87 results on '"Steuerwald, N."'
Search Results
2. Circadian Rhythms in Acute Intermittent Porphyria - a Pilot Study: OC7
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Larion, S., Caballes, F. R., Hwang, S. I., Lee, J. G., Rossman, W. E., Parsons, J., Steuerwald, N., Li, T., Maddukuri, V., Yazici, C., Groseclose, G., Finkielstein, C. V., and Bonkovsky, H. L.
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- 2013
3. Expression of genes regulating chromosome segregation, the cell cycle and apoptosis during human preimplantation development
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Wells, D., Bermudez, M.G., Steuerwald, N., Thornhill, A.R., Walker, D.L., Malter, H., Delhanty, J.D.A., and Cohen, J.
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- 2005
4. Quantification of human ooplasmic mitochondria
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Barritt, JA, Kokot, M, Cohen, J, Steuerwald, N, and Brenner, CA
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- 2002
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5. Liquid jet delivery method featuring S100A1 gene therapy in the rodent model following acute myocardial infarction
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Fargnoli, A S, primary, Katz, M G, additional, Williams, R D, additional, Kendle, A P, additional, Steuerwald, N, additional, and Bridges, C R, additional
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- 2015
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6. Whole exome sequencing of embryo biopsies reveals clinically-significant de novo mutations
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Steuerwald, N., primary, Durrett, R., additional, Parsons, J., additional, Hamilton, A., additional, Kontanstinidis, M., additional, Licciardi, F., additional, and Munne, S., additional
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- 2014
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7. The influence of ejaculatory abstinence on oxidative stress in semen: a mechanism that explains improved pregnancy outcomes after intrauterine insemination?
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Giddings, A.B., primary, Hurst, B., additional, Usadi, R., additional, Causby, S., additional, Steuerwald, N., additional, and Marshburn, P., additional
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- 2010
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8. O▪12 Comprehensive aneuploidy diagnosis in single cells
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Chu, L, primary, Wells, D, additional, Weier, H-U, additional, Steuerwald, N, additional, Bermudez, M, additional, Guan, J, additional, and Munné, S, additional
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- 2005
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9. O▪29 Microarray technology to assess gene expression profiles of human oocytes and embryos
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Steuerwald, N, primary, Bermúdez, MG, additional, Wells, D, additional, Munné, S, additional, and Cohen, J, additional
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- 2005
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10. Meiotic spindle checkpoints for assessment of aneuploid oocytes
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Steuerwald, N., primary
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- 2005
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11. Association between spindle assembly checkpoint expression and maternal age in human oocytes
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Steuerwald, N., primary
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- 2001
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12. Association Between Spindle Assembly Checkpoint Gene Expression and Maternal Age in Human Oocytes
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Steuerwald, N, primary, Wells, D, additional, Munne, S, additional, Escudero, T, additional, Cohen, J, additional, and Brenner, C.A, additional
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- 2000
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13. Analysis of gene expression in single oocytes and embryos by real-time rapid cycle fluorescence monitored RT-PCR
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Steuerwald, N., primary
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- 1999
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14. Infertility: Beneficial aspects of co-culture with assisted hatching when applied to multiple-failure in-vitro fertilization patients
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Wiemer, K.E., primary, Garrisi, J., additional, Steuerwald, N., additional, Alikani, M., additional, Reing, A.M., additional, Ferrara, T.A., additional, Noyes, N., additional, and Cohen, J., additional
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- 1996
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15. Blastocyst development in co-culture: development and morphological aspects
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Wiemer, K.E., primary, Dale, B., additional, Hu, Y., additional, Steuerwald, N., additional, Maxson, W.S., additional, and Hoffman, D.I., additional
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- 1995
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16. Fertilization and early embryology: Use of videocinematography to assess morphological qualities of conventionally cultured and cocultured embryos
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Morgan, K., primary, Wiemer, K., additional, Steuerwald, N., additional, Hoffman, D., additional, Maxson, W., additional, and Godke, R., additional
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- 1995
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17. Outcome comparison of in vitro fertilization treatment with highly purified subcutaneous follicle-stimulating hormone (Fertinex, a urofollitropin) versus intramuscular menotropins.
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Crain, Jack L., Wiemer, Klaus E., Steuerwald, Nury, Young, Erika D., Crain, J L, Wiemer, K E, Steuerwald, N, and Young, E D
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FERTILIZATION in vitro ,HORMONE therapy - Abstract
Objective: The aim of this study was to investigate various outcome measures of stimulation with highly purified subcutaneous follicle-stimulating hormone (Fertinex, a urofollitropin) compared with first- and second-generation urinary human menopausal gonadotropin standards (Pergonal, Metrodin).Study Design: Retrospective analysis was restricted to our most efficient in vitro fertilization age group (23-34 years). Data from Institute for Assisted Reproduction in vitro fertilization cycles 1 through 11 with Pergonal, Metrodin, or both were tabulated for hormonal values, oocyte quality, and embryo outcome as baseline data. Patients in cycles 12 through 13 were treated with Fertinex and Pergonal or Fertinex alone and then reviewed for the same parameters.Results: Two hundred thirty-eight in vitro fertilization records with embryo transfer were analyzed. Clinical pregnancy rates per embryo transfer in an optimal age group were similar despite use of first- through third-generation urinary gonadotropin preparations: Pergonal and Metrodin, 67%; Metrodin, 64%; Fertinex and Pergonal, 62%; and Fertinex, 54%. There were no discernible differences in hormonal response, oocyte recovery, or embryonic growth.Conclusion: Administered subcutaneously, the third-generation urinary gonadotropin preparation Fertinex is effective in in vitro fertilization treatment in young women. [ABSTRACT FROM AUTHOR]- Published
- 1998
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18. Beneficial aspects of co-culture with assisted hatching when applied to multiple-failure in-vitro fertilization patients.
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Wiemer, K E, Garrisi, J, Steuerwald, N, Alikani, M, Reing, A M, Ferrara, T A, Noyes, N, and Cohen, J
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INFERTILITY treatment ,CATTLE ,CYTOPLASM ,FALLOPIAN tubes ,FERTILIZATION in vitro ,INJECTIONS ,RESEARCH methodology ,BLASTOMERES ,TISSUE culture ,FETAL development - Abstract
A study was conducted on patients who had attempted and failed previous in-vitro fertilization (IVF) procedures an average of 3.8 times following the application of assisted hatching with conventional culture systems. The aim of this investigation was to determine if addition of co-culture methodologies could reduce embryonic abnormalities and thus improve the prognosis for pregnancy. The study population consisted of 123 patients, subdivided into three patient categories. Previous IVF results from conventional culture were used to evaluate any potential benefits derived from the present co-culture application. Following co-culture, the rate of blastomere development was increased and the rate of fragmentation decreased. An increased rate of blastomere development was most noticeable in the patients aged < or = 39 years with no male factor as well as the intracytoplasmic sperm injection (ICSI) subgroup. Similarly, the rate of fragmentation was significantly reduced in the aforementioned subgroups. The most pronounced impact of co-culture was on pregnancy and implantation rates. The overall clinical and ongoing pregnancy rates were 38% (47/123) and 36% (44/123) respectively. The corresponding implantation rate was 17% (72/ 412) as shown by embryonic cardiac activity. The ongoing pregnancy rates in the < or = 39 years no male factor, > or = 40 years no male factor and ICSI no age limit patient subgroups were 41% (21/51), 30% (8/27) and 33% (15/45) respectively. The results indicate that addition of co-culture to the IVF procedure for poor-prognosis patients may be advisable. [ABSTRACT FROM AUTHOR]
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- 1996
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19. Use of videocinematography to assess morphological qualities of conventionally cultured and cocultured embryos.
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Morgan, K, Wiemer, K, Steuerwald, N, Hoffman, D, Maxson, W, and Godke, R
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Videocinematography and image analysis procedures were utilized to evaluate the effect of conventional and coculture methodologies on morphological parameters in human embryos derived from in-vitro fertilization (IVF). Following 24-30 h of in-vitro development, cocultured embryos had more acceptable morphological features and less fragmentation present than embryos cultured in medium alone. Cocultured embryos were more advanced at the time of replacement when compared with conventionally cultured embryos. Zona pellucida variation (> or = 20%) also occurred more frequently in cocultured embryos. The morphological characteristic most enhanced after coculture was blastomere expansion. Patients who became pregnant across both culture treatments had a higher proportion of morphologically normal embryos replaced than patients who failed to achieve an ongoing pregnancy. Clinical pregnancy rate for patients following coculture was 49%, which was greater (P < 0.05) than the 29% detected for patients with embryos in the conventional culture group.
