37 results on '"Dang, Utkarsh J."'
Search Results
2. A population-based study of children suggests blunted morning cortisol rhythms are associated with alterations of the systemic inflammatory state
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Roy, Runia, Dang, Utkarsh J., Huffman, Kim M., Alayi, Tchilabalo, Hathout, Yetrib, Nagaraju, Kanneboyina, Visich, Paul S., and Hoffman, Eric P.
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- 2024
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3. Risk factors associated with prevalent vertebral fractures in Duchenne muscular dystrophy
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Phung, Kim, McAdam, Laura, Ma, Jinhui, McMillan, Hugh J., Jackowski, Stefan, Scharke, Maya, Matzinger, Mary-Ann, Shenouda, Nazih, Koujok, Khaldoun, Jaremko, Jacob L., Smit, Kevin, Walker, Scott, Hartigan, Colleen, Khan, Nasrin, Konji, Victor N., MacLeay, Lynn, Page, Marika, Sykes, Elizabeth, Robinson, Marie-Eve, Alos, Nathalie, Cummings, Elizabeth A., Ho, Josephine, Sbrocchi, Anne Marie, Stein, Robert, Saleh, David, Craven, B. Catharine, Dang, Utkarsh J., Siminoski, Kerry, Rauch, Frank, and Ward, Leanne M.
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- 2023
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4. Model-based clustering and classification using mixtures of multivariate skewed power exponential distributions
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Dang, Utkarsh J., Gallaugher, Michael P. B., Browne, Ryan P., and McNicholas, Paul D.
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Statistics - Computation ,Statistics - Methodology - Abstract
Families of mixtures of multivariate power exponential (MPE) distributions have been previously introduced and shown to be competitive for cluster analysis in comparison to other elliptical mixtures including mixtures of Gaussian distributions. Herein, we propose a family of mixtures of multivariate skewed power exponential distributions to combine the flexibility of the MPE distribution with the ability to model skewness. These mixtures are more robust to variations from normality and can account for skewness, varying tail weight, and peakedness of data. A generalized expectation-maximization approach combining minorization-maximization and optimization based on accelerated line search algorithms on the Stiefel manifold is used for parameter estimation. These mixtures are implemented both in the model-based clustering and classification frameworks. Both simulated and benchmark data are used for illustration and comparison to other mixture families.
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- 2019
5. Assessing Pharmacogenomic loci Associated with the Pharmacokinetics of Vamorolone in Boys with Duchenne Muscular Dystrophy.
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Li, Xiaonan, Sabbatini, Daniele, Pegoraro, Elena, Bello, Luca, Clemens, Paula, Guglieri, Michela, van den Anker, John, Damsker, Jesse, McCall, John, Dang, Utkarsh J., Hoffman, Eric P., and Jusko, William J.
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MEN ,RESEARCH funding ,STEROIDAL anti-inflammatory agents ,DUCHENNE muscular dystrophy ,GENETIC polymorphisms ,PHARMACOGENOMICS ,CHILDREN - Abstract
Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti‐inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP‐glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid‐naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one‐compartment model with zero‐order absorption (Tk0, duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25‐6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population Tk0 was 3.14 h yielding an average zero‐order absorption rate (k0) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on Tk0). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Optimization of DOTAP/chol Cationic Lipid Nanoparticles for mRNA, pDNA, and Oligonucleotide Delivery
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Sun, Mengwei, Dang, Utkarsh J., Yuan, Yuhao, Psaras, Alexandra Maria, Osipitan, Ositomiwa, Brooks, Tracy A., Lu, Fake, and Di Pasqua, Anthony J.
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- 2022
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7. Findings from the Longitudinal CINRG Becker Natural History Study
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Clemens, Paula R., primary, Gordish-Dressman, Heather, additional, Niizawa, Gabriela, additional, Gorni, Ksenija, additional, Guglieri, Michela, additional, Connolly, Anne M., additional, Wicklund, Matthew, additional, Bertorini, Tulio, additional, Mah, Jean, additional, Thangarajh, Mathula, additional, Smith, Edward C., additional, Kuntz, Nancy L., additional, McDonald, Craig M., additional, Henricson, Erik, additional, Upadhyayula, S, additional, Byrne, Barry, additional, Manousakis, Georgios, additional, Harper, Amy, additional, Iannaccone, Susan, additional, and Dang, Utkarsh J., additional
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- 2024
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8. Mixtures of Multivariate Power Exponential Distributions
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Dang, Utkarsh J., Browne, Ryan P., and McNicholas, Paul D.
