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Abnormal cytoplasmic accumulation of Fused in Sarcoma (FUS) in neurons defines subtypes of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). FUS is a member of the FET protein family that includes Ewing

Background Rates of preterm birth have increased in most industrialised countries but data on later lung function of late preterm births are limited. A study was undertaken to compare lung function at 8e9 and 14e17 years in children born late preterm (33e34 and 35e36 weeks gestation) with children of similar age born at term ($37 weeks gestation). Children born at 25e32 weeks gestation were also compared with children born at term. Methods All births from the Avon Longitudinal Study of Parents and Children (n¼14 049) who had lung spirometry at 8e9 years of age (n¼6705) and/or 14e17 years of age (n¼4508) were divided into four gestation groups. Results At 8e9 years of age, all spirometry measures were lower in the 33e34-week gestation group than in controls born at term but were similar to the spirometry decrements observed in the 25e32-week gestation group. The 35e36-week gestation group and term group had similar values. In the late preterm group, at 14e17 years of age forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were not significantly different from the term group but FEV 1 /FVC and forced expiratory flow at 25e75% FVC (FEF 25e75% ) remained significantly lower than term controls. Children requiring mechanical ventilation in infancy at 25e32 and 33e34 weeks gestation had in general lower airway function (FEV 1 and FEF 25e75 ) at both ages than those not ventilated in infancy. Conclusions Children born at 33e34 weeks gestation have significantly lower lung function values at 8e9 years of age, similar to decrements observed in the 25e32-week group, although some improvements were noted by 14e17 years of age.

Multidrug-resistance efflux pumps - in particular those belonging to the resistance-nodulation-cell-division (RND) family of transporters, with their unusually high degree of substrate promiscuity - significantly restrict the effectiveness of antibacterial therapy. Recent years have heralded remarkable insights into the structure and mechanisms of these fascinating molecular machines. Here, we review recent advances in the field and describe various approaches used in combating efflux-mediated resistance.

Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antiviral effect was observed. Binding was demonstrated via a solid state structure of the isolated p15-Ec domain of HIV-1 RT showing inhibitor and two Mn(II) ions bound to the RNase H active site.

Purpose: GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG), was designed as a cytotoxic agent that preferentially targets lymphoid cells. Our objective was to characterize the antiproliferative activity, pharmacokinetics, pharmacodynamics, and safety of GS-9219. Experimental Design: GS-9219 was selected through screening in proliferation assays and through pharmacokinetic screening. The activation pathway of GS-9219 was characterized in lymphocytes, and its cytotoxic activity was evaluated against a panel of hematopoietic and nonhematopoietic cell types. To test whether the prodrug moieties present in GS-9219 confer an advantage over PMEG in vivo, the pharmacokinetics, pharmacodynamics (lymph node germinal center depletion), and toxicity of equimolar doses of GS-9219 and PMEG were evaluated after i.v. administration to normal beagle dogs. Finally, proof of concept of the antitumor efficacy of GS-9219 was evaluated in five pet dogs with spontaneous, advanced-stage non^Hodgkin's lymphoma (NHL) following a single i.v. administration of GS-9219 as monotherapy. Results: In lymphocytes, GS-9219 is converted to its active metabolite, PMEG diphosphate, via enzymatic hydrolysis, deamination, and phosphorylation. GS-9219 has substantial antiproliferative activity against activated lymphocytes and hematopoietic tumor cell lines. In contrast, resting lymphocytes and solid tumor lines were less sensitive to GS-9219. GS-9219, but not PMEG, depleted the germinal centers in lymphoid tissues of normal beagle dogs at doses that were tolerated. In addition, GS-9219 displayed significant in vivo efficacy in five dogs with spontaneous NHL after a single administration, with either no or low-grade adverse events. Conclusion: GS-9219 may have utility for the treatment of NHL.

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