Baylor Research Institute

K, C. B., E. Mejia-Lopez, P. McCullough, K. Breathett, J. L. Kennedy, J. Tallaj, J. Bergin, S. Pamboukian, M. Abuannadi and S. Mazimba (2017). “Clinical impact of changes in hemodynamic indices of contractile function during treatment of acute decompensated heart failure.” J Card Fail: 2017 Jul [Epub ahead of print].

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BACKGROUND: The objective was to determine the impact of improving right ventricular versus left ventricular stroke work indices (RVSWI v. LVSWI) during therapy for acute decompensated heart failure (ADHF). METHODS AND RESULTS: Cox proportional hazards regression and logistic regression was used to analyze key factors associated with outcomes in 175 patients (age 56.7 +/- 13.6 years, 29.1% female) with hemodynamic data from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. In this cohort, 28.6% and 69.7%, respectively, experienced the outcomes of death, transplant, or ventricular assist device (DVADTX) and DVADTX or HF rehospitalization (DVADTXHF) during 6 months of follow-up. Increasing RVSWI (DeltaRVSWI) from baseline to discharge was associated with a decrease in DVADTXHF (HR 0.923 [95% CI 0.871-0.979] per 0.1 mmHg*L/m2 increase); however, increasing LVSWI (DeltaLVSWI) only had a non-significant association with decreased DVADTXHF (P=0.11) In a multivariable model, patients with DeltaRVSWI

Fox, R. J., R. Gold, J. T. Phillips, M. Okwuokenye, A. Zhang and J. L. Marantz (2017). “Efficacy and tolerability of delayed-release dimethyl fumarate in black, hispanic, and asian patients with relapsing-remitting multiple sclerosis: Post hoc integrated analysis of define and confirm.” Neurol Ther: 2017 Aug [Epub ahead of print].

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INTRODUCTION: Clinical course and treatment response may vary according to race/ethnicity in multiple sclerosis (MS) patients. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and a favorable benefit-risk profile in relapsing-remitting MS (RRMS) patients in the 2-year phase III DEFINE/CONFIRM studies. METHODS: In this post hoc analysis of integrated data from DEFINE/CONFIRM, we assessed clinical efficacy and safety/tolerability in black, Hispanic, and Asian patients treated with DMF 240 mg twice daily (approved dosage) or placebo. Eligible patients were 18-55 years of age with an Expanded Disability Status Scale score of 0-5.0. In the integrated intention-to-treat population, 769 and 771 patients were treated with DMF or placebo, respectively, of whom 10 and 19 were black, 31 and 23 were Hispanic, and 66 and 70 were Asian. RESULTS: In the black, Hispanic, and Asian subgroups, DMF was associated with lower annualized relapse rates at 2 years compared with placebo [rate ratio (95% confidence interval (CI)), 0.05 (0.00-1.07); 0.31 (0.10-0.95); and 0.64 (0.30-1.34), respectively]. The percentage of black, Hispanic, and Asian patients with 12-week confirmed disability progression was lower with DMF (43%, 8%, and 20%, respectively) compared with placebo [57%, 30%, and 25%, respectively; hazard ratio (95% CI), 0.53 (0.02-1.39); 0.17 (0.00-0.60); and 0.71 (0.32-1.58), respectively]. The safety/tolerability profile of DMF was generally consistent with that in the overall population of DEFINE/CONFIRM. The incidence of adverse events leading to treatment discontinuation in black, Hispanic, and Asian patients was 2/10, 2/31, and 3/66, respectively, with DMF, and 2/19, 1/23, and 8/70, respectively, with placebo. CONCLUSION: DMF may be an efficacious treatment with a favorable benefit-risk profile in black, Hispanic, and Asian patients with RRMS. Further clinical studies are needed to characterize differences in MS presentation and treatment outcomes across ethnic and racial groups.