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Statistics - Methodology ,Statistics - Computation - Abstract
An expanded family of mixtures of multivariate power exponential distributions is introduced. While fitting heavy-tails and skewness has received much attention in the model-based clustering literature recently, we investigate the use of a distribution that can deal with both varying tail-weight and peakedness of data. A family of parsimonious models is proposed using an eigen-decomposition of the scale matrix. A generalized expectation-maximization algorithm is presented that combines convex optimization via a minorization-maximization approach and optimization based on accelerated line search algorithms on the Stiefel manifold. Lastly, the utility of this family of models is illustrated using both toy and benchmark data.
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- 2015
9. Multivariate response and parsimony for Gaussian cluster-weighted models
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Dang, Utkarsh J., Punzo, Antonio, McNicholas, Paul D., Ingrassia, Salvatore, and Browne, Ryan P.
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Statistics - Computation ,Statistics - Methodology ,Statistics - Machine Learning - Abstract
A family of parsimonious Gaussian cluster-weighted models is presented. This family concerns a multivariate extension to cluster-weighted modelling that can account for correlations between multivariate responses. Parsimony is attained by constraining parts of an eigen-decomposition imposed on the component covariance matrices. A sufficient condition for identifiability is provided and an expectation-maximization algorithm is presented for parameter estimation. Model performance is investigated on both synthetic and classical real data sets and compared with some popular approaches. Finally, accounting for linear dependencies in the presence of a linear regression structure is shown to offer better performance, vis-\`{a}-vis clustering, over existing methodologies.
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- 2014
10. Accelerated Failure Time Models for Competing Risks in a Cluster Weighted Modelling Framework
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Dang, Utkarsh J. and McNicholas, Paul D.
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Statistics - Methodology - Abstract
A novel approach for dealing with censored competing risks regression data is proposed. This is implemented by a mixture of accelerated failure time (AFT) models for a competing risks scenario within a cluster-weighted modelling (CWM) framework. Specifically, we make use of the log-normal AFT model here but any commonly used AFT model can be utilized. The alternating expectation conditional maximization algorithm (AECM) is used for parameter estimation and bootstrapping for standard error estimation. Finally, we present our results on some simulated and real competing risks data.
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- 2013
11. Families of Parsimonious Finite Mixtures of Regression Models
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Dang, Utkarsh J. and McNicholas, Paul D.
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Statistics - Methodology ,Statistics - Computation ,Statistics - Machine Learning - Abstract
Finite mixtures of regression models offer a flexible framework for investigating heterogeneity in data with functional dependencies. These models can be conveniently used for unsupervised learning on data with clear regression relationships. We extend such models by imposing an eigen-decomposition on the multivariate error covariance matrix. By constraining parts of this decomposition, we obtain families of parsimonious mixtures of regressions and mixtures of regressions with concomitant variables. These families of models account for correlations between multiple responses. An expectation-maximization algorithm is presented for parameter estimation and performance is illustrated on simulated and real data.
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- 2013
12. Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.
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Dang, Utkarsh J., Damsker, Jesse M., Guglieri, Michela, Clemens, Paula R., Perlman, Seth J., Smith, Edward C., Horrocks, Iain, Finkel, Richard S., Mah, Jean K., Deconinck, Nicolas, Goemans, Nathalie M., Haberlová, Jana, Straub, Volker, Mengle-Gaw, Laurel, Schwartz, Benjamin D., Harper, Amy, Shieh, Perry B., De Waele, Liesbeth, Castro, Diana, and Yang, Michele L.
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- 2024
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13. Serum protein biomarkers for juvenile dermatomyositis: a pilot study
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Tawalbeh, Shefa M., Marin, Wilfredo, Morgan, Gabrielle A., Dang, Utkarsh J., Hathout, Yetrib, and Pachman, Lauren M.
