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  1. Article: In vivo

    D'Alessandro, Angelo / Nouraie, S Mehdi / Zhang, Yingze / Cendali, Francesca / Gamboni, Fabia / Reisz, Julie A / Zhang, Xu / Bartsch, Kyle W / Galbraith, Matthew D / Gordeuk, Victor R / Gladwin, Mark T

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Despite a wealth of exploratory plasma metabolomics studies in sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of hemoglobin SS, SC and transfused AA red blood ... ...

    Abstract Despite a wealth of exploratory plasma metabolomics studies in sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of hemoglobin SS, SC and transfused AA red blood cells (RBCs)
    Key points: In vivo dysregulation of RBC metabolism by HbS is evaluated by metabolic profiling of 587 patients with variable HbA, HbC and HbF levels;RBC acyl-carnitines, urate, pyruvate metabolism, S1P, kynurenine relate to hemolysis and cardiorenal dysfunction, respond to transfusion.
    Language English
    Publishing date 2023-02-14
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.13.528368
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients, as a function of therapeutic transfusion and hydroxyurea treatment.

    D'Alessandro, Angelo / Nouraie, S Mehdi / Zhang, Yingze / Cendali, Francesca / Gamboni, Fabia / Reisz, Julie A / Zhang, Xu / Bartsch, Kyle W / Galbraith, Matthew D / Espinosa, Joaquin M / Gordeuk, Victor R / Gladwin, Mark T

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with ... ...

    Abstract Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with sickle cell sickle cell disease (SCD) enrolled in the WALK-PHaSST study. Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (HbF%). We investigated metabolic correlates to the degree of hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures - including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.
    Language English
    Publishing date 2023-04-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.05.535693
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients as a function of therapeutic transfusion and hydroxyurea treatment.

    D'Alessandro, Angelo / Nouraie, S Mehdi / Zhang, Yingze / Cendali, Francesca / Gamboni, Fabia / Reisz, Julie A / Zhang, Xu / Bartsch, Kyle W / Galbraith, Matthew D / Espinosa, Joaquin M / Gordeuk, Victor R / Gladwin, Mark T

    Haematologica

    2023  Volume 108, Issue 12, Page(s) 3418–3432

    Abstract: Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with SCD ...

    Abstract Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with SCD enrolled in the WALK-PHaSST study (clinicaltrials gov. Identifier: NCT00492531). Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin [Hb] SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (fetal Hb%). We investigated metabolic correlates to the degree of intravascular hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma-free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures - including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.
    MeSH term(s) Humans ; Hydroxyurea/therapeutic use ; Kynurenine/therapeutic use ; Anemia, Sickle Cell/complications ; Anemia, Sickle Cell/drug therapy ; Hemoglobin SC Disease/complications ; Hemolysis ; Hemoglobin, Sickle ; Bile Acids and Salts/therapeutic use
    Chemical Substances Hydroxyurea (X6Q56QN5QC) ; Kynurenine (343-65-7) ; Hemoglobin, Sickle ; Bile Acids and Salts
    Language English
    Publishing date 2023-12-01
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2023.283288
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.76: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: In vivo evaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction.

    D'Alessandro, Angelo / Nouraie, S Mehdi / Zhang, Yingze / Cendali, Francesca / Gamboni, Fabia / Reisz, Julie A / Zhang, Xu / Bartsch, Kyle W / Galbraith, Matthew D / Gordeuk, Victor R / Gladwin, Mark T

    American journal of hematology

    2023  Volume 98, Issue 7, Page(s) 1017–1028

    Abstract: Despite a wealth of exploratory plasma metabolomics studies in sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of hemoglobin SS, SC and transfused AA red blood ... ...

    Abstract Despite a wealth of exploratory plasma metabolomics studies in sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of hemoglobin SS, SC and transfused AA red blood cells (RBCs) in vivo. The current study evaluates the RBC metabolome of 587 subjects with sickle cell sickle cell disease (SCD) from the WALK-PHaSST clinical cohort. The set includes hemoglobin SS, hemoglobin SC SCD patients, with variable levels of HbA related to RBC transfusion events. Here we explore the modulating effects of genotype, age, sex, severity of hemolysis, and transfusion therapy on sickle RBC metabolism. Results show that RBCs from patients with Hb SS genotypes-compared to AA RBCs from recent transfusion events or SC RBCs-are characterized by significant alterations of RBC acylcarnitines, pyruvate, sphingosine 1-phosphate, creatinine, kynurenine and urate metabolism. Surprisingly, the RBC metabolism of SC RBCs is dramatically different from SS, with all glycolytic intermediates significantly elevated in SS RBCs, with the exception of pyruvate. This result suggests a metabolic blockade at the ATP-generating phosphoenolpyruvate to pyruvate step of glycolysis, which is catalyzed by redox-sensitive pyruvate kinase. Metabolomics, clinical and hematological data were collated in a novel online portal. In conclusion, we identified metabolic signatures of HbS RBCs that correlate with the degree of steady state hemolytic anemia, cardiovascular and renal dysfunction and mortality.
    MeSH term(s) Humans ; Hemoglobin, Sickle/metabolism ; Erythrocytes/metabolism ; Anemia, Sickle Cell ; Sickle Cell Trait ; Pyruvates/metabolism
    Chemical Substances Hemoglobin, Sickle ; Pyruvates
    Language English
    Publishing date 2023-04-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 196767-8
    ISSN 1096-8652 ; 0361-8609
    ISSN (online) 1096-8652
    ISSN 0361-8609
    DOI 10.1002/ajh.26923
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1251: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome.

    Waugh, Katherine A / Araya, Paula / Pandey, Ahwan / Jordan, Kimberly R / Smith, Keith P / Granrath, Ross E / Khanal, Santosh / Butcher, Eric T / Estrada, Belinda Enriquez / Rachubinski, Angela L / McWilliams, Jennifer A / Minter, Ross / Dimasi, Tiana / Colvin, Kelley L / Baturin, Dmitry / Pham, Andrew T / Galbraith, Matthew D / Bartsch, Kyle W / Yeager, Michael E /
    Porter, Christopher C / Sullivan, Kelly D / Hsieh, Elena W / Espinosa, Joaquin M

    Cell reports

    2019  Volume 29, Issue 7, Page(s) 1893–1908.e4

    Abstract: People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms ... ...

    Abstract People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms driving this unique clinical profile await elucidation. We completed a deep mapping of the immune system in adults with DS using mass cytometry to evaluate 100 immune cell types, which revealed global immune dysregulation consistent with chronic inflammation, including key changes in the myeloid and lymphoid cell compartments. Furthermore, measurement of interferon-inducible phosphorylation events revealed widespread hypersensitivity to interferon-α in DS, with cell-type-specific variations in downstream intracellular signaling. Mechanistically, this could be explained by overexpression of the interferon receptors encoded on chromosome 21, as demonstrated by increased IFNAR1 surface expression in all immune lineages tested. These results point to interferon-driven immune dysregulation as a likely contributor to the developmental and clinical hallmarks of DS.
    MeSH term(s) Adult ; Down Syndrome/immunology ; Down Syndrome/pathology ; Female ; Flow Cytometry ; Humans ; Interferon-alpha/immunology ; Male ; Middle Aged
    Chemical Substances Interferon-alpha
    Language English
    Publishing date 2019-11-12
    Publishing country United States
    Document type Clinical Trial ; Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2019.10.038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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