Gandhi, M. J., D. Ferriola, C. Lind, J. L. Duke, A. Huynh, A. Papazoglou, K. Mackiewicz, M. Christiansen, W. Dong, S. Hsu, D. Thomas, B. Schneider, E. Pierce, J. Kearns, M. Kamoun, D. Monos and M. Askar (2017). “Assessing a single targeted next generation sequencing for human leukocyte antigen typing protocol for interoperability, as performed by users with variable experience.” Hum Immunol: 2017 Jul [Epub ahead of print].

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BACKGROUND: A simplified protocol for HLA-typing -by NGS, developed for use with the Illumina MiSeq, was performed by technologists with varying NGS experience to assess accuracy and reproducibility. METHODS: Technologists from six laboratories typed the same 16 samples at HLA-A, B, C, DRB1, and DQB1. The protocol includes long range PCR, library preparation, and paired-end 250bp sequencing. Two indexing strategies were employed: locus-specific indexing whereby each locus was tagged uniquely and sample-specific indexing whereby all 5 loci for a sample were pooled prior to library preparation. Sequence analysis was performed with two software packages, Target HLA (Omixon) and NGSengine (GenDx). RESULTS: The average number of sequence reads per library was 387,813; however, analysis was limited to 40,000 reads for locus-indexed libraries and 200,000 reads for sample-indexed libraries resulting in an average depth of coverage of 1444 reads per locus. Sufficient reads for genotype analysis were obtained for 98.4% of libraries. Genotype accuracy was >97% in pooled amplicons and >99% in individual amplicons by both software analysis. Inter-laboratory reproducibility was 99.7% and only cause of discordance was cross-contamination of a single amplicon. CONCLUSIONS: This NGS HLA-typing protocol is simple, reproducible, scalable, highly accurate and amenable to clinical testing.

Graham, J. P., P. Authie, A. Karolina Palucka and G. Zurawski (2017). “Targeting interferon-alpha to dendritic cells enhances a cd8+ t cell response to a human cd40-targeted cancer vaccine.” Vaccine: 2017 Jul [Epub ahead of print].

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Targeting antigens to antigen presenting cells (APC) enhances the potency of recombinant protein CD8+ T cell vaccines. Recent comparisons of recombinant protein-based dendritic cell (DC) targeting vaccines revealed differences in cross-presentation and identified CD40 as a potent human DC receptor target for antigen cross-presentation. Contrary to in vitro-derived monocyte (mo)DC, we found that interferon-alpha (IFNalpha) stimulation of human blood-derived DC was necessary for an antigen-specific IFNgamma CD8+ T cell response to a CD40 targeted cancer vaccine. Importantly, targeting an adjuvant in the form of IFNalpha to DC increased their potency to elicit antigen-specific production of IFNgamma by CD8+ T cells. Thus, we introduce the concept of DC adjuvant targeting to enhance the potency of vaccination.

Muriello, M. J., S. Viall, T. Bottiglieri, K. Cusmano-Ozog and C. R. Ferreira (2017). “Confirmation that mat1a p.Ala259val mutation causes autosomal dominant hypermethioninemia.” Mol Genet Metab Rep 13: 9-12.

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Methionine adenosyltransferase (MAT) I/III deficiency is an inborn error of metabolism caused by mutations in MAT1A, encoding the catalytic subunit of MAT responsible for the synthesis of S-adenosylmethionine, and is characterized by persistent hypermethioninemia. While historically considered a recessive disorder, a milder autosomal dominant form of MAT I/III deficiency occurs, though only the most common mutation p.Arg264His has ample evidence to prove dominant inheritance. We report a case of hypermethioninemia caused by the p.Ala259Val substitution and provide evidence of autosomal dominant inheritance by showing both maternal inheritance of the mutation and concomitant hypermethioninemia. The p.Ala259Val mutation falls in the dimer interface, and thus likely leads to dominant inheritance by a similar mechanism to that described in the previously reported dominant negative mutation, that is, by means of interference with subunits encoded by the wild-type allele.