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- 2020
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14. Families of Parsimonious Finite Mixtures of Regression Models
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Dang, Utkarsh J., McNicholas, Paul D., Arabie, Phipps, Series editor, Gaul, Wolfgang, Editor-in-chief, Baier, Daniel, Series editor, Vichi, Maurizio, Editor-in-chief, Bock, Hans-Hermann, Series editor, Bodendorf, Freimut, Series editor, Bryant, Peter G., Series editor, Critchley, Frank, Series editor, Decker, Reinhold, Series editor, Diday, Edwin, Series editor, Greenacre, Michael, Series editor, Ihm, Peter, Series editor, Wille, Rudolf, Series editor, Lauro, Carlo Natale, Series editor, Radermacher, Franz Josef, Series editor, Meulman, Jacqueline, Series editor, Monari, Paola, Series editor, Nishisato, Shizuhiko, Series editor, Ohsumi, Noboru, Series editor, Opitz, Otto, Series editor, Ritter, Gunter, Series editor, Schader, Martin, Series editor, Weihs, Claus, Editor-in-chief, Morlini, Isabella, editor, and Minerva, Tommaso, editor
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- 2015
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15. Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy
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Hathout, Yetrib, Liang, Chen, Ogundele, Michael, Xu, Ganggang, Tawalbeh, Shefa M., Dang, Utkarsh J, Hoffman, Eric P., Gordish-Dressman, Heather, Conklin, Laurie S., van den Anker, John N., Clemens, Paula R., Mah, Jean K., Henricson, Erik, and McDonald, Craig
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- 2019
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16. Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy
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Guglieri, Michela, primary, Clemens, Paula R., additional, Perlman, Seth J., additional, Smith, Edward C., additional, Horrocks, Iain, additional, Finkel, Richard S., additional, Mah, Jean K., additional, Deconinck, Nicolas, additional, Goemans, Nathalie, additional, Haberlova, Jana, additional, Straub, Volker, additional, Mengle-Gaw, Laurel J., additional, Schwartz, Benjamin D., additional, Harper, Amy D., additional, Shieh, Perry B., additional, De Waele, Liesbeth, additional, Castro, Diana, additional, Yang, Michelle L., additional, Ryan, Monique M., additional, McDonald, Craig M., additional, Tulinius, Mar, additional, Webster, Richard, additional, McMillan, Hugh J., additional, Kuntz, Nancy L., additional, Rao, Vashmi K., additional, Baranello, Giovanni, additional, Spinty, Stefan, additional, Childs, Anne-Marie, additional, Sbrocchi, Annie M., additional, Selby, Kathryn A., additional, Monduy, Migvis, additional, Nevo, Yoram, additional, Vilchez-Padilla, Juan J., additional, Nascimento-Osorio, Andres, additional, Niks, Erik H., additional, de Groot, Imelda J.M., additional, Katsalouli, Marina, additional, James, Meredith K., additional, van den Anker, Johannes, additional, Damsker, Jesse M., additional, Ahmet, Alexandra, additional, Ward, Leanne M., additional, Jaros, Mark, additional, Shale, Phil, additional, Dang, Utkarsh J., additional, and Hoffman, Eric P., additional
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- 2022
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17. Multivariate Response and Parsimony for Gaussian Cluster-Weighted Models
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Dang, Utkarsh J., Punzo, Antonio, McNicholas, Paul D., Ingrassia, Salvatore, and Browne, Ryan P.
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- 2017
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18. Modeling Early Heterogeneous Rates of Progression in Boys with Duchenne Muscular Dystrophy.
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Fang, Yuan, McDonald, Craig M., Clemens, Paula R., Gordish, Heather-Dressman, Illei, Kate, Hoffman, Eric P., and Dang, Utkarsh J.
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- 2023
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19. Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy
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Mah, Jean K., Clemens, Paula R., Guglieri, Michela, Smith, Edward C., Finkel, Richard S., Tulinius, Mar, Nevo, Yoram, Ryan, Monique M., Webster, Richard, Castro, Diana, Kuntz, Nancy L., McDonald, Craig M., Damsker, Jesse M., Schwartz, Benjamin D., Mengle-Gaw, Laurel J., Jackowski, Stefan, Stimpson, Georgia, Ridout, Deborah A., Ayyar-Gupta, Vandana, Baranello, Giovanni, Manzur, Adnan Y., Muntoni, Francesco, Gordish-Dressman, Heather, Leinonen, Mika, Ward, Leanne M., Hoffman, Eric P., and Dang, Utkarsh J.