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- 1995
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20. Maternal age-related differential global expression profiles observed in human oocytes
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Steuerwald, N. M., Bermúdez, M. G., Wells, D., Santiago Munne, and Cohen, J.
21. Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase ( DPYD ) Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.
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Nguyen DG, Morris SA, Hamilton A, Kwange SO, Steuerwald N, Symanowski J, Moore DC, Hanson S, Mroz K, Lopes KE, Larck C, Musselwhite L, Kadakia KC, Koya B, Chai S, Osei-Boateng K, Kalapurakal S, Swift K, Hwang J, and Patel JN
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- Humans, Male, Female, Middle Aged, Prospective Studies, Aged, Fluorouracil administration & dosage, Fluorouracil adverse effects, Fluorouracil therapeutic use, Neoplasms drug therapy, Neoplasms genetics, Antimetabolites, Antineoplastic adverse effects, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic therapeutic use, Cancer Care Facilities, Adult, Dihydrouracil Dehydrogenase (NADP) genetics, Hospitalization statistics & numerical data, Genotype
- Abstract
Purpose: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization., Methods: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization., Results: Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively ( P = .085); 64%, 25%, and 13% were hospitalized ( P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients ( P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups ( P < .001), with reactive carriers having the earliest onset and highest incidence., Conclusion: DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.
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- 2024
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22. Thrombosis Rates and Genetic Thrombophilia Risk Among Patients With Advanced Germ Cell Tumors Treated With Chemotherapy.
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Brown LC, Robinson M, McCormack M, Steuerwald N, Symanowski J, Sha W, Bose R, Neelands B, Akinyelu T, Livasy C, Li W, Haynes N, Hamilton A, Smith M, Clark PE, Patel J, and Burgess EF
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- Humans, Male, Adult, Venous Thromboembolism genetics, Venous Thromboembolism epidemiology, Venous Thromboembolism etiology, Thrombophilia genetics, Thrombophilia drug therapy, Middle Aged, Risk Factors, Anticoagulants therapeutic use, Anticoagulants administration & dosage, Young Adult, Incidence, Testicular Neoplasms drug therapy, Testicular Neoplasms genetics, Genetic Predisposition to Disease, Retrospective Studies, Neoplasms, Germ Cell and Embryonal drug therapy, Neoplasms, Germ Cell and Embryonal genetics, Polymorphism, Single Nucleotide
- Abstract
Introduction: Men with advanced germ cell tumors (GCT) treated with chemotherapy are at high risk of venous thromboembolism (VTE). Predictors of VTE may identify patients who would benefit from prophylactic anticoagulation., Patients and Methods: Men with advanced GCT (Stage IS, II, III) treated with chemotherapy were identified at 2 centers. High genomic risk was defined from a 5 single nucleotide polymorphism (SNP) germline panel. Logistic regression was used to evaluate the impact of genomic risk on VTE within 6 months of chemotherapy initiation. Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) was used to build models to predict VTE based on clinical variables and an 86 SNP panel., Results: This 123-patient cohort experienced a VTE rate of 26% with an incidence of high genomic risk of 21%. Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5-3.5, P = .54). Incorporation of clinical variables (Khorana score, N3 status and elevated LDH) resulted in adjusted OR 2.1 (95% CI 0.7-6.5, P = .18). A combined model using clinical variables and 86 SNPs performed similarly (AUC 0.77) compared to clinical variables alone (AUC 0.72)., Conclusions: A previously established 5-SNP panel was not associated with VTE among patients with GCT receiving chemotherapy. However, multivariable models based on clinical variables alone warrant further validation to inform prophylactic anticoagulation strategies., Competing Interests: Disclosure LCB declares the following relationships: Consulting with Seattle Genetics and Pfizer. MR, MM, NS, JS, WS, RP, BN, TA, CL, WL, NH, AH, MH, and PEC report no conflicts of interest pertaining to this project. JP declares the following relationships: Research funding from Bristol Myer Squibb. EFB declares the following relationships: Stock/ownership with Exelixis, Becton Dickson, Gilead Sciences, Medtronic; Honoraria from Exelixis, Janssen Oncology, Novartis, Pfizer, Merck, Consulting for Johnson & Johnson; Speakers Bureau for AstraZenica and Exelixis, Research funding from Pfizer and Astellas Pharma., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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23. Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.
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Nguyen DG, Morris SA, Chen A, Moore DC, Hanson SL, Larck C, Musselwhite LW, Turner JD, Salem ME, Kwange SO, Hamilton A, Steuerwald N, and Patel JN
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- Genotyping Techniques, False Negative Reactions, Female, Aged, Genetic Variation, Pharmacogenetics, Dihydrouracil Dehydrogenase (NADP) genetics, Colonic Neoplasms drug therapy, Colonic Neoplasms genetics, Sigmoid Neoplasms drug therapy, Sigmoid Neoplasms genetics, Anus Neoplasms drug therapy, Anus Neoplasms genetics, Pyrimidines adverse effects, Pyrimidines therapeutic use
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Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.
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- 2024
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24. Genetic Predictors of Ibrutinib-related Cardiovascular Side Effects in Patients with Chronic Lymphocytic Leukemia.
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Hamadeh IS, Patel JN, Jacobs R, Zeng H, He J, Hu B, Moyo TK, Soni A, Park S, Copelan E, Avalos B, Hamilton A, Steuerwald N, and Ghosh N
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- Humans, Retrospective Studies, KCNQ1 Potassium Channel, Piperidines therapeutic use, Protein Kinase Inhibitors therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
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Purpose: Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib are at risk of developing cardiovascular side effects (CVSE). The molecular determinants of CVSEs have not been fully elucidated. We interrogated genetic polymorphisms in the Bruton tyrosine kinase (BTK) signaling pathway for their association with ibrutinib-related CVSEs., Experimental Design: We conducted a retrospective/prospective observational pharmacogenetic study of 50 patients with newly diagnosed or relapsed CLL who received ibrutinib at a starting daily dose of 420 mg for at least 6 months. CVSEs, primarily atrial fibrillation and hypertension, occurred in 10 patients (20%), of whom 4 discontinued therapy. DNA was isolated from buccal swabs of all 50 patients and genotyped for 40 SNPs in GATA4, SGK1, KCNQ1, KCNA4, NPPA, and SCN5A using a customized next-generation sequencing panel. Univariate and multivariate logistic regression analysis were performed to determine genetic and clinical factors associated with the incidence of ibrutinib-related CVSEs., Results: GATA4 rs804280 AA (P = 0.043), KCNQ1 rs163182 GG (P = 0.036), and KCNQ1 rs2237895 AA (P = 0.023) genotypes were univariately associated with ibrutinib-related CVSEs. On the basis of multivariate analysis, a high genetic risk score, defined as the presence of at least two of these genotypes, was associated with 11.5-fold increased odds of CVSEs (P = 0.019; 95% confidence interval, 1.79-119.73)., Conclusions: Our findings suggest possible genetic determinants of ibrutinib-related CVSEs in CLL. If replicated in a larger study, pretreatment pharmacogenetic testing for GATA4 and KCNQ1 polymorphisms may be a useful clinical tool for personalizing treatment selection for CLL and/or instituting early risk mitigation strategies., (©2023 American Association for Cancer Research.)
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- 2023
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25. Pharmacogenetic and clinical predictors of voriconazole concentration in hematopoietic stem cell transplant recipients receiving CYP2C19-guided dosing.
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Patel JN, Robinson M, Morris SA, Jandrisevits E, Lopes KE, Hamilton A, Steuerwald N, Druhan LJ, Avalos B, Copelan E, Ghosh N, and Grunwald MR
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- Humans, Voriconazole therapeutic use, Pharmacogenetics, Cytochrome P-450 CYP2C19 genetics, Retrospective Studies, Genotype, Antifungal Agents therapeutic use, Hematopoietic Stem Cell Transplantation
- Abstract
CYP2C19-guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19-guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19-guided voriconazole dosing. Patients were genotyped for ABCB1, ABCG2, CYP2C9, CYP3A4, CYP3A5, and the CYP2C haplotype. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 phenotype and letermovir use were significantly associated with subtherapeutic voriconazole concentrations and may be used to improve voriconazole precision dosing, while further research is needed to clarify the role of ABCG2 in voriconazole dosing., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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26. Evaluation of pentamidine tolerability and efficacy between CYP2C19 phenotypes.
