Specific inhibition of human β-D-glucuronidase and α-L-iduronidase by a trihydroxy pipecolic acid of plant origin

AbstractThe glucuronic acid analogue of 1-deoxynojirimycin, 2(S)-carboxy-3(R), 4(R), 5(S)-trihydroxypiperidine, recently isolated from seeds of Baphia racemosa, is a novel specific inhibitor of human liver β-D-glucuronidase and α-L-iduronidase. No other glycosidases are inhibited. The inhibition of β-D-glucuronidase is competitive, with a Ki of 8 × 10−5 M and is pH-dependent. This inhibitor may be useful to induce a mucopolysaccharidosis or to investigate the function of microsomal β-D-glucoronidase

Inhibition of HIV replication by amino-sugar derivatives

AbstractThe plant alkaloids castanospermine, dihydroxymethyldihydroxypyrrolidine and deoxynojirimycin have recently been shown to have potential anti-HIV activity [(1987) Proc. Natl. Acad. Sci. USA 84, 8120–8124; (1987) Nature 330, 74–77; (1987) Lancet i, 1025–1026]. They are thought to act by inhibiting α-glucosidase I, an enzyme involved in the processing of N-linked oligosaccharides on glycoproteins. We report here the relative efficacy of a spectrum of amino-sugar derivatives as inhibition of HIV cytopathicity. Several α-glucosidase inhibitors and α-fucosidase inhibitors were found to be active at concentrations which were non-cytotoxic

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Moisture absorption in low level porosity, thermoplastic toughened epoxy composites

In this report, a new polyethersulphone toughened epoxy resin system, developed by ICI Materials Research Centre, is studied. The moisture absorption characteristics are determined over a range of test temperatures for nine varieties of the blend - each containing a different amount of thermoplastic. Results reveal that the addition of thermoplastic causes a decrease in saturation level, an increase in diffusivity and a decrease in activation energy. Equations are developed to fully describe the relationship between the absorption characteristics and thermoplastic content - enabling values to be extrapolated for any thermoplastic content blend at any temperature below glass transition temperature. The changes in absorption characteristics are attributed to a decrease in polarity on copolymerisation of the constituents, in addition to an initial increase in free volume. The absorption is shown to be initially Fickian in all blends, with non-Fickian anomalies occurring at the latter stages of testing in both neat resin and composite samples.The existing equation for edge diffusion in three-dimensional samples was found to be inaccurate at low aspect ratios. A new equation is developed for use with all sample geometries, which gives results accurate to ± 4%. Modification of the diffusion equations for uni-directional composites has been made (including a new for anisotropic edge effects). When fitted to our data the model shows no enhanced diffusion at the fibre matrix interface, but supports the theory that differences in diffusion parallel and perpendicular fibre can be attributed to geometrical blocking effects alone. Diffusion coefficients and saturation levels are shown to be sensitive to void contents even below 1% volume fraction. This correlation between absorption properties and sample quality is shown even more closely when using ultrasonic attenuation rather than void content analysis.</p