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Male ,Research ,Anti-Inflammatory Agents ,Body Height ,United Kingdom ,Muscular Dystrophy, Duchenne ,Online Only ,Treatment Outcome ,Neurology ,Child, Preschool ,Humans ,Muscle Strength ,Child ,Glucocorticoids ,Pregnadienediols ,Original Investigation - Abstract
This nonrandomized controlled trial examines efficacy of vamorolone treatment for Duchenne muscular dystrophy among boys compared with glucocorticoid treatment., Key Points Question Is long-term treatment with vamorolone associated with sustained disease modification and decrease of glucocorticoid-associated adverse outcomes among patients with Duchenne muscular dystrophy (DMD)? Findings In this nonrandomized controlled trial of 46 boys with DMD, higher-dose vamorolone treatment for up to 30 months was not associated with a change in time to stand velocity. Vamorolone was associated with continued disease-modification and similar efficacy compared with glucocorticoid treatment from 2 historical control cohorts, and long-term vamorolone treatment was associated with decreased adverse outcomes compared with traditional glucocorticoid therapy. Meaning These findings suggest that vamorolone may have potential as a standard of care disease-modifying treatment for boys with DMD., Importance Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups. Objective To investigate outcomes after 30 months of open-label vamorolone treatment. Design, Setting, and Participants This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021. Interventions Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d. Main Outcomes and Measures Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone. Results Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (−0.011 rises/s; CI, −0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, −4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, −0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time. Conclusions and Relevance This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD. Trial Registration ClinicalTrials.gov Identifier: NCT03038399
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- 2022
20. Acute serum protein and cytokine response of single dose of prednisone in adult volunteers
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Roy, Runia, primary, Soldin, Steven J., additional, Stolze, Brian, additional, Barbieri, Marissa, additional, Tawalbeh, Shefa M., additional, Rouhana, Nicole, additional, Fronczek, Ann E., additional, Nagaraju, Kanneboyina, additional, van den Anker, John, additional, Dang, Utkarsh J., additional, and Hoffman, Eric P., additional
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- 2022
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21. Interrogation of Dystrophin and Dystroglycan Complex Protein Turnover After Exon Skipping Therapy
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Novak, James S., primary, Spathis, Rita, additional, Dang, Utkarsh J., additional, Fiorillo, Alyson A., additional, Hindupur, Ravi, additional, Tully, Christopher B., additional, Mázala, Davi A.G., additional, Canessa, Emily, additional, Brown, Kristy J., additional, Partridge, Terence A., additional, Hathout, Yetrib, additional, and Nagaraju, Kanneboyina, additional
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- 2021
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22. Findings from the Longitudinal CINRG Becker Natural History Study
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Clemens, Paula R., Gordish-Dressman, Heather, Niizawa, Gabriela, Gorni, Ksenija, Guglieri, Michela, Connolly, Anne M., Wicklund, Matthew, Bertorini, Tulio, Mah, Jean, Thangarajh, Mathula, Smith, Edward C., Kuntz, Nancy L., McDonald, Craig M., Henricson, Erik, Upadhyayula, S, Byrne, Barry, Manousakis, Georgios, Harper, Amy, Iannaccone, Susan, and Dang, Utkarsh J.
- Abstract
Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. A cohort of 83 patients with Becker muscular dystrophy (5–75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. Deletion mutations of dystrophin exons 45–47 or 45–48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.