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Koon A, He J, Patel J, Morse A, Boseman V, Hamilton A, Knight T, Shah N, Ragon B, Chojecki A, Ai J, Steuerwald N, Gerber J, Copelan E, Grunwald M, and Arnall J
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- Humans, Pentamidine adverse effects, Antifungal Agents therapeutic use, Retrospective Studies, Cytochrome P-450 CYP2C19 genetics, Phenotype, Pneumonia, Pneumocystis drug therapy, Pneumonia, Pneumocystis genetics, Pneumocystis carinii genetics, Drug-Related Side Effects and Adverse Reactions
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Intravenous pentamidine is used for prophylaxis against Pneumocystis jirovecii pneumonia, an infection seen in hematopoietic stem cell transplant recipients. Pentamidine is partially metabolized by CYP2C19 , which is vulnerable to pharmacogenetic variation. This retrospective study evaluated allogeneic hematopoietic stem cell transplant patients who received intravenous pentamidine as P. jirovecii pneumonia prophylaxis. The primary objective was the association between CYP2C19 phenotype and discontinuation of pentamidine due to drug-related side effects based on univariate logistic regression (N = 81). Ten patients (12.3%) discontinued pentamidine because of side effects. There was no difference in discontinuation between phenotype groups (p = 0.18) or discontinuation due to side effects (p = 0.76). Overall, no association was seen between phenotypes and pentamidine-related side effects (p = 0.475). Drug discontinuation rates and P. jirovecii pneumonia infection rates were low.
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- 2023
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27. Addressing barriers to increased adoption of DPYD genotyping at a large multisite cancer center.
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Morris SA, Moore DC, Musselwhite LW, Lopes KE, Hamilton A, Steuerwald N, Hanson SL, Larck C, Swift K, Smith M, Kadakia KC, Chai S, Hwang JJ, and Patel JN
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- Humans, Genotype, Antimetabolites, Antineoplastic therapeutic use, Capecitabine therapeutic use, Fluorouracil, Dihydrouracil Dehydrogenase (NADP) genetics, Dihydrouracil Dehydrogenase (NADP) metabolism, Neoplasms drug therapy, Neoplasms genetics
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Purpose: To describe the implementation of an in-house genotyping program to detect genetic variants linked to impaired dihydropyrimidine dehydrogenase (DPD) metabolism at a large multisite cancer center, including barriers to implementation and mechanisms to overcome barriers to facilitate test adoption., Summary: Fluoropyrimidines, including fluorouracil and capecitabine, are commonly used chemotherapy agents in the treatment of solid tumors, such as gastrointestinal cancers. DPD is encoded by the DPYD gene, and individuals classified as DPYD intermediate and poor metabolizers due to certain genetic variations in DPYD can experience reduced fluoropyrimidine clearance and an increased risk of fluoropyrimidine-related adverse events. Although pharmacogenomic guidelines provide evidence-based recommendations for DPYD genotype-guided dosing, testing has not been widely adopted in the United States for numerous reasons, including limited education/awareness of clinical utility, lack of testing recommendations by oncology professional organizations, testing cost, lack of accessibility to a comprehensive in-house test and service, and prolonged test turnaround time. Based on stakeholder feedback regarding barriers to testing, we developed an in-house DPYD test and workflow to facilitate testing in multiple clinic locations at Levine Cancer Institute. Across 2 gastrointestinal oncology clinics from March 2020 through June 2022, 137 patients were genotyped, and 13 (9.5%) of those patients were heterozygous for a variant and identified as DPYD intermediate metabolizers., Conclusion: Implementation of DPYD genotyping at a multisite cancer center was feasible due to operationalization of workflows to overcome traditional barriers to testing and engagement from all stakeholders, including physicians, pharmacists, nurses, and laboratory personnel. Future directions to scale and sustain testing in all patients receiving a fluoropyrimidine across all Levine Cancer Institute locations include electronic medical record integration (eg, interruptive alerts), establishment of a billing infrastructure, and further refinement of workflows to improve the rate of pretreatment testing., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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28. Pharmacogenomics-guided supportive oncology: A tale of two trials.
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Patel JN, Arnall J, Jandrisevits E, Morse AL, Steuerwald N, Copelan E, and Walsh D
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- Humans, Medical Oncology, Prospective Studies, Quality of Life, Neoplasms drug therapy, Neoplasms genetics, Pharmacogenetics
- Abstract
Cancer-related symptoms, like depression, nausea, and pain, are common and negatively affect quality of life. Unfortunately, there is large inter-individual variability in response to supportive care medications for these symptoms. Pharmacogenomics may inform prescribing by identification of those genetically at risk for drug related adverse events or therapeutic failure. While such information can be applied to many drugs, there are specific oncology populations that could greatly benefit from pharmacogenomics-guided supportive care management due to high symptom burden, including those receiving palliative medicine and hematopoietic stem cell transplantation. The goal of this paper is to provide an overview of, and lessons learned from, the development of two prospective pharmacogenomics-guided interventional trials ("Supportive Care PGx Trial" and "Transplant PGx Trial") across two different clinical settings at the Levine Cancer Institute: the Department of Supportive Oncology and the Transplant and Cellular Therapy section. Key considerations included the appropriate study design and endpoints (balancing study goals and resources), dissemination and application of individual pharmacogenetics results, technical details about assay development, and overall care coordination to minimize clinic disruption., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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29. Dexrazoxane enhances efficacy of all- trans retinoic acid in acute myeloid leukemia patient blast cells and cell lines.
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Norris EJ, Patel YC, Klotz KE, Steuerwald N, Jones WD, Maciejewski JP, Ganapathi RN, and Ganapathi MK
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- Cell Differentiation, Cell Line, Humans, Tretinoin, Dexrazoxane, Leukemia, Myeloid, Acute drug therapy, Leukemia, Promyelocytic, Acute drug therapy
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- 2021
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30. North Carolina's multi-institutional pharmacogenomics efforts with the North Carolina Precision Health Collaborative.
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Patel JN, Voora D, Bell G, Bates J, Cipriani A, Bendz L, Frick A, Hamadeh I, McGee AS, Steuerwald N, Imhof S, and Wiltshire T
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- Antibody Diversity, Hospitals, University, Humans, North Carolina, Public-Private Sector Partnerships, Research, Translational Research, Biomedical, Pharmacogenetics, Precision Medicine
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The North Carolina Precision Health Collaborative is an interdisciplinary, public-private consortium of precision health experts who strategically align statewide resources and strengths to elevate precision health in the state and beyond. Pharmacogenomics (PGx) is a key area of focus for the North Carolina Precision Health Collaborative. Experts from Atrium Health's Levine Cancer Institute, Duke University/Duke Health System, Mission Health and the University of North Carolina (UNC) at Chapel Hill/UNC Health System have collaborated since 2017 to implement strategic PGx initiatives, including basic sciences research, translational research and clinical implementation of germline testing into practice and policy. This institutional profile highlights major PGx programs and initiatives across these organizations and how the collaborative is working together to advance PGx science and implementation.
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- 2021
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31. Ex vivo efficacy of BCMA-bispecific antibody TNB-383B in relapsed/refractory multiple myeloma.
