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  • Ovid Technologies (Wolters Kluwer Health)  (4)
  • 1
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Research Vol. 131, No. Suppl_1 ( 2022-08-05)
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. Suppl_1 ( 2022-08-05)
    Abstract: The W.H.O. estimates that globally 400,000 children under 19 are diagnosed with cancer annually. 60% of pediatric cancers are treated with chemotherapy using anthracyclines, mainly doxorubicin. Survivors of childhood cancer are approximately 15 times more likely to be diagnosed with congestive heart failure. African American (AA) survivors had a 2.5-fold increased risk of severe or life-threatening cardiomyopathy vs European Americans (EA). In recent WGS studies, 2 novel loci in chromosome 1 & 6 were identified to be correlated with an increased risk of doxorubicin-induced cardiotoxicity (DIC) in AA and EA population groups respectively and were reduced or absent in the other group. Our study aims to validate these loci using patient specific hiPSC-derived cardiomyocytes (hiPSC-CM), and for that we recruited and generated 20 hiPSC lines from the blood of AA and EA pediatric patients. Using a novel bioreactor system, a large-scale production of hiPSC-CM for this patient specific samples is underway, and the cells will be utilized for phenotypic and genotypic characterization. Our aim is to assess the effect of doxorubicin on cardiomyocyte viability, apoptosis, mitochondrial function, and calcium dynamics. Differential cardiac gene regulation after exposure to doxorubicin will be studied using RNA sequencing. In conclusion, our findings will validate the genetic variants predisposing AA and EA populations to DIC. This study will clinically impact therapeutic approaches on both AA and EA populations and at individual levels while using doxorubicin. The validated hiPSC-CMs could help in identifying personalized cardioprotectants to reduce DIC without modifying chemotherapy. This study could also potentially provide data for genomically-informed drug discovery for novel cardioprotectants.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
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  • 2
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. Suppl_1 ( 2022-08-05)
    Abstract: Anthracycline chemotherapies cause heart failure in a subset of cancer patients. Emerging evidence suggests that genetic factors might contribute to the interindividual variations in cardiac sensitivity to anthracyclines. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through activation of cyclin-dependent kinase 2 (CDK2). The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates CDK2 activity and anthracycline sensitivity in the heart. Here, we showed that loss of endogenous Rbl2 increased basal cardiac CDK2 activity. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. Disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to upregulation of the pro-apoptotic protein Bim. Inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, human RBL2 gene single nucleotide polymorphism (rs17800727) was also associated with anthracycline cardiotoxicity in childhood cancer survivors. In conclusion, loss of Rbl2 provokes cardiac CDK2 activation, resulting in increased sensitivity to DOX-induced cardiotoxicity. Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated pro-apoptotic gene expression. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity in individual patient prior to initiation of anthracycline-based chemotherapy.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
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  • 3
    In: Medicine & Science in Sports & Exercise, Ovid Technologies (Wolters Kluwer Health), Vol. 55, No. 9S ( 2023-9), p. 306-307
    Type of Medium: Online Resource
    ISSN: 1530-0315 , 0195-9131
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2031167-9
    SSG: 31
    Location Call Number Limitation Availability
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  • 4
    In: Annals of Medicine & Surgery, Ovid Technologies (Wolters Kluwer Health)
    Abstract: Tuberculous meningitis (TBM) is a severe form of tuberculosis affecting the meninges, primarily caused by Mycobacterium tuberculosis. Diagnosis of TBM poses numerous challenges due to its non-specific clinical presentation and the limitations of diagnostic tests like GeneXpert. Case presentation: We report a case of a 22-year-old female from Eastern Nepal presenting with acute onset fever, headache, vomiting, and neck pain. CSF analysis showed lymphocytic pleocytosis, elevated protein, low glucose levels, and cobweb coagulum indicative of TBM. However, the GeneXpert test revealed negative results. Discussion: In resource-limited settings like Nepal, where access to GeneXpert MTB/Rif is limited, CSF analysis and clinical algorithms play a crucial role in diagnosing tuberculous meningitis (TBM). Relying solely on GeneXpert results may lead to false negatives, so a high level of suspicion based on patient risk factors is essential. Prompt initiation of empirical anti-tubercular therapy is vital for a favorable outcome in TBM cases. Conclusion: Negative MTB PCR results from CSF can be misleading in diagnosis of Tubercular meningitis. Therefore, comprehensive evaluations, including detailed patient history, physical examination, and CSF fluid analysis, are crucial in high TB prevalence countries to ensure accurate and timely diagnosis.
    Type of Medium: Online Resource
    ISSN: 2049-0801
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2745440-X
    Location Call Number Limitation Availability
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