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- 2023
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23. Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice
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Ziemba, Michael, primary, Barkhouse, Molly, additional, Uaesoontrachoon, Kitipong, additional, Giri, Mamta, additional, Hathout, Yetrib, additional, Dang, Utkarsh J., additional, Gordish-Dressman, Heather, additional, Nagaraju, Kanneboyina, additional, and Hoffman, Eric P., additional
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- 2021
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24. Implementation of a two-point pharmacokinetic AUC-based vancomycin therapeutic drug monitoring approach in patients with methicillin-resistant Staphylococcus aureus bacteraemia
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Mogle, Bryan T., primary, Steele, Jeffrey M., additional, Seabury, Robert W., additional, Dang, Utkarsh J., additional, and Kufel, Wesley D., additional
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- 2018
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25. Divergent subgenome evolution after allopolyploidization in African clawed frogs (Xenopus)
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Furman, Benjamin L. S., primary, Dang, Utkarsh J., additional, Evans, Ben J., additional, and Golding, G. Brian, additional
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- 2018
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26. Serum biomarkers associated with baseline clinical severity in young steroid-naïve Duchenne muscular dystrophy boys.
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Dang, Utkarsh J, Ziemba, Michael, Clemens, Paula R, Hathout, Yetrib, Conklin, Laurie S, Investigators, CINRG Vamorolone 002/003, and Hoffman, Eric P
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- 2020
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27. Estimation of Gene Insertion/Deletion Rates with Missing Data
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Dang, Utkarsh J, primary, Devault, Alison M, additional, Mortimer, Tatum D, additional, Pepperell, Caitlin S, additional, Poinar, Hendrik N, additional, and Golding, G Brian, additional
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- 2016
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28. Interactions between immunization strategies and pandemic influenza associated severe outcomes
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Dang, Utkarsh J. and Bauch, Chris T.
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intensive care unit admissions ,seasonal morbidity function ,pandemic scenarios ,pandemic wave ,morbidity ,vaccination ,immunization ,H1N1 pandemic - Abstract
The effect of multiple pandemic waves on morbidity as quantified by the number of intensive care unit admissions is investigated. A seasonal morbidity function based on probability data from the H1N1 pandemic of 2009 is used and compared to the most common approach used in current literature. We find pandemic scenarios where due to vaccination, a second wave in winter, spring or summer can have a higher number of intensive care unit (ICU) admissions overall even though vaccination is successful in reducing the number of infections in total. This occurs because of additional susceptibility available in winter due to vaccination in the fall. We also find that predicted estimates of ICU cases differ significantly on how the data on severe outcomes from a pandemic is modeled - whether the probability of an ICU admission is held constant or modeled as a seasonally varying function.
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- 2011
29. markophylo: Markov chain analysis on phylogenetic trees
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Dang, Utkarsh J., primary and Golding, G. Brian, additional
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- 2015
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30. Mixtures of multivariate power exponential distributions
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Dang, Utkarsh J., primary, Browne, Ryan P., additional, and McNicholas, Paul D., additional
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- 2015
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31. Can Interactions between Timing of Vaccine-Altered Influenza Pandemic Waves and Seasonality in Influenza Complications Lead to More Severe Outcomes?
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Dang, Utkarsh J., primary and Bauch, Chris T., additional
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- 2011
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32. markophylo: Markov chain analysis on phylogenetic trees.
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Dang, Utkarsh J. and Golding, G. Brian
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MARKOV processes , *FINITE element method , *DISCRETE choice models , *PHYLOGENY , *MATRICES (Mathematics) - Abstract
Continuous-time Markov chain models with finite state space are routinely used for analysis of discrete character data on phylogenetic trees. Examples of such discrete character data include restriction sites, gene family presence/absence, intron presence/absence and gene family size data. While models with constrained substitution rate matrices have been used to good effect, more biologically realistic models have been increasingly implemented in the recent literature combining, e.g., site rate variation, site partitioning, branch-specific rates, allowing for nonstationary prior root probabilities, correcting for sampling bias, etc. to name a few. Here, a flexible and fast R package is introduced that infers evolutionary rates of discrete characters on a tree within a probabilistic framework. The package, markophylo, fits maximum-likelihood models using Markov chains on phylogenetic trees. The package is efficient, with the workhorse functions written in C++ and the interface in user-friendly R. [ABSTRACT FROM AUTHOR]
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- 2016
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33. Validation of Chemokine Biomarkers in Duchenne Muscular Dystrophy.
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Ogundele, Michael, Zhang, Jesslyn S., Goswami, Mansi V., Barbieri, Marissa L., Dang, Utkarsh J., Novak, James S., Hoffman, Eric P., Nagaraju, Kanneboyina, and Hathout, Yetrib
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DUCHENNE muscular dystrophy ,BECKER muscular dystrophy ,BLOOD proteins ,LABORATORY mice ,DISEASE progression - Abstract
Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca
2+ influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan® aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients' reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD. [ABSTRACT FROM AUTHOR]- Published
- 2021
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34. Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys.
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Tawalbeh, Shefa, Samsel, Alison, Gordish-Dressman, Heather, Hathout, Yetrib, and Dang, Utkarsh J.
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DUCHENNE muscular dystrophy ,WEIGHT gain ,STUNTED growth ,DIABETES complications ,BONE density - Abstract
Prednisone (Pred) and Deflazacort (Dfz) are commonly used glucocorticoids (GCs) for Duchenne muscular dystrophy (DMD) treatment and management. While GCs are known to delay the loss of ambulation and motor abilities, chronic use can result in onerous side effects, e.g., weight gain, growth stunting, loss of bone density, etc. Here, we use the CINRG Duchenne natural history study to gain insight into comparative safety of Pred versus Dfz treatment through GC-responsive pharmacodynamic (PD) biomarkers. Longitudinal trajectories of SOMAscan
® protein data obtained on serum of DMD boys aged 4 to 10 (Pred: n = 7; Dfz: n = 8) were analyzed after accounting for age and time on treatment. Out of the pre-specified biomarkers, seventeen candidate proteins were differentially altered between the two drugs (p < 0.05). These include IGFBP-2 and AGER associated with diabetes complications, and MMP-3 associated with extracellular remodeling. As a follow-up, IGFBP-2, MMP-3, and IGF-I were quantified with an ELISA using a larger sample size of DMD biosamples (Dfz: n = 17, Pred: n = 12; up to 76 sera samples) over a longer treatment duration. MMP-3 and IGFBP-2 validated the SOMAscan® signal, however, IGF-I did not. This study identified GC-responsive biomarkers, some associated with safety, that highlight differential PD response between Dfz and Pred. [ABSTRACT FROM AUTHOR]- Published
- 2020
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35. Phenethyl Isothiocyanate and Cisplatin Co-Encapsulated in a Liposomal Nanoparticle for Treatment of Non-Small Cell Lung Cancer.
- Author
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Sun, Mengwei, Shi, Yi, Dang, Utkarsh J., Di Pasqua, Anthony J., and Kakkar, Ashok
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LUNG cancer ,DEATH ,CISPLATIN ,ISOTHIOCYANATES - Abstract
Lung cancer is the leading cause of cancer-related death in the Unites States, and approximately 85% of all lung cancers are classified as non-small cell lung cancer (NSCLC), which is extremely difficult to treat and its survival rate is low. After decades of clinical trials, the most effective treatments are still those that implement the first-generation platinum anticancer agent cisplatin (CDDP) in combination with other drugs. We previously demonstrated that the naturally-occurring compound phenethyl isothiocyanate (PEITC) can be used to sensitize NSCLC cells to CDDP. Furthermore, co-encapsulation of PEITC and CDDP in liposomes enhances their toxicity toward NSCLC cells. We here optimize liposomal-PEITC-CDDP, demonstrate the release of PEITC and CDDP from the nanoparticle, and show that liposomal-PEITC-CDDP is much more toxic toward both A549 and H596 human NSCLC cell lines than toward WI-38 and BEAS-2B human normal lung cell lines. Thus, we have prepared an efficacious therapy that has significantly higher toxicity toward cancer cell lines than normal cell lines. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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36. Adrenal suppression from vamorolone and prednisone in Duchenne muscular dystrophy: results from the phase 2b clinical trial.