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Foureau DM, Bhutani M, Robinson M, Guo F, Pham D, Buelow B, Steuerwald N, Rigby K, Tjaden E, Leonidas M, Paul BA, Atrash S, Ndiaye A, Symanowski JT, Voorhees PM, and Usmani SZ
- Abstract
TNB-383B is a fully human BCMA-targeting T-cell engaging bispecific monoclonal antibody (T-BsAb). We assessed ex vivo efficacy of this drug to mediate killing of bone marrow mononuclear cells (BMMCs) freshly isolated from 10 patients with relapsed multiple myeloma (MM). BMMC were treated ex vivo with TNB-383B at doses ranging from 0.001-1 μg. Plasma cell (PC) lysis, viability, BCMA expression, CTL distribution, and degranulation were assessed by flow cytometry. Cytokine response to TNB-383B was quantified by multiplex protein assay. Dose-dependent PC lysis was triggered in all cases by TNB-383B at doses as low as 0.001 μg ( P = .0102). Primary MM cells varied in BCMA expression. High BCMA
+ PC count correlated with increased PC lysis ( P = .005) and significant CTL degranulation specific to TNB-383B treatment ( P = .0153 at 1 μg). High E:T ratio in bone marrow specimens led to lower viable and higher apoptotic PC compared with low E:T ratio ( P < .001). Three cytokines were significantly modulated by TNB-383B: IL-2/TNFα increased by ∼4 ± 3.5-fold average ( P < .005 at 1 μg) and IP10 increased by ∼50 ± 15-fold ( P < .001 at 1 μg). We conclude that TNB-383B triggers primary PC lysis and CTL degranulation in a dose-dependent fashion ex vivo with no T cell expansion and mild increase of CRS-associated cytokines., Competing Interests: D.F. received research funding from TeneoBio; M.B. served on speaker bureau for Amgen, BMS and Takeda; consultant for Sanofi Genzyme; received research funding from Janssen, MedImmune, Takeda and Prothena. D.P. and B.B are employees of TeneBio; B.P. was formally employed by Bristol‐Myers Squibb; S.A. received research funding from Mundipharma‐EDO, consulted for Celgene, served in advisory committee for Takeda, Celgene, Amgen, Sanofi, Karyopharm; P.V. served on speaker bureau of Celgene, Janssen, Takeda, served in advisory committee for Amgen, Celgene, Janssen; S.U. received research funding from Array BioPharma, Amgen. Celgene, Onyx, Sanofi, Janssen, Pharmacyclics, Bristol‐Myer‐Squibb, Seattle Genetics, SkylineDX, TeneoBio, served on speaker bureau for Amgen, Celgene, Takeda, Janssen, served in advisory committee for Abbvie, Amgen, Celgene, GSK, BMS, Sanofi, SkylineDX, Takeda, Seattle Genetics, Janssen., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2020
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32. Evaluation of CYP2C19 Genotype-Guided Voriconazole Prophylaxis After Allogeneic Hematopoietic Cell Transplant.
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Patel JN, Hamadeh IS, Robinson M, Shahid Z, Symanowski J, Steuerwald N, Hamilton A, Reese ES, Plesca DC, Arnall J, Taylor M, Trivedi J, Grunwald MR, Gerber J, Ghosh N, Avalos B, and Copelan E
- Subjects
- Adult, Aged, Antifungal Agents pharmacokinetics, Cost Savings, Dose-Response Relationship, Drug, Female, Genotype, Humans, Invasive Fungal Infections etiology, Male, Middle Aged, Prospective Studies, Voriconazole pharmacokinetics, Antifungal Agents administration & dosage, Cytochrome P-450 CYP2C19 genetics, Hematopoietic Stem Cell Transplantation, Invasive Fungal Infections prevention & control, Voriconazole administration & dosage
- Abstract
There is a high risk of voriconazole failure in those with subtherapeutic drug concentrations, which is more common in CYP2C19 (cytochrome P450 2C19) rapid/ultrarapid metabolizers (RMs/UMs). We evaluated CYP2C19 genotype-guided voriconazole dosing on drug concentrations and clinical outcomes in adult allogeneic hematopoietic cell transplant recipients. Poor (PMs), intermediate (IMs), and normal metabolizers (NMs) received voriconazole 200 mg twice daily; RMs/UMs received 300 mg twice daily. Steady-state trough concentrations were obtained after 5 days, targeting 1.0-5.5 mg/L. Of 89 evaluable patients, 29% had subtherapeutic concentrations compared with 50% in historical controls (P < 0.001). Zero, 26%, 50%, and 16% of PMs, IMs, NMs, and RMs/UMs were subtherapeutic. Voriconazole success rate was 78% compared with 54% in historical controls (P < 0.001). No patients experienced an invasive fungal infection (IFI). Genotype-guided dosing resulted in $4,700 estimated per patient savings as compared with simulated controls. CYP2C19 genotype-guided voriconazole dosing reduced subtherapeutic drug concentrations and effectively prevented IFIs., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
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33. Indomethacin enhances anti-tumor efficacy of a MUC1 peptide vaccine against breast cancer in MUC1 transgenic mice.
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Curry JM, Besmer DM, Erick TK, Steuerwald N, Das Roy L, Grover P, Rao S, Nath S, Ferrier JW, Reid RW, and Mukherjee P
- Subjects
- Animals, Breast Neoplasms immunology, Cancer Vaccines immunology, Combined Modality Therapy methods, Female, Humans, Immunogenicity, Vaccine drug effects, Immunogenicity, Vaccine immunology, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental immunology, Mice, Mice, Transgenic, Mucin-1 genetics, Tumor Burden drug effects, Tumor Burden immunology, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit immunology, Breast Neoplasms therapy, Cancer Vaccines administration & dosage, Cyclooxygenase Inhibitors administration & dosage, Indomethacin administration & dosage, Mammary Neoplasms, Experimental therapy, Mucin-1 immunology
- Abstract
In recent years, vaccines against tumor antigens have shown potential for combating invasive cancers, including primary tumors and metastatic lesions. This is particularly pertinent for breast cancer, which is the second-leading cause of cancer-related death in women. MUC1 is a glycoprotein that is normally expressed on glandular epithelium, but is overexpressed and under-glycosylated in most human cancers, including the majority of breast cancers. This under-glycosylation exposes the MUC1 protein core on the tumor-associated form of the protein. We have previously shown that a vaccine consisting of MUC1 core peptides stimulates a tumor-specific immune response. However, this immune response is dampened by the immunosuppressive microenvironment within breast tumors. Thus, in the present study, we investigated the effectiveness of MUC1 vaccination in combination with four different drugs that inhibit different components of the COX pathway: indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inhibitor), and AH6809 (prostaglandin E2 receptor antagonist). These treatment regimens were explored for the treatment of orthotopic MUC1-expressing breast tumors in mice transgenic for human MUC1. We found that the combination of vaccine and indomethacin resulted in a significant reduction in tumor burden. Indomethacin did not increase tumor-specific immune responses over vaccine alone, but rather appeared to reduce the proliferation and increase apoptosis of tumor cells, thus rendering them susceptible to immune cell killing., Competing Interests: Pinku Mukherjee is the founder and Chief Scientific Officer (CSO) of OncoTAb, Inc., a startup company that owns patents and rights to the TAB004 antibody and markets the TAB004-based ELISA as a Laboratory Developed Test under the commercial name AgkuraTM Personal Score. OncoTAb, Inc. provided support in the form of salary for Pinku Mukherjee, but did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This commercial affiliation does not alter our adherence to PLOS One policies on sharing data and materials. Other authors declare no financial interests.
- Published
- 2019
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34. Effect of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients.
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Hamadeh IS, Zhang Q, Steuerwald N, Hamilton A, Druhan LJ, McSwain M, Diez Y, Rusin S, Han Y, Symanowski J, Gerber J, Grunwald MR, Ghosh N, Plesca D, Arnall J, Trivedi J, Avalos B, Copelan E, and Patel JN
- Subjects
- ATP Binding Cassette Transporter, Subfamily B metabolism, Administration, Intravenous, Female, Humans, Male, Cytochrome P-450 CYP3A metabolism, Hematopoietic Stem Cell Transplantation methods, Immunosuppressive Agents adverse effects, Polymorphism, Genetic genetics, Tacrolimus adverse effects, Transplantation Conditioning methods
- Abstract
Pharmacogenetics influences oral tacrolimus exposure; however, little data exist regarding i.v. tacrolimus. We investigated the impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on i.v. tacrolimus exposure and toxicity in adult patients receiving an allogeneic hematopoietic stem cell transplant for hematologic malignancies. Germline DNA was extracted from buccal swabs and genotyped for CYP3A4, CYP3A5, and ABCB1 polymorphisms. Continuous i.v. infusion of tacrolimus .03 mg/kg/day was initiated on day +5 post-transplant, and steady-state blood concentrations were measured 4days later. We evaluated the association between phenotypes and prevalence of nontherapeutic target concentrations (below or above 5 to 15 ng/mL) as well as tacrolimus-related toxicities. Of 63 patients, 28.6% achieved the target concentration; 71.4% were >15ng/mL, which was more common in CYP3A4 intermediate/normal metabolizers (compared with rapid) and those with at least 1 ABCB1 C2677T loss-of-function allele (P < .05). ABCB1 C2677T was significantly associated with concentrations >15ng/mL (odds ratio, 6.2; 95% confidence interval, 1.8 to 23.6; P = .004) and tacrolimus-related toxicities (odds ratio, 7.5; 95% confidence interval, 1.6 to 55.2; P = .02). ABCB1 C2677T and CYP3A4 are important determinants of i.v. tacrolimus exposure, whereas ABCB1 C2677T also impacts tacrolimus-related toxicities in stem cell transplants., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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35. Correction: Cytokine profiles in acute liver injury-Results from the US Drug-Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group.
