Oestrogen receptor α (ERα) antagonists are used in endocrine therapies for ERα-positive (ERα+) breast cancer patients. Unfortunately the clinical benefit is limited due to intrinsic and acquired drug resistance. Here using integrated genomic and functional studies, we report that amplification and/or overexpression of COPS5 (CSN5/JAB1) confers resistance to tamoxifen. Amplification and overexpression of COPS5, a catalytic subunit of the COP9 complex, is present in about 9% of the ERα+ primary breast cancer and more frequently (86.7%, 26/30) in tamoxifen-refractory tumours. Overexpression of COPS5, through its isopeptidase activity, leads to ubiquitination and proteasome-mediated degradation of NCoR, a key corepressor for ERα and tamoxifen-mediated suppression of ERα target genes. Importantly, COPS5 overexpression causes tamoxifen-resistance in preclinical breast cancer models in vitro and in vivo. We also demonstrate that genetic inhibition of the isopeptidase activity of COPS5 is sufficient to re-sensitize the resistant breast cancer cells to tamoxifen-treatment, offering a potential therapeutic approach for endocrine-resistant breast cancer patients.

Energy migration (energy transfer among identical luminescence centers) is always thought to be related to the concentration quenching in luminescence materials. However, the novel Eu 3+ -doped Ba 6 Gd 2 Ti 4 O 17 phosphor seems to be an exception. In the series of Ba 6 Gd 2(1−x) Ti 4 O 17 :xEu 3+ (x = 0.1, 0.3, 0.5, 0.7, and 0.9) phosphors prepared and investigated, no concentration quenching is found. Detailed investigations of the crystal structure and the luminescence properties of Ba 6 Gd 2(1−x) Ti 4 O 17 :xEu 3+ reveal that the nonoccurrence of concentration quenching is related to the dimensional restriction of energy migration inside the crystal lattices. In Ba 6 Gd 2 Ti 4 O 17 , directly increasing the number of Eu 3+ ions to absorb as much excitation energy as possible allows to achieve a higher brightness. The highly Eu 3+ -doped Ba 6 Gd 2(1−x) Ti 4 O 17 :xEu 3+ (x = 0.9) sample can convert near-UV excitation into red light, whose Commission Internationale de l'Eclairage (CIE) coordinates are (0.64, 0.36) and the color purity can reach up to 94.4%. Moreover, warm white light with the CIE chromaticity coordinates of (0.39, 0.39), the correlated color temperature of 3756 K, and the color rendering index of 82.2 is successfully generated by fabricating this highly Eu 3+ -doped phosphor in a near-UV light-emitting diode chip together with the green YGAB:Tb 3+ and blue BAM:Eu 2+ phosphors. KEYWORDS: Eu 3+ -doped phosphor, Ba 6 Gd 2 Ti 4 O 17 host, nonconcentration quenching, energy migration, light-emitting diodes

BackgroundDengue virus (DENV) infection is the most important arthropod- borne viral disease in human, but antiviral therapy and approved vaccines remain unavailable due to antibody-dependent enhancement (ADE) phenomenon. Many studies showed that pre-membrane (prM)-specific antibodies do not efficiently neutralize DENV infection but potently promote ADE infection. However, most of the binding epitopes of these antibodies remain unknown.ResultsIn the present study, we characterized a DENV cross-reactive monoclonal antibody (mAb), 4D10, that neutralized poorly but potently enhanced infection of four standard DENV serotypes and immature DENV (imDENV) over a broad range of concentration. In addition, the epitope of 4D10 was successfully mapped to amino acid residues 14 to18 of DENV1-4 prM protein using a phage-displayed peptide library and comprehensive bioinformatics analysis. We found that the epitope was DENV serocomplex cross-reactive and showed to be highly immunogenic in Balb/c mice. Furthermore, antibody against epitope peptide PL10, like 4D10, showed broad cross-reactivity and weak neutralizing activtity with four standard DENV serotypes and imDENV but significantly promoted ADE infection. These results suggested 4D10 and anti-PL10 sera were infection-enhancing antibodies and PL10 was infection-enhancing epitope.ConclusionsWe mapped the epitope of 4D10 to amino acid residues 14 to18 of DENV1-4 prM and found that this epitope was infection-enhancing. These findings may provide significant implications for future vaccine design and facilitate understanding the pathogenesis of DENV infection.

The envelope glycoprotein (E) of flavivirus is the major structural protein on the surface of the mature virions. The complexes of premembrane (prM) and E play important roles in virus assembly and fusion modulation and in potential immunity-inducing vaccines. In the present study, the cDNA encoding prM and E proteins of dengue virus type 2 (DENV-2) was subcloned into the pGAPZalphaA vector and further integrated into the genome of Pichia pastoris under the control of the glyceraldehyde-3-phosphate dehydrogenase (GAP) constitutive promoter. The high-level constitutive expression of recombinant E antigen was achieved in P. pastoris. Both the cell lysate and the culture supernatant, examined by electron microscopy, were found to contain DENV-2 virus-like particles (VLPs) with diameters of about 30 nm. After immunization of BALB/c mice, the VLPs exhibited similar efficacies as inactivated virus in terms of antibody induction and neutralization titer. These results suggest that recombinant DENV VLPs can be efficiently produced in the GAP promoter-based P. pastoris expression system. This system may be useful for the development of effective and economic dengue subunit vaccine.

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