Browsing by Author "Schneider, Bryan Paul"

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    A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes
    (Springer Nature, 2022-11-22) Wu, Xi; Shen, Fei; Jiang, Guanglong; Xue, Gloria; Philips, Santosh; Gardner, Laura; Cunningham, Geneva; Bales, Casey; Cantor, Erica; Schneider, Bryan Paul; Medicine, School of Medicine
    Anthracyclines, widely used to treat breast cancer, have the potential for cardiotoxicity. We have previously identified and validated a germline single nucleotide polymorphism, rs28714259, associated with an increased risk of anthracycline-induced heart failure. We now provide insights into the mechanism by which rs28714259 might confer increased risk of cardiac damage. Using hiPSC-derived cardiomyocyte cell lines with either intrinsic polymorphism or CRISPR-Cas9-mediated deletion of rs28714259 locus, we demonstrate that glucocorticoid receptor signaling activated by dexamethasone pretreatment prior to doxorubicin exposure preserves cardiomyocyte viability and contractility in cardiomyocytes containing the major allele. Homozygous loss of the rs28714259 major allele diminishes dexamethasone’s protective effect. We further demonstrate that the risk allele of rs28714259 disrupts glucocorticoid receptor and rs28714259 binding affinity. Finally, we highlight the activation of genes and pathways involved in cardiac hypertrophy signaling that are blocked by the risk allele, suggesting a decreased adaptive survival response to doxorubicin-related stress.
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    Cognitive dysfunction in cancer: Neuroimaging and genetic approaches to identify biological mechanisms
    (2015-04-22) Nudelman, Kelly N. H.; Saykin, Andrew J.; Foroud, Tatiana M.; McDonald, Brenna Cathleen; Schneider, Bryan Paul; Shen, Li
    Although cancer and treatment-associated cognitive dysfunction has been well-documented in the literature, much work remains to elucidate the biological mechanisms driving this effect, hampering current therapeutic efforts. To address this gap, we first reviewed studies utilizing neuroimaging to characterize cognitive dysfunction in cancer, as studies of neurodegenerative diseases point to neuroimaging as a sensitive measure of cognitive dysfunction. This review highlighted the need for longitudinal imaging studies of cancer and treatment-related changes in cerebral structure and function. Subsequently, we utilized multimodal neuroimaging techniques in a female breast cancer cohort to investigate the longitudinal impact of cancer and chemotherapy treatment on cerebral perfusion and gray matter. Our findings indicate that chemotherapy is associated with elevated perfusion, primarily in posterior brain regions, as well as depressed frontal perfusion associated with decreased frontal gray matter density. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. We also investigated the relationship of cognitive dysfunction and chemotherapy-induced peripheral neuropathy (CIPN), another type of chemotherapy-related nervous system sequelae, again utilizing multimodal, longitudinal neuroimaging, and found that peripheral neuropathy symptoms following chemotherapy were associated with changes in cerebral perfusion and gray matter density. Together, these findings support the hypothesis that multiple biological mechanisms drive cancer and treatment-related cognitive dysfunction. Interestingly, although cancer is associated with cognitive dysfunction, epidemiological studies have shown that cancer and Alzheimer's disease (AD) are inversely correlated. To extend our imaging analysis beyond breast cancer, we leveraged the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate the inverse relationship of cancer and AD and investigate the impact of both of these diseases on gray matter density. We found that though the inverse relationship of these diseases was replicated in the ADNI cohort, cancer history was associated with lower gray matter density, similar to findings from breast cancer studies, independent of AD diagnostic group. Finally, we reviewed microRNA studies, as microRNAs are important regulators of many cell signaling pathways and have been actively investigated in relation to both diseases. This review suggests several pathways that may be driving the inverse association and may contribute to cognitive dysfunction.
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    Microsatellite instability may predict response to sipuleucel-T in patients with prostate cancer
    (Elsevier, 2019) Zhang, Kevin Juan; Schneider, Bryan Paul; Albany, Constantine; Medicine, School of Medicine
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    Osteonecrosis of the Jaw Risk Factors in Bisphosphonate Treated Patients with Metastatic Cancer
    (Wiley, 2022) Van Poznak, Catherine; Reynolds, Evan L.; Estilo, Cherry L.; Hu, Mimi; Schneider, Bryan Paul; Hertz, Daniel L.; Gersch, Christina; Thibert, Jacklyn; Thomas, Dafydd; Banerjee, Mousumi; Rae, James M.; Hayes, Daniel F.; Medicine, School of Medicine
    Background: A case-control study was performed to define clinical and genetic risk factors associated with osteonecrosis of the jaw in patients with metastatic cancer treated with bisphosphonates. Methods: Clinical data and tissues were collected from patients treated with bisphosphonates for metastatic bone disease who were diagnosed with osteonecrosis of the jaw (cases) and matched controls. Clinical data included patient, behavioral, disease, and treatment information. Genetic polymorphisms in CYP2C8 (rs1934951) and other candidate genes were genotyped. Odds ratios from conditional logistic regression models were examined to identify clinical and genetic characteristics associated with case or control status. Results: The study population consisted of 76 cases and 126 controls. In the final multivariable clinical model, patients with osteonecrosis of the jaw were less likely to have received pamidronate than zoledronic acid (odds ratio = 0.18, 95% Confidence interval: 0.03-0.97, p = .047) and more likely to have been exposed to bevacizumab (OR = 5.15, 95% CI: 1.67-15.95, p = .005). The exploratory genetic analyses suggested a protective effect for VEGFC rs2333496 and risk effects for VEGFC rs7664413 and PPARG rs1152003. Conclusions: We observed patients with ONJ were more likely to have been exposed to bevacizumab and zoledronic and identified potential genetic predictors that require validation prior to clinical translation.