Identification of the P-TEFb complex-interacting domain of Brd4 as an inhibitor of HIV-1 replication by functional cDNA library screening in MT-4 cells

AbstractWe conducted a phenotypic cDNA screening using a T cell line-based assay to identify human genes that render cells resistant to human immunodeficiency virus type 1 (HIV-1). We isolated potential HIV-1 resistance genes, including the carboxy terminal domain (CTD) of bromodomain-containing protein 4 (Brd4). Expression of GFP-Brd4-CTD was tolerated in MT-4 and Jurkat cells in which HIV-1 replication was markedly inhibited. We provide direct experimental data demonstrating that Brd4-CTD serves as a specific inhibitor of HIV-1 replication in T cells. Our method is a powerful tool for the identification of host factors that regulate HIV-1 replication in T cells

Exposure to Cigarette Smoke Increases Urate Level and Decreases Glutathione Level in Larval Drosophila melanogaster

Recently, we reported experimental evidence to support the notion that in Drosophila melanogaster, urate is involved in defense against toxic effects of environmental cigarette smoke (ECS). To obtain further information pertaining to the defense mechanisms involving urate and other antioxidants, the present study measured the levels of urate, its precursors and glutathione, and SOD activity in larval flies of wild-type strains (Oregon-R and Canton-S) and two urate-null mutant strains (ma-l and ry1) following exposure to ECS for various durations. In both wild type strains, unlike the case in either of the mutant strains, the urate level significantly increased above the basal level in a manner dependent on the duration of ECS exposure. Similar increases in the level of urate precursors were found in Canton-S and in both of the urate-null strains. There was a slight increase in glutathione level above the control level following ECS exposure for a short time, followed by an exposure-dependent decrease to less than 60% of the control level within the exposure range used in all of the four strains. On the other hand, no appreciable change was found in the SOD activity prior to or following ECS exposure, irrespective of the strain examined. In terms of the survival of treated larvae to adulthood under the conditions used for the measurements of urate and others, it was found that wild-type strain Canton-S was as sensitive as the urate-null mutant strains and clearly more sensitive than wild-type strains Oregon-R and Hikone-R. This was so despite the fact that, compared with Oregon-R, Canton-S contained urate at relatively higher levels prior to and following ECS exposure, and that the glutathione levels in Canton-S prior to and following treatment were comparable with those in other strains. These results are discussed with respect to the involvement of urate and glutathione in defense against the toxicity of ECS and the possible existence of another defense mechanism which is deficient in the Canton-S strain

Antibiotic-dependent effect of probiotics in patients with non-small cell lung cancer treated with PD-1 checkpoint blockade

Background We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. Materials and methods We evaluated the prognostic ability of a “drug score” computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Results Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Conclusions Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted