St. Jude Children's Research Hospital

About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.

Infectivity, Transmission, and Pathology of Human-Isolated H7N9 Influenza Virus in Ferrets and Pigs

Abstract: The emergence of the H7N9 influenza virus in humans in Eastern China has raised concerns that a new influenza pandemic could occur. Here, we used a ferret model to evaluate the infectivity and transmissibility of A/Shanghai/2/2013 (SH2), a human H7N9 virus isolate. This virus replicated in the upper and lower respiratory tracts of the ferrets and was shed at high titers for 6 to 7 days, with ferrets showing relatively mild clinical signs. SH2 was efficiently transmitted between ferrets via direct contact, but less efficiently by airborne exposure. Pigs were productively infected by SH2 and shed virus for 6 days but were unable to transmit the virus to naive pigs or ferrets. Under appropriate conditions, human-to-human transmission of the H7N9 virus may be possible.

Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir.

Abstract: Acyclic nucleotide phosphonates (adefovir, cidofovir, and tenofovir) are eliminated predominantly into the urine, and renal failure is their dose-limiting toxicity, particularly for adefovir and cidofovir. In this study, we examined the involvement of multidrug resistance-associated protein (MRP)4 (ABCC4) in their luminal efflux in the kidney. ATP-dependent uptake of adefovir and tenofovir but not cidofovir was observed only in the membrane vesicles expressing MRP4. The ATP-dependent uptake of adefovir and tenofovir by MRP4 was not saturated at 1 mM. The ATP-dependent uptake of adefovir by membrane vesicles expressing MRP4 was osmotic-sensitive. No ATP-dependent uptake of either agent was observed in the membrane vesicles expressing human MRP2 or breast cancer resistance protein. These nucleotide analogs were given to mice by constant intravenous infusion, and the plasma, urine, and tissue concentrations were determined. The kidney accumulation of adefovir and tenofovir was significantly greater in Mrp4 knockout mice (130 versus 66 and 191 versus 87 pmol/g tissue, respectively); thus, the renal luminal efflux clearance was estimated to be 37 and 46%, respectively, of the control. There was no difference in the fraction of mono- and diphosphorylated forms of adefovir in the kidney between wild-type and Mrp4 knockout mice. In mice, cidofovir was also eliminated via the urine by tubular secretion as well as glomerular filtration. There was no change in the kinetic parameters of cidofovir in Mrp4 knockout mice. Our results suggest that MRP4 is involved in the luminal efflux of both adefovir and tenofovir, but it makes only a limited contribution to the urinary excretion of cidofovir.

Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases

Abstract: One general principle of gene regulation is that DNA-binding transcription factors modulate transcription by recruiting cofactors that modify histones and chromatin structure. A second implicit principle is that a particular cofactor is necessary at all the target genes where the cofactor is recruited. Increasingly, these principles do not appear to be absolute, as experimentally defined relationships between transcription, cofactors and chromatin modification grow in complexity. The KAT3 histone acetyltransferases CREB binding protein (CBP) and p300 have at least 400 interacting protein partners, thereby acting as hubs in gene regulatory networks. Studies using mutant primary cells indicate that the occurrence of CBP and p300 at any given target gene sometimes correlates with, rather than dictates transcription. This suggests that there are unexpected levels of redundancy between CBP/p300 and other unrelated coactivators, or that CBP/p300 recruitment may sometimes be coincidental. A transcription factor may therefore recruit the same group of coactivators as part of its "toolbox", but it is the characteristics of the individual target gene that determine which coactivation "tools" are required for its transcription.

Glucocorticoid use in acute lymphoblastic leukaemia

Abstract: Glucocorticoids (prednisone and dexamethasone) play an essential part in the treatment of acute lymphoblastic leukaemia (ALL), but their optimum doses and bioequivalence have not been established. Results of preclinical studies have shown that dexamethasone has a longer half-life and better CNS penetration than does prednisone. In prospective randomised trials, dexamethasone improved control of CNS leukaemia. At a prednisone-to-dexamethasone dose ratio of less than seven, dexamethasone (6-18 mg/m(2) per day) resulted in a better event-free survival than did prednisone (40-120 mg/m(2) per day), and high-dose dexamethasone (10-18 mg/m(2) per day) improved the outcome of T-cell ALL and high-risk ALL. However, dexamethasone caused more adverse effects, including infection, bone fracture, osteonecrosis, mood and behaviour problems, and myopathy. At a dose ratio greater than seven, the two drugs showed no difference in efficacy. Therefore, the efficacy of prednisone and dexamethasone is dose dependent and needs to be carefully assessed against the toxic effects. Moreover, although dexamethasone generally showed increased activity in ALL cells in vitro, the dose ratio of the two drugs that exerted equivalent cytotoxic effects differed substantially in samples from individuals. The selection of the type and dose of glucocorticoid should be based on the risk of relapse, treatment phase, and the chemotherapeutic drugs used concomitantly.