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Bonkovsky HL, Barnhart HX, Foureau DM, Steuerwald N, Lee WM, Gu J, Fontana RJ, Hayashi PH, Chalasani N, Navarro VM, Odin J, Stolz A, Watkins PB, and Serrano J
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0206389.].
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- 2019
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36. Cell Cycle Arrest in G 2 /M Phase Enhances Replication of Interferon-Sensitive Cytoplasmic RNA Viruses via Inhibition of Antiviral Gene Expression.
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Bressy C, Droby GN, Maldonado BD, Steuerwald N, and Grdzelishvili VZ
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- Animals, Antiviral Agents pharmacology, Cell Cycle Checkpoints genetics, Cell Line, Tumor, Cytoplasm, G2 Phase physiology, G2 Phase Cell Cycle Checkpoints physiology, Gene Expression genetics, Humans, Interferon Type I metabolism, Interferon-gamma metabolism, Interferons, M Phase Cell Cycle Checkpoints physiology, Oncolytic Virotherapy methods, Oncolytic Viruses genetics, RNA Viruses immunology, RNA Viruses metabolism, Sendai virus genetics, Sendai virus metabolism, Signal Transduction, Vesicular stomatitis Indiana virus genetics, Vesiculovirus metabolism, Viral Matrix Proteins genetics, Virus Replication immunology, Interferon Lambda, Cell Cycle Checkpoints physiology, Vesiculovirus genetics, Virus Replication genetics
- Abstract
Vesicular stomatitis virus (VSV) (a rhabdovirus) and its variant VSV-ΔM51 are widely used model systems to study mechanisms of virus-host interactions. Here, we investigated how the cell cycle affects replication of these viruses using an array of cell lines with different levels of impairment of antiviral signaling and a panel of chemical compounds arresting the cell cycle at different phases. We observed that all compounds inducing cell cycle arrest in G
2 /M phase strongly enhanced the replication of VSV-ΔM51 in cells with functional antiviral signaling. G2 /M arrest strongly inhibited type I and type III interferon (IFN) production as well as expression of IFN-stimulated genes in response to exogenously added IFN. Moreover, G2 /M arrest enhanced the replication of Sendai virus (a paramyxovirus), which is also highly sensitive to the type I IFN response but did not stimulate the replication of a wild-type VSV that is more effective at evading antiviral responses. In contrast, the positive effect of G2 /M arrest on virus replication was not observed in cells defective in IFN signaling. Altogether, our data show that replication of IFN-sensitive cytoplasmic viruses can be strongly stimulated during G2 /M phase as a result of inhibition of antiviral gene expression, likely due to mitotic inhibition of transcription, a global repression of cellular transcription during G2 /M phase. The G2 /M phase thus could represent an "Achilles' heel" of the infected cell, a phase when the cell is inadequately protected. This model could explain at least one of the reasons why many viruses have been shown to induce G2 /M arrest. IMPORTANCE Vesicular stomatitis virus (VSV) (a rhabdovirus) and its variant VSV-ΔM51 are widely used model systems to study mechanisms of virus-host interactions. Here, we investigated how the cell cycle affects replication of VSV and VSV-ΔM51. We show that G2 /M cell cycle arrest strongly enhances the replication of VSV-ΔM51 (but not of wild-type VSV) and Sendai virus (a paramyxovirus) via inhibition of antiviral gene expression, likely due to mitotic inhibition of transcription, a global repression of cellular transcription during G2 /M phase. Our data suggest that the G2 /M phase could represent an "Achilles' heel" of the infected cell, a phase when the cell is inadequately protected. This model could explain at least one of the reasons why many viruses have been shown to induce G2 /M arrest, and it has important implications for oncolytic virotherapy, suggesting that frequent cell cycle progression in cancer cells could make them more permissive to viruses., (Copyright © 2019 Bressy et al.)- Published
- 2019
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37. Baseline Hepatic Levels of miR-29b and Claudin are Respectively Associated with the Stage of Fibrosis and HCV RNA in Hepatitis C.
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Sendi H, Mehrab-Mohseni M, Russo MW, Steuerwald N, Jacobs C, Clemens MG, and Bonkovsky HL
- Abstract
We sought to determine if the baseline hepatic levels of miR-122, miR-29b, Claudin, Occludin, Protein Kinase R (PKR) or PKR activator (PRKRA) were correlated with HCV RNA or stage of fibrosis in patients with chronic hepatitis C (CHC). A total of 25 CHC patients (genotype 1) who were treatment naive at the time of sample collection enrolled in this study. By multivariate analysis, CLDN RNA was found as the single independent factor positively correlated with HCV RNA levels (p=0.003), while hepatic miR-29b levels was found as the single independent factor for predicting advanced stage of fibrosis (p=0.028). Conclusion: Our results highlight miR-29b and CLDN as novel predictors of advanced stage of liver fibrosis and baseline HCV RNA in CHC., Competing Interests: Conflict of Interest None declared.
- Published
- 2019
38. Cytokine profiles in acute liver injury-Results from the US Drug-Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group.
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Bonkovsky HL, Barnhart HX, Foureau DM, Steuerwald N, Lee WM, Gu J, Fontana RJ, Hayashi PJ, Chalasani N, Navarro VM, Odin J, Stolz A, Watkins PB, and Serrano J
- Subjects
- Adolescent, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Observational Studies as Topic, Registries, Chemical and Drug Induced Liver Injury metabolism, Cytokines blood, Liver Failure, Acute metabolism
- Abstract
Changes in levels of cytokines and chemokines have been proposed as possible biomarkers of tissue injury, including liver injury due to drugs. Recently, in acute drug-induced liver injury (DILI), we showed that 19 of 27 immune analytes were differentially expressed and that disparate patterns of immune responses were evident. Lower values of serum albumin (< 2.8 g/dL) and lower levels of only four analytes, namely, IL-9, IL-17, PDGF-bb, and RANTES, were highly predictive of early death [accuracy = 96%]. The goals of this study were to assess levels of the same 27 immune analytes in larger numbers of subjects to learn whether the earlier findings would be confirmed in new and larger cohorts of subjects, compared with a new cohort of healthy controls. We studied 127 subjects with acute DILI enrolled into the US DILIN. We also studied 118 subjects with severe acute liver injury of diverse etiologies, enrolled into the ALF SG registry of subjects. Controls comprised 63 de-identified subjects with no history of liver disease and normal liver tests. Analytes associated with poor outcomes [death before 6 months, n = 32 of the total of 232 non-acetaminophen (Apap) subjects], were lower serum albumin [2.6 vs 3.0 g/dL] and RANTES [6,458 vs 8,999 pg/mL] but higher levels of IL-6 [41 vs 18], IL-8 [78 vs 48], and MELD scores [30 vs 24]. Similar patterns were observed for outcome of death/liver transplant within 6 months. A model that included only serum albumin < 2.8 g/dL and RANTES below its median value of 11,349 had 83% (or 81%) accuracy for predicting early death (or early death/liver transplant) in 127 subjects from DILIN. No patterns of serum immune analytes were reflective of the etiologies of acute liver failure, but there were cytokine patterns that predicted prognosis in both acute DILI and ALF., Competing Interests: Within the past three years Dr. Bonkovsky has served as a consultant to Alnylam, Inc, Blue Pharma, Clinuvel, Inc, Mitsubishi-Tanabe, Recordati Rare Chemicals, and Stoke Pharma; he has received research support from Alnylam and Gilead Sciences, Inc; none of these is related to this paper. Dr. Lee serves as consultant to Lilly, Novartis and Repros and receives research support for non-DILI studies from Gilead, Merck, Ocera, Cumberland, and Conatus; none of these is related to this paper. Dr. Fontana has received research support from Gilead, Bristol-Myers Squibb and Janssen; none of these is related to this paper. Dr. Chalasani has consulting agreements with several pharmaceutical companies none of which is relevant to this paper. Dr. Odin has served as a consultant to Intercept Pharmaceuticals and has received research support from Zydus Pharma., Cymabay Therapeutics, and Taiwanj Pharma; none of these is related to this paper. Dr. Watkins has consulting agreements with several pharmaceutical companies none of which is relevant to this paper. Drs. Barnhart, Foureau, Gu, Hayashi, Navarro, Serrano, and Steuerwald report no conflicts of interest. All authors also affirm that none of their disclosures alters their adherence to all PLOS ONE policies on sharing data and materials, as detailed in the PLOS ONE guide for authors [http://journals.plos.org/ploosone/s/competing-interests].
- Published
- 2018
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39. Profiles of miRNAs in serum in severe acute drug induced liver injury and their prognostic significance.
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Russo MW, Steuerwald N, Norton HJ, Anderson WE, Foureau D, Chalasani N, Fontana RJ, Watkins PB, Serrano J, and Bonkovsky HL
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- Adult, Aged, Biomarkers blood, Case-Control Studies, Female, Humans, Liver Transplantation, Male, Middle Aged, Prognosis, Prospective Studies, Sensitivity and Specificity, Serum Albumin, Severity of Illness Index, United States, Chemical and Drug Induced Liver Injury blood, Chemical and Drug Induced Liver Injury mortality, MicroRNAs blood
- Abstract
Background & Aims: Drug induced liver injury (DILI) is challenging because of the lack of biomarkers to predict mortality. Our aim was to describe miRNA changes in sera of subjects with acute idiosyncratic DILI and determine if levels of miRNAs were associated with 6 month mortality., Methods: Clinical data and sera were collected from subjects enrolled in the Drug Induced Liver Injury Network prospective study. miRNAs were isolated from serum obtained from 78 subjects within 2 weeks of acute DILI and followed up for 6 months or longer. miRNAs were compared to 40 normal controls and 6 month survivors vs non-survivors., Results: The mean age of the DILI cohort was 48 years, and 55% were female. Eleven (14.1%) subjects died, 10 within 6 months of DILI onset, 5 (45%) liver related. Lower levels of miRNAs-122, -4463 and -4270 were associated with death within 6 months (P<.05). None of the subjects with miRNA-122 greater than the median value died within 6 months for a sensitivity of 100% and specificity of 57%. In subjects with a serum albumin <2.8 g/dL and miR-122<7.89 RFU the sensitivity, specificity, positive and negative predictive values for death within 6 months were 100%, 57%, 38% and 100% respectively., Conclusions: Serum miRNA-122 combined with albumin accurately identified subjects who died within 6 months of drug induced liver injury. If confirmed prospectively, miRNA-122 and albumin may be useful in identifying patients at high risk for mortality or liver transplantation., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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40. Chronic neutrophilic leukemia in a child with a CSF3R T618I germ line mutation.
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Druhan LJ, McMahon DP, Steuerwald N, Price AE, Lance A, Gerber JM, and Avalos BR
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- Amino Acid Substitution, Child, Female, Humans, Isoleucine genetics, Threonine genetics, Germ-Line Mutation, Leukemia, Neutrophilic, Chronic genetics, Mutation, Missense, Receptors, Colony-Stimulating Factor genetics
- Published
- 2016
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41. Novel biomarkers of resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus.
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Hastie E, Cataldi M, Moerdyk-Schauwecker MJ, Felt SA, Steuerwald N, and Grdzelishvili VZ
- Subjects
- Adaptor Proteins, Signal Transducing, Amides pharmacology, Apoptosis Regulatory Proteins, Carcinoma, Pancreatic Ductal genetics, Cell Line, Tumor, DNA Mutational Analysis, Down-Regulation, GTP-Binding Proteins metabolism, Gene Expression drug effects, Gene Expression Profiling, Humans, I-kappa B Kinase antagonists & inhibitors, Interferon Type I metabolism, Intracellular Signaling Peptides and Proteins metabolism, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 2 antagonists & inhibitors, Mutation, Myxovirus Resistance Proteins genetics, Myxovirus Resistance Proteins metabolism, Neoplasm Proteins metabolism, Nitriles, Pancreatic Neoplasms genetics, Pyrazoles pharmacology, Pyrimidines, RNA Interference, RNA, Small Interfering metabolism, Thiophenes pharmacology, Transcriptome drug effects, Virus Replication drug effects, Biomarkers, Tumor metabolism, Carcinoma, Pancreatic Ductal therapy, Oncolytic Virotherapy methods, Oncolytic Viruses physiology, Pancreatic Neoplasms therapy, Protein Kinase Inhibitors pharmacology, Vesiculovirus physiology
- Abstract
Vesicular stomatitis virus (VSV) based recombinant viruses (such as VSV-ΔM51) are effective oncolytic viruses (OVs) against a majority of pancreatic ductal adenocarcinoma (PDAC) cell lines. However, some PDAC cell lines are highly resistant to VSV-ΔM51. We recently showed that treatment of VSV-resistant PDAC cells with ruxolitinib (JAK1/2 inhibitor) or TPCA-1 (IKK-β inhibitor) breaks their resistance to VSV-ΔM51. Here we compared the global effect of ruxolitinib or TPCA-1 treatment on cellular gene expression in PDAC cell lines highly resistant to VSV-ΔM51. Our study identified a distinct subset of 22 interferon-stimulated genes (ISGs) downregulated by both ruxolitinib and TPCA-1. Further RNA and protein analyses demonstrated that 4 of these genes (MX1, EPSTI1, XAF1, and GBP1) are constitutively co-expressed in VSV-resistant, but not in VSV-permissive PDACs, thus serving as potential biomarkers to predict OV therapy success. Moreover, shRNA-mediated knockdown of one of such ISG, MX1, showed a positive effect on VSV-ΔM51 replication in resistant PDAC cells, suggesting that at least some of the identified ISGs contribute to resistance of PDACs to VSV-ΔM51. As certain oncogene and tumor suppressor gene variants are often associated with increased tropism of OVs to cancer cells, we also analyzed genomic DNA in a set of PDAC cell lines for frequently occurring cancer associated mutations. While no clear correlation was found between such mutations and resistance of PDACs to VSV-ΔM51, the analysis generated valuable genotypic data for future studies., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
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42. An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells.
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Hastie E, Cataldi M, Steuerwald N, and Grdzelishvili VZ
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- Cell Line, Tumor, Host-Pathogen Interactions, Humans, Recombinant Proteins genetics, Recombinant Proteins metabolism, Tumor Suppressor Protein p53 genetics, Vesiculovirus genetics, Vesiculovirus immunology, Viral Proteins genetics, Viral Proteins metabolism, Interferon Type I antagonists & inhibitors, Signal Transduction, Transgenes, Tumor Suppressor Protein p53 metabolism, Vesiculovirus physiology, Virus Replication
- Abstract
Virus-encoded tumor suppressor p53 transgene expression has been successfully used in vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) to enhance their anticancer activities. However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses. To examine whether p53 transgenes enhance antiviral signaling in human pancreatic ductal adenocarcinoma (PDAC) cells, we engineered novel VSV recombinants encoding human p53 or the previously described chimeric p53-CC, which contains the coiled-coil (CC) domain from breakpoint cluster region (BCR) protein and evades the dominant-negative activities of endogenously expressed mutant p53. Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses. Our data suggest that this occurs through p53-mediated inhibition of the NF-κB pathway. Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retained their resistance to all tested VSV recombinants. To the best of our knowledge, this is the first report of p53-mediated inhibition of antiviral signaling, and it suggests that OV-encoded p53 can simultaneously produce anticancer activities while assisting, rather than inhibiting, virus replication in cancer cells., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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43. MiR-122 decreases HCV entry into hepatocytes through binding to the 3' UTR of OCLN mRNA.
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Sendi H, Mehrab-Mohseni M, Foureau DM, Ghosh S, Walling TL, Steuerwald N, Zamor PJ, Kaplan KJ, Jacobs C, Ahrens WA, Russo MW, Clemens MG, Schrum LW, and Bonkovsky HL
- Subjects
- Animals, Binding Sites, Cell Line, Claudins metabolism, Computer Simulation, Databases, Genetic, Down-Regulation, Hepatitis C, Chronic genetics, Hepatitis C, Chronic metabolism, Host-Pathogen Interactions, Humans, MicroRNAs genetics, Occludin genetics, RNA, Messenger genetics, Transfection, Up-Regulation, 3' Untranslated Regions, Hepacivirus pathogenicity, Hepatocytes metabolism, Hepatocytes virology, MicroRNAs metabolism, Occludin metabolism, RNA, Messenger metabolism, Virus Internalization
- Abstract
Background & Aims: Analysis in silico suggests that occludin (OCLN), a key receptor for HCV, is a candidate target of miR-122; the most abundant hepatic micro RNA. We aimed to determine if miR-122 can decrease HCV entry through binding to the 3' UTR of OCLN mRNA., Design: Huh7.5 cells were cotransfected with luciferase construct containing 3' UTR of OCLN (pLuc-OCLN) and with selected miRNAs (0-50 nM) and luciferase activity was measured. Huh7.5 cells were also infected by viral particles containing lenti-miR122 genome or control virus. After 48 h, the cells were infected with HCV pseudo-particles (HCVpp) and VSV pseudo-particles (VSVpp). After 72 h of infection, luciferase activity was measured and HCVpp activity was normalized to VSVpp activity., Results: miR-122 binds to the 3'-UTR of OCLN and down-regulates its expression; cotransfection of miR-122 mimic with pLuc-OCLN resulted in a significant decrease in luciferase activity [by 55% (P < 0.01)], while a non-specific miRNA and a mutant miR-122 did not have any effect. miR-122 mimic significantly down-regulated [by 80% (P < 0.01)] OCLN protein in Huh7.5 cells. Accordingly, patients with chronic hepatitis C and higher levels of hepatic miR-122 have lower hepatic expression of OCLN. Immuno-fluorescence imaging showed a decrease in colocalization of OCLN and CLDN following miR-122 over-expression in HCV infected cells. Huh7.5 cells transiently expressing Lenti-miR122 system showed 42% (P < 0.01) decrease in HCV entry., Conclusion: This study uncovers a novel antiviral effect of miR-122 on human liver cells and shows that over-expression of miR-122 can decrease HCV entry into hepatocytes through down-regulation of OCLN., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2015
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44. Influence of ejaculatory abstinence on seminal total antioxidant capacity and sperm membrane lipid peroxidation.
