Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149265/1/ijc32118.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149265/2/ijc32118_am.pd

Impact of selective immune-cell depletion on growth of Mycobacterium tuberculosis (Mtb) in a whole-blood bactericidal activity (WBA) assay

10.1371/journal.pone.0216616PLOS ONE14

Impact of selective immune-cell depletion on growth of Mycobacterium tuberculosis (Mtb) in a whole-blood bactericidal activity (WBA) assay.

We investigated the contribution of host immune cells to bacterial killing in a whole-blood bactericidal activity (WBA) assay, an ex vivo model used to test efficacy of drugs against mycobacterium tuberculosis (Mtb). We performed WBA assays with immuno-magnetic depletion of specific cell types, in the presence or absence of rifampicin. Innate immune cells decreased Mtb growth in absence of drug, but appeared to diminish the cidal activity of rifampicin, possibly attributable to intracellular bacterial sequestration. Adaptive immune cells had no effect with or without drug. The WBA assay may have potential for testing adjunctive host-directed therapies acting on phagocytic cells

Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model

10.1128/AAC.00482-17ANTIMICROBIAL AGENTS AND CHEMOTHERAPY611

Activity of faropenem with and without rifampicin against Mycobacterium tuberculosis: evaluation in a whole-blood bactericidal activity trial

10.1093/jac/dkx081JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY7272012-201

Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model

Abstract COX-2 inhibition may be of benefit in the treatment of tuberculosis (TB) through a number of pathways including efflux pump inhibition (increasing intracellular TB drug levels) and diverse effects on inflammation and the immune response. We investigated celecoxib (a COX-2 inhibitor) alone and with standard anti-tuberculosis drugs in the whole-blood bactericidal activity (WBA) model. Healthy volunteers took a single dose of celecoxib (400 mg), followed (after 1 week) by a single dose of either rifampicin (10 mg/kg) or pyrazinamide (25 mg/kg), followed (after 2 or 7 days respectively) by the same anti-tuberculosis drug with celecoxib. WBA was measured at intervals until 8 hours post-dose (by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial colony forming units after 72 hours incubation). Celecoxib had no activity alone in the WBA assay (cumulative WBA over 8 hours post-dose: 0.03 ± 0.01ΔlogCFU, p = 1.00 versus zero). Celecoxib did not increase cumulative WBA of standard TB drugs (mean cumulative WBA −0.10 ± 0.13ΔlogCFU versus −0.10 ± 0.12ΔlogCFU for TB drugs alone versus TB drugs and celecoxib; mean difference −0.01, 95% CI −0.02 to 0.00; p = 0.16). The lack of benefit of celecoxib suggests that efflux pump inhibition or eicosanoid pathway-related responses are of limited importance in mycobacterial killing in the WBA assay

Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia

Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc–FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell–Morell receptors, which is fundamentally different from the classical Fc–FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP