfaces. Preliminary glycan microarrays and 2D gel electrophoresis show that phage adherence can rapidly adapt to hosts mucus glycan profiles, and in response, the host may regulate its mucus glycosylation to select for a beneficial phage community. This adaptation between phage and host provide a mechanism for the manipulation and selection of the mucosal microbiota. Based on these observations, we present the Bacteriophage Adherence to Mucus (BAM) model describing a phage-derived mucosal immunity with potential applicability to all mucosal surfaces, thus opening a novel field of immunological study.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.190.Supp.61.8
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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  • 9
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    US Severe Acute Respiratory Syndrome Coronavirus 2 Epsilon Variant: Highly Transmissible but With an Adjusted Muted Host T-Cell Response
    Oxford University Press (OUP) ; 2022
    In:  Clinical Infectious Diseases Vol. 75, No. 11 ( 2022-11-30), p. 1940-1949
    Details
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 75, No. 11 ( 2022-11-30), p. 1940-1949
    Abstract: The multiple mutations comprising the epsilon variant demonstrate the independent convergent evolution of severe acute respiratory syndrome coronavirus (SARS-CoV-2), with its spike protein mutation L452R present in the delta (L452R), kappa (L452R), and lambda (L452Q) variants. Methods Coronavirus disease 2019 (COVID-19) variants were detected in 1017 patients using whole-genome sequencing and were assessed for outcome and severity. The mechanistic effects of the epsilon versus non-epsilon variants were investigated using a multiomic approach including cellular response assays and paired cell and host transcriptomic and proteomic profiling. Results We found that patients carrying the epsilon variant had increased mortality risk but not increased hospitalizations (P & lt; .02). Cells infected with live epsilon compared with non-epsilon virus displayed increased sensitivity to neutralization antibodies in all patients but a slightly protective response in vaccinated individuals (P & lt; .001). That the epsilon SARS-CoV-2 variant is more infectious but less virulent is supported mechanistically in the down-regulation of viral processing pathways seen by multiomic analyses. Importantly, this paired transcriptomics and proteomic profiling of host cellular response to live virus revealed an altered leukocyte response and metabolic messenger RNA processing with the epsilon variant. To ascertain host response to SARS-CoV-2 infection, primary COVID-19–positive nasopharyngeal samples were transcriptomically profiled and revealed a differential innate immune response (P & lt; .001) and an adjusted T-cell response in patients carrying the epsilon variant (P & lt; .002). In fact, patients infected with SARS-CoV-2 and those vaccinated with the BNT162b2 vaccine have comparable CD4+/CD8+ T-cell immune responses to the epsilon variant (P & lt; .05). Conclusions While the epsilon variant is more infectious, by altering viral processing, we showed that patients with COVID-19 have adapted their innate immune response to this fitter variant. A protective T-cell response molecular signature is generated by this more transmissible variant in both vaccinated and unvaccinated patients.
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    URL: Article
    DOI: 10.1093/cid/ciac295
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2002229-3
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  • 10
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    Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 9 ( 2018-05-01), p. 3047-3052
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 9 ( 2018-05-01), p. 3047-3052
    Abstract: The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1–dependent secretion of the proinflammatory cytokines IL-1β and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1701723
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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