- Author
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Marshburn PB, Giddings A, Causby S, Matthews ML, Usadi RS, Steuerwald N, and Hurst BS
- Subjects
- Adult, Case-Control Studies, Cell Membrane metabolism, Humans, Infertility metabolism, Male, Oxidative Stress, Reactive Oxygen Species metabolism, Semen Analysis, Ejaculation, Lipid Peroxidation, Sexual Abstinence physiology, Spermatozoa metabolism
- Abstract
Objective: To determine whether the period of ejaculatory abstinence (EA) influences the total antioxidant capacity (TAC) of semen or lipid peroxidation (LPO) of sperm membranes., Design: A prospective experimental trial., Setting: Academic medical center for reproductive endocrinology and infertility., Patient(s): Forty men from infertile couples planning intrauterine insemination., Intervention(s): Men provided semen specimens after EA periods of 1 and 4 days., Main Outcome Measure(s): Semen analysis, peroxidase staining, and assays for seminal TAC and sperm membrane LPO, with measures compared between days 1 and 4 within individuals (internal control) using paired t tests., Result(s): The shorter period of EA (1 day vs. 4 days) resulted in statistically significant decreases in semen volume (-24%), sperm density (-28%), and total sperm count (-3.2%). There was a statistically significant increase in TAC with the shorter period of EA (1 day) compared with 4 days of EA. No difference was detected in sperm membrane LPO comparing 1 day of EA and 4 days of EA., Conclusion(s): Higher seminal TAC obtained after a shorter period of EA could diminish oxidative stress-induced sperm damage by a mechanism independent of LPO. Shorter periods of EA may thus improve sperm quality by protecting from reactive oxygen species damage, even though lower numbers of motile sperm are produced after a shorter period of EA. This would be consistent with prior research indicating improved results after intrauterine insemination under these circumstances., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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45. A novel catechol-O-methyltransferase variant associated with human disc degeneration.
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Gruber HE, Sha W, Brouwer CR, Steuerwald N, Hoelscher GL, and Hanley EN Jr
- Subjects
- Adult, Female, Genetic Association Studies, Humans, Intervertebral Disc Degeneration complications, Intervertebral Disc Degeneration pathology, Low Back Pain complications, Low Back Pain pathology, Male, Middle Aged, Pain complications, Pain pathology, Polymorphism, Single Nucleotide, Sex Characteristics, Catechol O-Methyltransferase genetics, Intervertebral Disc Degeneration genetics, Low Back Pain genetics, Pain genetics
- Abstract
Background: Disc degeneration and its associated low back pain are a major health care concern causing disability with a prominent role in this country's medical, social and economic structure. Low back pain is devastating and influences the quality of life for millions. Low back pain lifetime prevalence approximates 80% with an estimated direct cost burden of $86 billion per year. Back pain patients incur higher costs, greater health care utilization, and greater work loss than patients without back pain., Methods: Research was performed following approval of our Institutional Review Board. DNA was isolated, processed and amplified using routine techniques. Amplified DNA was hybridized to Affymetrix Genome-Wide Human SNP Arrays. Quality control and genotyping analysis were performed using Affymetrix Genotyping Console. The Birdseed v2 algorithm was used for genotyping analysis. 2589 SNPs were selected a priori to enter statistical analysis using lotistic regression in SAS., Results: Our objective was to search for novel single nucleotide polymorphisms (SNPs) associated with disc degeneration. Four SNPs were found to have a significant relationship to disc degeneration; three are novel. Rs165656, a new SNP found to be associated with disc degeneration, was in catechol-O-methyltransferase (COMT), a gene with well-recognized pain involvement, especially in female subjects (p=0.01). Analysis confirmed the previously association between COMT SNP rs4633 and disc degeneration. We also report two novel disc degeneration-related SNPs (rs2095019 and rs470859) located in intergenic regions upstream to thrombospondin 2., Conclusions: Findings contribute to the challenging field of disc degeneration and pain, and are important in light of the high clinical relevance of low back pain and the need for improved understanding of its fundamental basis.
- Published
- 2014
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46. GSK3β inhibition and LEF1 upregulation in skeletal muscle following a bout of downhill running.
- Author
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Amin H, Vachris J, Hamilton A, Steuerwald N, Howden R, and Arthur ST
- Subjects
- Animals, Cadherins metabolism, Glycogen Synthase Kinase 3 beta, Male, Mice, Mice, Inbred C57BL, Models, Animal, Time Factors, Wnt Signaling Pathway physiology, Wnt3A Protein metabolism, beta Catenin metabolism, Down-Regulation physiology, Glycogen Synthase Kinase 3 metabolism, Lymphoid Enhancer-Binding Factor 1 metabolism, Muscle, Skeletal metabolism, Physical Conditioning, Animal physiology, Running physiology, Up-Regulation physiology
- Abstract
Canonical Wnt signaling is important in skeletal muscle repair but has not been well characterized in response to physiological stimuli. The objective of this study was to assess the effect of downhill running (DHR) on components of Wnt signaling. Young, male C57BL/J6 mice were exposed to DHR. Muscle injury and repair (MCadherin) were measured in soleus. Gene and protein expression of Wnt3a, active β-catenin, GSK3β, and LEF1 were measured in gastrocnemius. Muscle injury increased 6 days post-DHR and MCadherin protein increased 5 days post-DHR. Total and active GSK3β protein decreased 3 days (9-fold and 3.6-fold, respectively) post-DHR. LEF1 protein increased 6 days (5-fold) post-DHR. DHR decreased GSK3β and increased LEF1 protein expression, but did not affect other components of Wnt signaling. Due to their applicability, using models of physiological stimuli such as DHR will provide significant insight into cellular mechanisms within muscle.
- Published
- 2014
- Full Text
- View/download PDF
47. Cardiac surgical delivery of the sarcoplasmic reticulum calcium ATPase rescues myocytes in ischemic heart failure.
- Author
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Fargnoli AS, Katz MG, Yarnall C, Isidro A, Petrov M, Steuerwald N, Ghosh S, Richardville KC, Hillesheim R, Williams RD, Kohlbrenner E, Stedman HH, Hajjar RJ, and Bridges CR
- Subjects
- Animals, Cardiac Surgical Procedures, Gene Transfer Techniques, Sheep, Genetic Therapy methods, Heart Failure surgery, Myocytes, Cardiac physiology, Sarcoplasmic Reticulum Calcium-Transporting ATPases administration & dosage
- Abstract
Background: The sarcoplasmic reticulum calcium ATPase (SERCA2a) is an important molecular regulator of contractile dysfunction in heart failure. Gene transfer of SERCA2a mediated by molecular cardiac surgery with recirculating delivery (MCARD) is a novel and clinically translatable strategy., Methods: Ischemic heart failure was induced by ligation of OM1 and OM2 in 14 sheep. Seven sheep underwent MCARD-mediated AAV1-SERCA2a delivery 4 weeks after myocardial infarction, and seven sheep served as untreated controls. Magnetic resonance imaging-based mechanoenergetic studies were performed at baseline, 3 weeks, and 12 weeks after infarction. Myocyte apoptosis was quantified by Tdt-mediated nick-end labeling assay. Myocyte cross-sectional area and caspase-8 and caspase-9 activity was measured with imaging software, specific fluorogenic peptides, and immunohistochemistry., Results: MCARD-mediated AAV1-SERCA2a gene delivery resulted in robust cardiac-specific SERCA2a expression and stable improvements in global and regional contractility. There were significantly higher stroke volume index, left ventricular fractional thickening, and ejection fraction at 12 weeks in the MCARD group than in the control group (30 ± 3 vs 21 ± 2 mL/m(2); 12% ± 5% vs 3% ± 3%; and 43 ± 4 vs 32 ± 4, respectively, all p < 0.05). Apoptotic myocytes were observed more frequently in the control group than in the MCARD-SERCA2a group (0.57.2 ± 0.16 AU vs 0.32.4 ± 0.08 AU, p < 0.05). MCARD-SERCA2a also resulted in decreased caspase-8 and caspase-9 expression and decreased myocyte area in the border zone of transgenic sheep compared with control sheep (14.6% ± 1.2% vs 2.9% ± 0.7%; 18.2% ± 1.9% vs 8.6% ± 1.4%; and 102.1 ± 3.8 μm(2) vs 88.1 ± 3.6 μm(2), all p < 0.05)., Conclusions: MCARD-mediated SERCA2a delivery results in robust cardiac specific gene expression, improved contractility, and a decrease in both myocyte apoptosis and myocyte hypertrophy., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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48. Circadian rhythms in acute intermittent porphyria--a pilot study.
