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St. Louis, MO, United States

Strober B.E.,University of Connecticut | Armour K.,Monash Medical Center | Romiti R.,University of Sao Paulo | Smith C.,St Johns Institute Of Dermatology | And 3 more authors.
Journal of the American Academy of Dermatology | Year: 2012

The entry of biosimilar forms of biopharmaceutical therapies for the treatment of psoriasis and other immune-mediated disorders has provoked considerable interest. Although dermatologists are accustomed to the use of a wide range of generic topical agents, recognition of key differences between original agent (ie, the name brand) and the generic or biosimilar agent is necessary to support optimal therapy management and patient care. In this review we have summarized the current state of the art related to the impending introduction of biosimilars into dermatology. Biosimilars represent important interventions that are less expensive and hence offer the potential to deliver benefit to large numbers of patients who may not currently be able to access these therapies. But the development of biosimilars is not equivalent to that of small molecule generic therapies because of differences in molecular structure and processes of manufacture. The planned regulatory guidelines and path to approval may not encompass all of these potentially important differences and this may have clinical relevance to the prescriber and patient. Consequently, we have identified a series of key issues that should be considered to support the full potential of biosimilars for the treatment of psoriasis; ie, that of increased access to appropriate therapy for the psoriasis population worldwide. © 2010 by the American Academy of Dermatology, Inc. Source

Rodin M.B.,St Louis University Medical School
Journal of Geriatric Oncology | Year: 2012

Geriatric oncology just makes sense. Cancers are age-associated diseases and one cannot treat one without attending to the other. We are in the phase of professional evolution now where we need to develop, test and report on models of care that fuse knowledge and tools of both fields. © 2011 Elsevier Inc. Source

Heyduk E.,St Louis University Medical School | Heyduk T.,St Louis University Medical School
Biochemistry | Year: 2014

Promoter melting by bacterial RNA polymerase is a key step in transcription initiation. We used a next generation sequencing (NGS) based approach to analyze in parallel promoter melting of all 4096 sequence variants of the 6 bp -10 promoter element. We used NGS read count for each sequence of a promoter library containing a randomized -10 sequence as an observable to determine relative enrichment of -10 element sequence variants at different time points of the promoter melting reaction. The analysis reinforced the dominating role of consensus bases at positions -11 and -7, demonstrated an enhanced preference for A at -11 among sequences exhibiting the fastest melting kinetics, and showed higher overall importance of the T at -7 compared to the A at -11 for efficient promoter melting. Sequences lacking the consensus bases at -7 or -11 could still melt fast if they contained compensatory base patterns at other positions. We observed a significant correlation between the duplex melting energy of -10 element and the kinetics of promoter melting that became more pronounced when the dominating base-specific interactions with RNAP were diminished. These observations indicate that promoter melting kinetics is determined by a combination of base-specific effects/interactions and sequence-dependent stability of DNA duplex with the former playing a dominating role. Our data show that NGS can provide a reliable, quantitative readout for a highly parallel analysis of DNA template sequence dependence of activities of proteins that bind or operate on a DNA template. © 2013 American Chemical Society. Source

Ko J.,St Louis University Medical School | Heyduk T.,St Louis University Medical School
Biochemical Journal | Year: 2014

Promoter escape by RNA polymerase, the transition between the initiation and elongation, is a critical step that defines transcription output at many promoters. In the present study we used a realtime fluorescence assay for promoter melting and escape to study the determinants of the escape. Perturbation of core promoter- polymerase contacts had opposing effects on the rates of melting and escape, demonstrating a direct role of core promoter elements sequence in setting not only the kinetics of promoter melting, but also the kinetics of promoter escape. The start of RNA synthesis is accompanied by an enlargement of the transcription bubble and pulling in of the downstream DNA into the enzyme, resulting in DNA scrunching. Promoter escape results in collapse of the enlarged bubble. To test whether the energy that could be potentially released by the collapse of the bubble plays a role in determining escape kinetics, we measured the rates of promoter escape in promoter constructs, in which the amount of this energy was perturbed by introducing sequence mismatches. We found no significant changes in the rate of promoter escape with these promoter constructs suggesting that the energy released upon bubble collapse does not play a critical role in determining the kinetics of promoter escape. © 2014 Biochemical Society. Source

Heyduk E.,St Louis University Medical School | Heyduk T.,St Louis University Medical School
Analytical Biochemistry | Year: 2014

Detection of antibodies in serum has many important applications. Our goal was to develop a facile general experimental approach for identifying antibody-specific peptide ligands that could be used as the reagents for antibody detection. Our emphasis was on an approach that would allow identification of peptide ligands for antibodies in serum without the need to isolate the target antibody or to know the identity of its antigen. We combined ribosome display (RD) with the analysis of peptide libraries by next generation sequencing (NGS) of their coding RNA to facilitate identification of antibody-specific peptide ligands from random sequence peptide library. We first demonstrated, using purified antibodies, that with our approach-specific peptide ligands for antibodies with simple linear epitopes, as well as peptide mimotopes for antibodies recognizing complex epitopes, were readily identified. Inclusion of NGS analysis reduced the number of RD selection rounds that were required to identify specific ligands and facilitated discrimination between specific and spurious nonspecific sequences. We then used a model of human serum spiked with a known target antibody to develop NGS-based analysis that allowed identification of specific ligands for a target antibody in the context of an overwhelming amount of unrelated immunoglobins present in serum. © 2014 Elsevier Inc. All rights reserved. Source

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