Erwinia amylovora is a plant pathogen belonging to the Enterobacteriaceae family, a family containing many plant and animal pathogens. Herein, we announce nine genome sequences of E. amylovora ...bacteriophages isolated from infected apple trees along the Wasatch Front in Utah.
Abstract Background This global, open-label, single-arm, multicenter, Phase IIb study was designed to determine efficacy and tolerability of oral vorinostat in combination with standard doses of ...bortezomib in multiple myeloma patients considered refractory to novel myeloma agents. Patients Eligible patients were ≥18 years, received ≥2 prior regimens, and were required to be refractory to at least one prior bortezomib-containing regimen and to have received at least one dose of an immunomodulatory drug (thalidomide or lenalidomide)-based regimen. Methods Patients received 21-day cycles of bortezomib (1.3 mg/m2 intravenously; days 1, 4, 8, 11) + oral vorinostat (400 mg/d; days 1–14); oral dexamethasone 20 mg on the day of and day after each dose of bortezomib could be added to patients with progressive disease after 2 cycles or no change after 4 cycles. The primary endpoint was objective response rate. Results Objective response rate was 11.3% (95% CI: 6.6%, 17.7%) and median duration of response of 211 days (64-550). Median overall survival was 11.2 months (95% CI: 8.5, 14.4), with a 2-year survival rate of 32%. Frequently reported adverse events were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%); the overall safety profile was consistent with bortezomib and vorinostat. Conclusion The combination of vorinostat + bortezomib is active in multiple myeloma patients refractory to novel treatment modalities and offers a new therapeutic option for this difficult-to-treat patient population (clinicaltrials.gov: NCT00773838).
Abstract
D2-like dopamine receptors (DRD2/3/4) are G protein-coupled receptors (GPCRs) that are overexpressed in glioblastoma (GBM) and their antagonism induces tumor cell apoptosis. We describe the ...first selective DRD2/3 antagonist for neuro-oncology using computational, receptor pharmacology, biochemical and clinical studies. Consistent with an in-silico prediction and in contrast to antipsychotics that target several dopamine receptors and other GPCRs, β-arrestin recruitment and cAMP assays determined that ONC201 is a selective DRD2/3 antagonist. Schild analyses and radioligand competition assays revealed competitive and non-competitive DRD2 antagonism with a potency (2-3 µM) that is consistent with anticancer activity and driven by an unusually slow association rate. Proof-of-concept studies show that selective DRD2 inhibition induces superior anti-cancer efficacy relative to pan-targeting of the dopamine receptor family. In accordance with superior selectivity, ONC201 also exhibited a wider therapeutic window compared to antipsychotics. Shotgun mutagenesis across 350 amino acids of DRD2 identified 8 residues that are critical for ONC201-mediated DRD2 antagonism. Consistent with competitive inhibition, several mutated residues were within the orthosteric binding site. However, distal residues were identified that were not involved in DRD2 antagonism by antipsychotics and may explain the selectivity and non-competitive antagonism of ONC201. In vitro and in vivo studies have previously demonstrated single agent ONC201 efficacy in GBM models (Allen et al 2013). Analyses of The Cancer Genome Atlas and tissue microarrays revealed high DRD2 expression relative to other dopamine receptors, correlation with poor prognosis and high DRD2 expression in primary rather than secondary GBM. A linear correlation between DRD2 mRNA and ONC201 GI50 was observed among GBM cell lines in the NCI60 panel. Interestingly expression of DRD5, a D1-like dopamine receptor that counteracts DRD2 signaling, was significantly inversely correlated with ONC201 potency in the NCI60 dataset (P <.05). Furthermore, a de novo missense DRD5 mutation was identified in cancer cells with acquired resistance to ONC201, and overexpression of the mutant construct could recapitulate resistance. ONC201 exhibited biological activity in a phase II recurrent GBM study, including tumor regressions (Arrillaga et al, 2017). Among the 15 available archival patient tumor specimens from the first cohort of this trial, all had DRD2 expression and 8 had low DRD5 expression that was associated with superior progression-free and overall survival, with 4/8 DRD5- and 0/7 DRD5+ patients alive after 15 months (P=0.012). Thus, ONC201 possesses unique receptor pharmacology as the first selective DRD2/3 antagonist for clinical neuro-oncology that has exhibited clinical activity in biomarker-defined recurrent high grade glioma patients.
Citation Format: Varun Vijay Prabhu, Neel Madhukar, C. Leah B. Kline, Rohinton Tarapore, Wafik S. El-Deiry, Joseph Rucker, Benjamin Doranz, Faye Doherty, Alexander VanEngelenburg, Jessica Durrant, Cyril Benes, Sean Deacon, Neil Charter, R. Benjamin Free, Wolfgang Oster, David Sibley, Isabel Arrillaga, Olivier Elemento, Joshua E. Allen. Selective targeting of dopamine receptor dysregulation in high grade gliomas with imipridone ONC201 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3857.
We demonstrate the formation of a charge transfer cascade at a nanostructured TiO2/dye/polymer/molecular hole transport multilayer interface. Charge recombination dynamics at this interface are shown ...to be retarded when the ionisation potential of the polymer layer exceeds that of the molecular hole transport layer.
Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in ...normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. DOX has been very effective at treating several different cancers and is still widely used today however its clinical use is limited due to cumulative dose dependent cardiotoxicity. Therefore, combination therapy targeting survival pathways is utilized to minimize the cumulative dose of DOX without ameliorating its anti-tumor effects.
We investigated the potential anti-cancer effects of combining the dual PI3K/mTOR inhibitor, BEZ235 (BEZ), with DOX in pancreatic, breast and other cancer cells lines as well as its associated effects on the heart. Our results showed that co-treatment of BEZ with DOX increased apoptosis in a manner that was dependent on inhibition of the AKT survival pathway. Moreover, BEZ co-treatment with DOX had additive effects towards cell viability while it significantly enhanced necrotic cell death compared to either drug alone. Furthermore, we observed that physiological concentrations of BEZ inhibited ABCB1 efflux resulting in increased intracellular accumulation of DOX, which led to increased DNA damage. In addition, BEZ in combination with gemcitabine (Gem) reduced cell proliferation but did not enhance necrosis or apoptosis. Treatment with BEZ and DOX in mice bearing tumor xenographs reduced tumor growth as compared to BEZ, DOX or Gem. Moreover, BEZ reduced DOX toxicity in rat myoblast cells and did not potentiate the effects of DOX in tumor-bearing mice. We propose that combining BEZ with DOX could be a novel therapeutic approach for the treatment of patients with cancer in the hope of improving the prognosis of this deadly disease.
A series of four dihydropyrroloindoledione-based organic semi-conducting polymers are examined for performance in transistor and photovoltaic cell devices. The dihydropyrroloindoledione unit was ...alternately copolymerized with phenyl, thiophene and bithiophene comonomers, and the resultant polymers exhibit broad absorption, low-bandgaps and deep energy levels, with charge carrier mobilities approaching 0.1 cm super(2) V super(-1) s super(-1). Solar cells processed in a printing friendly solvent (m-xylene) exhibited >2% PCE with a high fill-factor of 0.62 and V sub(oc) of 0.75 V.
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