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Larion S, Caballes FR, Hwang SI, Lee JG, Rossman WE, Parsons J, Steuerwald N, Li T, Maddukuri V, Groseclose G, Finkielstein CV, and Bonkovsky HL
- Subjects
- 5-Aminolevulinate Synthetase blood, Adult, Aged, Case-Control Studies, Circadian Clocks genetics, Female, Heme biosynthesis, Heme genetics, Humans, Hydrocortisone blood, Melatonin blood, Middle Aged, Pilot Projects, Porphobilinogen blood, Porphyria, Acute Intermittent genetics, RNA, Messenger blood, Circadian Rhythm physiology, Porphyria, Acute Intermittent metabolism
- Abstract
Background: Acute intermittent porphyria (AIP) is an inherited disorder of haem synthesis wherein a partial deficiency of porphobilinogen (PBG) deaminase (PBGD) with other factors may give rise to biochemical and clinical manifestations of disease. The biochemical hallmarks of active AIP are relative hepatic haem deficiency and uncontrolled up-regulation of hepatic 5-aminolevulinic acid (ALA) synthase-1 (ALAS1) with over-production of ALA and PBG. The treatment of choice is intravenous haem, which restores the deficient regulatory haem pool of the liver and represses ALAS1. Recently, haem has been shown to influence circadian rhythms by controlling their negative feedback loops. We evaluated whether subjects with AIP exhibited an altered circadian profile., Materials and Methods: Over a 21-h period, we measured levels of serum cortisol, melatonin, ALA, PBG and mRNA levels (in peripheral blood mononuclear cells) of selected clock-controlled genes and genes involved in haem synthesis in 10 Caucasian (European-American) women who were either postmenopausal or had been receiving female hormone therapy, six of whom have AIP and four do not and are considered controls., Results: Four AIP subjects with biochemical activity exhibited higher levels of PBG and lower levels and dampened oscillation of serum cortisol, and a trend for lower levels of serum melatonin, than controls or AIP subjects without biochemical activity. Levels of clock-controlled gene mRNAs showed significant increases over baseline in all subjects at 5 a.m. and 11 p.m., whereas mRNA levels of ALAS1, ALAS2 and PBGD were increased only at 11 p.m. in subjects with active AIP., Conclusions: This pilot study provides evidence for disturbances of circadian markers in women with active AIP that may trigger or sustain some common clinical features of AIP., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)
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- 2013
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49. Heme status affects human hepatic messenger RNA and microRNA expression.
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Bonkovsky HL, Hou W, Steuerwald N, Tian Q, Li T, Parsons J, Hamilton A, Hwang S, and Schrum L
- Subjects
- Cell Line, Tumor, Gene Expression Profiling methods, Gene Expression Regulation, Heme deficiency, Heptanoates pharmacology, Humans, Liver drug effects, Oligonucleotide Array Sequence Analysis, Protoporphyrins metabolism, Protoporphyrins pharmacology, Time Factors, Heme metabolism, Liver metabolism, MicroRNAs metabolism, RNA, Messenger metabolism
- Abstract
Aim: To assess effects of heme on messenger RNA (mRNA) and microRNA (miRNA) profiles of liver cells derived from humans., Methods: We exposed human hepatoma cell line Huh-7 cells to excess iron protoporphyrin (heme) (10 μmol/L) or induced heme deficiency by addition of 4, 6-dioxoheptanoic acid (500 μmol/L), a potent inhibitor of aminolevulinic acid dehydratase, for 6 h or 24 h. We harvested total RNA from the cells and performed both mRNA and miRNA array analyses, with use of Affymetrix chips, reagents, and instruments (human genome U133 plus 2.0 and miRNA 2.0 arrays). We assessed changes and their significance and interrelationships with Target Scan, Pathway Studios, and Ingenuity software., Results: Changes in mRNA levels were most numerous and striking at 6 h after heme treatment but were similar and still numerous at 24 h. After 6 h of heme exposure, the increase in heme oxygenase 1 gene expression was 60-fold by mRNA and 88-fold by quantitative reverse transcription-polymerase chain reaction. We found striking changes, especially up-regulation by heme of nuclear erythroid-2 related factor-mediated oxidative stress responses, protein ubiquitination, glucocorticoid signaling, P53 signaling, and changes in RNAs that regulate intermediary metabolism. Fewer mRNAs were down-regulated by heme, and the fold decreases were less exuberant than were the increases. Notable decreases after 24 h of heme exposure were patatin-like phospholipase domain-containing protein 3 (-6.5-fold), neuronal PAS domain protein 2 (-1.93-fold), and protoporphyrinogen oxidase (-1.7-fold)., Conclusion: Heme excess exhibits several toxic effects on liver and kidney, which deserve study in humans and in animal models of the human porphyrias or other disorders.
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- 2013
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50. Legalon-SIL downregulates HCV core and NS5A in human hepatocytes expressing full-length HCV.
- Author
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Mehrab-Mohseni M, Sendi H, Steuerwald N, Ghosh S, Schrum LW, and Bonkovsky HL
- Subjects
- Animals, Basic-Leucine Zipper Transcription Factors genetics, Basic-Leucine Zipper Transcription Factors metabolism, Cell Line, Down-Regulation, Fanconi Anemia Complementation Group Proteins genetics, Fanconi Anemia Complementation Group Proteins metabolism, Heme Oxygenase-1 genetics, Heme Oxygenase-1 metabolism, Hepacivirus physiology, Hepatocytes cytology, Hepatocytes physiology, Humans, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, RNA, Viral genetics, RNA, Viral metabolism, Viral Core Proteins genetics, Viral Nonstructural Proteins genetics, Antioxidants pharmacology, Hepacivirus drug effects, Hepatocytes drug effects, Hepatocytes virology, Silymarin pharmacology, Viral Core Proteins metabolism, Viral Nonstructural Proteins metabolism
- Abstract
Aim: To determine the effect of Legalon-SIL (LS) on hepatitis C virus (HCV) core and NS5A expression and on heme oxygenase-1 (HMOX-1) and its transcriptional regulators in human hepatoma cells expressing full length HCV genotype 1b., Methods: CON1 cells were treated with 50 μmol/L or 200 μmol/L LS. Cells were harvested after 2, 6 and 24 h. HCV RNA and protein levels were determined by quantitative real-time polymerase chain reaction and Western blotting, respectively., Results: HCV RNA (core and NS5A regions) was decreased after 6 h with LS 200 μmol/L (P < 0.05). Both 50 and 200 μmol/L LS decreased HCV RNA levels [core region (by 55% and 88%, respectively) and NS5A region (by 62% and 87%, respectively) after 24 h compared with vehicle (dimethyl sulphoxide) control (P < 0.01). Similarly HCV core and NS5A protein were decreased (by 85%, P < 0.01 and by 65%, P < 0.05, respectively) by LS 200 μmol/L. Bach1 and HMOX-1 RNA were also downregulated by LS treatment (P < 0.01), while Nrf2 protein was increased (P < 0.05)., Conclusion: Our results demonstrate that treatment with LS downregulates HCV core and NS5A expression in CON1 cells which express full length HCV genotype 1b, and suggests that LS may prove to be a valuable alternative or adjunctive therapy for the treatment of HCV infection.
- Published
- 2011
- Full Text
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