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Ahmet A, Tobin R, Dang UJ, Rooman R, Guglieri M, Clemens PR, Hoffman EP, and Ward LM
- Abstract
Context: Vamorolone, a novel "dissociative" steroid, demonstrated similar efficacy in muscle function relative to prednisone 0.75 mg/kg/day but improved linear growth and bone turnover markers in a randomized trial of pediatric Duchenne muscular dystrophy (DMD)., Objectives: To determine the frequency of adrenal suppression (AS) induced by vamorolone and prednisone in pediatric DMD, and to assess cortisol thresholds using a monoclonal antibody immunoassay., Methods: Post-hoc analysis of cortisol levels was performed on data from a randomized, double-blind, placebo- and prednisone-controlled 24-week trial of vamorolone with a 24-week crossover extension. Morning and ACTH-stimulated cortisol levels were measured using the Elecsys II immunoassay, with AS defined as a stimulated cortisol of <500nmol/L ("historical threshold") and <400nmol/L ("revised threshold")., Results: Mean age at enrolment was 5.41±0.86 years (N=118). At Week 24, proportion of participants with AS using the historical and revised cortisol thresholds, respectively, were as follows: prednisone 0.75 mg/kg/day=100% (25/25) and 92.0% (23/25); vamorolone 6 mg/kg/day=95.2% (20/21) and 90.5% (19/21); vamorolone 2 mg/kg/day=84.2% (16/19) and 47.5% (9/19); and placebo=20.0% (4/20) and 0% (0/20). Morning and peak ACTH-stimulated cortisol were strongly correlated in steroid-treated boys (Spearman correlation week 48=0.83)., Conclusions: AS after vamorolone and prednisone was frequent and vamorolone-associated AS appeared dose-dependent. A lower stimulated cortisol threshold may be appropriate when using a monoclonal assay. We recommend hydrocortisone for glucocorticoid stress dosing in patients receiving vamorolone., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2024
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37. Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.
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Smith EC, Conklin LS, Hoffman EP, Clemens PR, Mah JK, Finkel RS, Guglieri M, Tulinius M, Nevo Y, Ryan MM, Webster R, Castro D, Kuntz NL, Kerchner L, Morgenroth LP, Arrieta A, Shimony M, Jaros M, Shale P, Gordish-Dressman H, Hagerty L, Dang UJ, Damsker JM, Schwartz BD, Mengle-Gaw LJ, and McDonald CM
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- Adrenal Cortex Hormones adverse effects, Child, Child, Preschool, Disease Progression, Glucocorticoids adverse effects, Humans, Male, Prednisone therapeutic use, Pregnadienediols metabolism, Treatment Outcome, Walking physiology, Motor Activity drug effects, Muscular Dystrophy, Duchenne drug therapy, Pregnadienediols therapeutic use
- Abstract
Background: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD., Methods and Findings: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators., Conclusions: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy., Trial Registration: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399]., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LSC, JMD, LH and EPH are employees of ReveraGen BioPharma. LSC, JMD, LH own stock options of ReveraGen. UD is a paid consultant for ReveraGen. MJ and PS are employees of Summit Analytical, a biostatistics clinical research organization. BDS and LJM G own Camden Group, LLC, a clinical research organization. EPH and HG-D are co-founders and members of the Board, and ALD’A, LPM, AA, and MS are employees of TRiNDS LLC, a clinical trials management organization. PRC, ECS, JKM, RSF, MG, MT, YN, MMR, RW, DC, NLK, and CMM have received grant funding from ReveraGen for the conduct of clinical trials but they have not received compensation from ReveraGen for other activities. CMM has served as a consultant for clinical trials in Duchenne muscular dystrophy outside the submitted work for Astellas, Biomarin, Capricor Therapeutics, Cardero Therapeutics, Inc., Catabasis Pharmaceuticals, Eli Lilly, FibroGen, Marathon Pharmaceuticals, Pfizer, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta Therapeutics, PTC Therapeutics; serves on external advisory boards related to Duchenne muscular dystrophy for PTC Therapeutics, Eli Lilly, Sarepta Therapeutics, Santhera Pharmaceuticals, and Capricor; and reports grants US Dept. of Education/NIDRR, NIDILRR, US NIH/NIAMS, US Dept. of Defense, and Parent Project Muscular Dystrophy US, during the conduct of the study. Patents awarded relevant to the results include: WO2017004205 (A1), US2016060289 (A1), US2015011519 (A1), US9649320 (B2); US2017027959 (A1). The authors have declared that no other competing interests exist.
- Published
- 2020
- Full Text
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