Browsing by Author "Stram, Amanda R."

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    Mediastinal Germ Cell Tumors: Updates in Diagnosis and Management
    (Elsevier, 2020-10) Stram, Amanda R.; Kesler, Kenneth A.; Surgery, School of Medicine
    Primary mediastinal nonseminomatous germ cell tumors represent a rare but important malignancy that occurs in otherwise young and healthy patients. Treatment is challenging and involves cisplatin-based chemotherapy followed by surgery to remove residual disease. Avoiding bleomycin-containing chemotherapy in the treatment of primary mediastinal nonseminomatous germ cell tumors is important. Prechemotherapy and postchemotherapy pathology as well as postoperative serum tumor markers are independent predictors of long-term survival.
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    Mitochondrial protein acetylation and left ventricular function in a model of hypertrophic cardiomyopathy and heart failure
    (2017-05-23) Stram, Amanda R.; Payne, R. Mark; Brustovetsky, Nickolay; Herring, B. Paul; Tune, Johnathan
    Rationale: The childhood heart disease of Friedreich’s Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and SIRT3 is protective in heart disease. The underlying pathophysiology of heart failure in FRDA is unclear. I suspect that increased acetylation in FRDA heart mitochondria damages cardiac energy homeostasis by inhibiting activity of key enzymes involved in heart metabolism. Objective: My project tested the hypothesis that altered acetylation of mitochondrial proteins contributes to the cardiomyopathy of FRDA. Methods: Conditional mouse models of FRDA cardiomyopathy with ablation of FXN (FXN KO) or FXN and SIRT3 (FXN/SIRT3 DKO) in the heart were compared to healthy controls. Hearts were evaluated using echocardiography, cardiac catheterization, histology, protein acetylation and expression. FXN KO mice were treated with NAD+ replacement therapy with nicotinamide riboside (NR), and FXN/SIRT3 DKO mice were treated with FXN protein replacement therapy. Results: Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. High levels of acetylation were associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction. Acetylation correlated strongly with worse heart function, and loss of SIRT3 in the FXN KO mouse resulted in significant decrease in ejection fraction and fractional shortening. Treatment of the FXN/SIRT3 DKO with FXN protein therapy reduced acetylation but was not sufficient to fully rescue heart function. Increasing NAD+ with NR-treatment in the FXN KO lead to increased mitochondrial protein acetylation and did not improve cardiac outcome. Conclusion: I found a strong negative correlation between heart function and mitochondrial protein acetylation. My findings also provide evidence that absence of SIRT3 expression in the FXN KO heart exacerbates features of heart failure, and that SIRT3 expression is necessary to rescue the FXN KO heart. These results suggest that SIRT3 inactivation and abnormal acetylation contribute to the pathophysiology of heart disease in FRDA.
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    Outcomes following surgery for primary mediastinal nonseminomatous germ cell tumors in the cisplatin era
    (Elsevier, 2021-06) Kesler, Kenneth A.; Stram, Amanda R.; Timsina, Lava R.; Turrentine, Mark W.; Brown, John W.; Einhorn, Lawrence H.; Surgery, School of Medicine
    Objective Treatment of primary mediastinal nonseminomatous germ cell tumors involves cisplatin-based chemotherapy followed by surgery to remove residual disease. We undertook a study to determine short and long-term outcomes. Methods A retrospective analysis of patients with primary mediastinal nonseminomatous germ cell tumors who underwent surgery at our institution from 1982 to 2017 was performed. Results A total of 255 patients (mean age, 29.2 years) were identified. Acute respiratory distress syndrome occurred postoperatively in 27 patients (10.9%), which was responsible for all 11 (4.3%) postoperative deaths. Of patients who developed acute respiratory distress syndrome, more patients received bleomycin-containing chemotherapy (25 out of 169; 14.8%) than non-bleomycin regimens (2 out of 77; 2.6%) (P = .004). With respect to variables independently predictive of long-term survival, evidence of choriocarcinoma before chemotherapy (n = 12) was determined to be an adverse factor (P = .006). In contrast, biopsy-proven elements of seminoma (n = 34) were predictive of improved survival (P = .04). The worst pathology identified in the residual mediastinal mass after chemotherapy was necrosis in 61 patients (25.0%), teratoma in 84 patients (34.4%), and malignant (persistent germ cell or non–germ cell cancer) in 97 patients (39.8%), which influenced overall survival (P < .001). Additionally, teratoma with stromal atypia (n = 18) demonstrated decreased survival compared with teratoma without atypia (n = 66; P = .031). Patients with malignancy involving >50% of the residual mass (n = 47) had a 2.3-fold increased risk of death compared with ≤50% malignancy (n = 45; P = .008). Finally, elevated postoperative serum tumor markers (n = 40) was significantly predictive of adverse survival (P < .001). Conclusions In the treatment of primary mediastinal nonseminomatous germ cell tumors, avoiding bleomycin-containing chemotherapy is important. Pre- and postchemotherapy pathology and postoperative serum tumor markers are independent predictors of long-term survival.
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    Posttranslational Modifications in Mitochondria: Protein Signaling in the Powerhouse
    (Springer, 2016-11) Stram, Amanda R.; Payne, R. Mark; Pediatrics, School of Medicine
    There is an intimate interplay between cellular metabolism and the pathophysiology of disease. Mitochondria are essential to maintaining and regulating metabolic function of cells and organs. Mitochondrial dysfunction is implicated in diverse diseases, such as cardiovascular disease, diabetes and metabolic syndrome, neurodegeneration, cancer and aging. Multiple reversible post-translational protein modifications are located in the mitochondria that are responsive to nutrient availability and redox conditions, and which can act in protein-protein interactions to modify diverse mitochondrial functions. Included in this are physiologic redox signaling via reactive oxygen and nitrogen species, phosphorylation, O-GlcNAcylation, acetylation, and succinylation, among others. With the advent of mass proteomic screening techniques, there has been a vast increase in the array of known mitochondrial post-translational modifications and their protein targets. The functional significance of these processes in disease etiology, and the pathologic response to their disruption, are still under investigation. However, many of these reversible modifications act as regulatory mechanisms in mitochondria and show promise for mitochondrial-targeted therapeutic strategies. This review addresses the current knowledge of post-translational processing and signaling mechanisms in mitochondria, and their implications in health and disease.
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    Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich's ataxia cardiomyopathy
    (PLoS, 2017-05-25) Stram, Amanda R.; Wagner, Gregory R.; Fogler, Brian D.; Pride, P. Melanie; Hirschey, Matthew D.; Payne, R. Mark; Surgery, School of Medicine
    INTRODUCTION: The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and loss of SIRT3 increases susceptibility of the heart to stress-induced cardiac hypertrophy and ischemic injury. The underlying pathophysiology of heart failure in FRDA is unclear. The purpose of this study was to examine in detail the physiologic and acetylation changes of the heart that occur over time in a model of FRDA heart failure. We predicted that increased mitochondrial protein acetylation would be associated with a decrease in heart function in a model of FRDA. METHODS: A conditional mouse model of FRDA cardiomyopathy with ablation of FXN (FXN KO) in the heart was compared to healthy controls at postnatal days 30, 45 and 65. We evaluated hearts using echocardiography, cardiac catheterization, histology, protein acetylation and expression. RESULTS: Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function. CONCLUSION: These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.