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PubMed | Simmons Comprehensive Cancer Center, SCCC, UTSW, Immuneering Corporation and 2 more.
Type: Journal Article | Journal: Cancer cell | Year: 2016

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and -lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1

Dong J.,U.S. National Institutes of Health | Munoz A.,Johns Hopkins University | Munoz A.,U.S. National Institutes of Health | Kolitz S.E.,Johns Hopkins University | And 8 more authors.
Genes and Development | Year: 2014

Eukaryotic initiator tRNA (tRNAi) contains several highly conserved unique sequence features, but their importance in accurate start codon selection was unknown. Here we show that conserved bases throughout tRNAi, from the anticodon stem to acceptor stem, play key roles in ensuring the fidelity of start codon recognition in yeast cells. Substituting the conserved G31:C39 base pair in the anticodon stem with different pairs reduces accuracy (the Sui- [suppressor of initiation codon] phenotype), whereas eliminating base pairing increases accuracy (the Ssu- [suppressor of Sui-] phenotype). The latter defect is fully suppressed by a Sui- substitution of T-loop residue A54. These genetic data are paralleled by opposing effects of Sui- and Ssu- substitutions on the stability of methionylated tRNAi (Met-tRNAi) binding (in the ternary complex [TC] with eIF2-GTP) to reconstituted preinitiation complexes (PICs). Disrupting the C3:G70 base pair in the acceptor stem produces a Sui- phenotype and also reduces the rate of TC binding to 40S subunits in vitro and in vivo. Both defects are suppressed by an Ssu- substitution in eIF1A that stabilizes the open/POUT conformation of the PIC that exists prior to start codon recognition. Our data indicate that these signature sequences of tRNAi regulate accuracy by distinct mechanisms, promoting the open/POUT conformation of the PIC (for C3:G70) or destabilizing the closed/PIN state (for G31:C39 and A54) that is critical for start codon recognition. © 2014 Dong et al.

Carrero J.A.,University of Washington | Calderon B.,University of Washington | Towfic F.,Immuneering Corporation | Artyomov M.N.,University of Washington | Unanue E.R.,University of Washington
PLoS ONE | Year: 2013

Our ability to successfully intervene in disease processes is dependent on definitive diagnosis. In the case of autoimmune disease, this is particularly challenging because progression of disease is lengthy and multifactorial. Here we show the first chronological compendium of transcriptional and cellular signatures of diabetes in the non-obese diabetic mouse. Our data relates the immunological environment of the islets of Langerhans with the transcriptional profile at discrete times. Based on these data, we have parsed diabetes into several discrete phases. First, there is a type I interferon signature that precedes T cell activation. Second, there is synchronous infiltration of all immunological cellular subsets and a period of control. Finally, there is the killing phase of the diabetogenic process that is correlated with an NF-kB signature. Our data provides a framework for future examination of autoimmune diabetes and its disease progression markers. © 2013 Carrero et al.

Towfic F.,Immuneering Corporation | Funt J.M.,Immuneering Corporation | Fowler K.D.,Immuneering Corporation | Bakshi S.,Teva Pharmaceutical Industries | And 6 more authors.
PLoS ONE | Year: 2014

For decades, policies regarding generic medicines have sought to provide patients with economical access to safe and effective drugs, while encouraging the development of new therapies. This balance is becoming more challenging for physicians and regulators as biologics and non-biological complex drugs (NBCDs) such as glatiramer acetate demonstrate remarkable efficacy, because generics for these medicines are more difficult to assess. We sought to develop computational methods that use transcriptional profiles to compare branded medicines to generics, robustly characterizing differences in biological impact. We combined multiple computational methods to determine whether differentially expressed genes result from random variation, or point to consistent differences in biological impact of the generic compared to the branded medicine. We applied these methods to analyze gene expression data from mouse splenocytes exposed to either branded glatiramer acetate or a generic. The computational methods identified extensive evidence that branded glatiramer acetate has a more consistent biological impact across batches than the generic, and has a distinct impact on regulatory T cells and myeloid lineage cells. In summary, we developed a computational pipeline that integrates multiple methods to compare two medicines in an innovative way. This pipeline, and the specific findings distinguishing branded glatiramer acetate from a generic, can help physicians and regulators take appropriate steps to ensure safety and efficacy. © 2014 Towfic et al.

PubMed | Immuneering Corporation and Teva Pharmaceutical Industries
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidines potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25WT mouse models. A broad, unbiased pathway analysis was conducted, followed by testing the enrichment of relevant pathways. Pridopidine upregulated the BDNF pathway (P=1.73E-10), and its effect on BDNF secretion was sigma 1 receptor (S1R) dependent. Many of the same genes were independently found to be downregulated in Q175 KI mice compared to WT (5.2e-7

PubMed | Immuneering Corporation and Teva Pharmaceutical Industries
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2016

Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntingtons disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR

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