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Articles by A Wong
Total Records ( 3 ) for A Wong
  X Zheng , D Lian , A Wong , M Bygrave , T. E Ichim , M Khoshniat , X Zhang , H Sun , T De Zordo , J. C Lacefield , B Garcia , A. M Jevnikar and W. P. Min
 

Background— Ischemia/reperfusion injury is a major factor in graft quality and subsequent function in the transplantation setting. We hypothesize that the process of RNA interference may be used to "engineer" a graft to suppress expression of genes associated with inflammation, apoptosis, and complement, which are believed to cause ischemia/reperfusion injury. Such manipulation of pathological gene expression may be performed by treatment of the graft ex vivo with small interfering RNA (siRNA) as part of the preservation procedure.

Methods and Results— Heart grafts from BALB/c mice were preserved in UW solution (control) or UW solution containing siRNAs targeting tumor necrosis factor-, C3, and Fas genes (siRNA solution) at 4°C for 48 hours and subsequently transplanted into syngeneic recipients. Tumor necrosis factor-, C3, and Fas genes were elevated by ischemia/reperfusion injury after 48 hours of preservation in UW solution. Preservation in siRNA solution knocked down gene expression at the level of messenger RNA and protein in the grafts after transplantation. All grafts preserved in siRNA solution showed strong contraction, whereas grafts preserved in control solution demonstrated no detectable contraction by high-frequency ultrasound scanning. siRNA solution–treated organs exhibited improved histology and diminished neutrophil and lymphocyte infiltration compared with control solution–treated organs. Furthermore, the treated heart grafts retained strong beating up to the end of the observation period (>100 days), whereas all control grafts lost function within 8 days.

Conclusion— Incorporation of siRNA into organ storage solution is a feasible and effective method of attenuating ischemia/reperfusion injury, protecting cardiac function, and prolonging graft survival.

  B Schiller , A Wong , M Blair and J. Moran
 

Background. Fluctuating parathyroid hormone values (PTH) are common in patients undergoing haemodialysis. Widely varying PTH results in an 82-year-old haemodialysis (HD) patient could not be explained. When PTH in the same blood sample was no longer detectable 24 h after blood draw, it was hypothesized that contamination with the catheter lock solution containing tissue plasminogen activator (tPA, alteplase) caused degradation of PTH in vitro.

Methods. Leftover samples from 21 patients on maintenance HD as well as control samples from healthy volunteers (n = 3) were incubated at 4°C with small amounts of tPA (25 and 50 µL). In addition, pooled samples from HD patients with various PTH levels were incubated with 6.5, 12.5 and 25 µL of tPA and analysed with two different PTH assays with incubation times up to 48 h.

Results. A rapid decline of PTH values to 2.5–33.5% of the original baseline was observed after 24 h with a further decrease to <1–15% after 48 h. The two different assays gave very similar results when the samples were incubated with tPA.

Conclusion. Minimal contamination of a blood sample with tPA results in degradation of PTH in a time-dependent manner. The tPA is therefore unique as a contaminant since its enzymatic activity means that even tiny amounts of contamination will lead to major errors in PTH results by digestion of the protein. This phenomenon was independent of the assay used. Strict attention to the technique when drawing a blood sample from a catheter is mandatory to prevent contamination and avoid spurious test results.

  J. Q Hang , Y Yang , S. F Harris , V Leveque , H. J Whittington , S Rajyaguru , G Ao Ieong , M. F McCown , A Wong , A. M Giannetti , S Le Pogam , F Talamas , N Cammack , I Najera and K. Klumpp
 

The binding affinity of four palm and thumb site representative non-nucleoside inhibitors (NNIs) of HCV polymerase NS5B to wild-type and resistant NS5B polymerase proteins was determined, and the influence of RNA binding on NNI binding affinity was investigated. NNIs with high binding affinity potently inhibited HCV RNA polymerase activity and replicon replication. Among the compounds tested, HCV-796 showed slow binding kinetics to NS5B. The binding affinity of HCV-796 to NS5B increased 27-fold over a 3-h incubation period with an equilibrium Kd of 71 ± 2 nm. Slow binding kinetics of HCV-796 was driven by slow dissociation from NS5B with a koff of 4.9 ± 0.5 x 10–4 s–1. NS5B bound a long, 378-nucleotide HCV RNA oligonucleotide with high affinity (Kd = 6.9 ± 0.3 nm), whereas the binding affinity was significantly lower for a short, 21-nucleotide RNA (Kd = 155.1 ± 16.2 nm). The formation of the NS5B-HCV RNA complex did not affect the slow binding kinetics profile and only slightly reduced NS5B binding affinity of HCV-796. The magnitude of reduction of NNI binding affinity for the NS5B proteins with various resistance mutations in the palm and thumb binding sites correlated well with resistance -fold shifts in NS5B polymerase activity and replicon assays. Co-crystal structures of NS5B-Con1 and NS5B-BK with HCV-796 revealed a deep hydrophobic binding pocket at the palm region of NS5B. HCV-796 interaction with the induced binding pocket on NS5B is consistent with slow binding kinetics and loss of binding affinity with mutations at amino acid position 316.

 
 
 
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