Cheng, Huiming
Johann, Stephen
Mullen, Stanley
Chunduru, Srinivas K.
Young, Dorothy C.
Bard, Joel
Chopra, Rajiv
Krishnamurthy, Girija
Mansour, Tarek
O'Connell, John
HCV-796 selectively inhibits hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. In hepatoma cells containing a genotype 1b HCV replicon, HCV-796 reduced HCV RNA levels by 3 to 4 log(10) HCV copies/mu g total RNA (the concentration of the compound that inhibited 50% of the HCV RNA level was 9 nM). Cells bearing replicon variants with reduced susceptibility to HCV-796 were generated in the presence of HCV-796, followed by G418 selection. Sequence analysis of the NS5B gene derived from the replicon variants revealed several amino acid changes within 5 angstrom of the drug-binding pocket. Specifically, mutations were observed at Leu314, Cys316, Ile363, Ser365, and Met414 of NS5B, which directly interact with HCV-796. The impacts of the amino acid substitutions on viral fitness and drug susceptibility were examined in recombinant replicons and NS5B enzymes with the single-amino-acid mutations. The replicon variants were 10- to 1,000-fold less efficient in forming colonies in cells than the wild-type replicon; the S365L variant failed to establish a stable cell line. Other variants (L314F, I363V, and M414V) had four-to ninefold-lower steady-state HCV RNA levels. Reduced binding affinity with HCV-796 was demonstrated in an enzyme harboring the C316Y mutation. The effects of these resistance mutations were structurally rationalized using X-ray crystallography data. While different levels of resistance to HCV-796 were observed in the replicon and enzyme variants, these variants retained their susceptibilities to pegylated interferon, ribavirin, and other HCV-specific inhibitors. The combined virological, biochemical, biophysical, and structural approaches revealed the mechanism of resistance in the variants selected by the potent polymerase inhibitor HCV-796.
Vallejo-Giraldo, Catalina
Pampaloni, Niccolo Paolo
Pallipurath, Anuradha R.
Mokarian-Tabari, Parvaneh
O'Connell, John
Holmes, Justin D.
Trotier, Alexandre
Krukiewicz, Katarzyna
Orpella-Aceret, Gemma
Pugliese, Eugenia
Ballerini, Laura
Kilcoyne, Michelle
Dowd, Eilis
Quinlan, Leo R.
Pandit, Abhay
Kavanagh, Paul
Biggs, Manus Jonathan Paul
Physicochemical modification of implantable electrode systems is recognized as a viable strategy to enhance tissue/electrode integration and electrode performance in situ. In this work, a bench-top electrochemical process to formulate anodized indium tin oxide (ITO) films with altered roughness, conducting profiles, and thickness is explored. In addition, the influence of these anodized films on neural cell adhesion, proliferation, and function indicates that anodized ITO film cytocompatibility can be altered by varying the anodization current density. Furthermore, ITO-anodized films formed with a current density of 0.4 mA cm(-2) show important primary neural cell survival, modulation of glial scar formation, and promotion of neural network activity.
Ghoshal, Tandra
Ntaras, Christos
O'Connell, John
Shaw, Matthew T.
Holmes, Justin D.
Avgeropoulos, Apostolos
Morris, Michael A.
The use of a low-chi, symmetric block copolymer as an alternative to the high-chi systems currently being translated towards industrial silicon chip manufacture has been demonstrated. Here, the methodology for generating on-chip, etch resistant masks and subsequent pattern transfer to the substrate using ultrasmall dimension, lamellar, microphase separated polystyrene-b-poly(ethylene oxide) (PS-b-PEO) block copolymer (BCP) is described. Well-controlled films of a perpendicularly oriented lamellar pattern with a domain size of similar to 8 nm were achieved through amplification of an effective interaction parameter (chi(eff)) of the BCP system. The self-assembled films were used as 'templates' for the generation of inorganic oxides nanowire arrays through selective metal ion inclusion and subsequent processing. Inclusion is a significant challenge because the lamellar systems have less chemical and mechanical robustness than the cylinder forming materials. The oxide nanowires of uniform diameter (similar to 8 nm) were isolated and their structure mimics the original BCP nanopatterns. We demonstrate that these lamellar phase iron oxide nanowire arrays could be used as a resist mask to fabricate densely packed, identical ordered, good fidelity silicon nanowire arrays on the substrate. Possible applications of the materials prepared are discussed, in particular, in the area of photonics and photoluminescence where the properties are found to be similar to those of surface-oxidized silicon nanocrystals and porous silicon.
Krishnamoorthy, Janaki
Salame-Alfie, Adela
O'Connell, John
From 2001 through 2009, the New York State Department of Health (NYSDOH) has documented 244 reports of radiation therapy events, of which 228 have resulted from the delivery of radiation beam therapy using linear accelerators (LINACs). Historically, radiation therapy events involving LINACs have not been uniformly reported across the country because LINACs are regulated by state radiation control programs, and reporting requirements vary among states. The Nuclear Regulatory Commission's Nuclear Material Events Database (NMED) only tracks events involving radioactive materials (RAM). Efforts to track medical events involving LINACs at a national level have begun only recently. This article highlights the importance of tracking and analyzing all medical radiation events in order to improve quality of care and patient safety. An analysis of a subset of the data collected by the NYSDOH from 2001-2009 is presented. This subset consists of only events arising from the use of LINACs in radiation therapy. There are very few publications on errors and error rates in the use of medical accelerators in radiation therapy. This analysis highlights the most common types of errors, causes and contributing factors, areas for improvement and actions taken to bring this information to the regulated community. An error rate of 0.07% per patient receiving radiation treatment is estimated using these data and the New York State Tumor Registry data for the same period. NY State Regulations governing the practice of Radiation Oncology have been revised recently to reflect the increased complexity in the delivery of therapeutic radiation. Collaboration and sharing of data such as those presented here, between federal, state and local regulators, professional organizations such as the Conference of Radiation Control Program Directors (CRCPD), American Society for Radiation Oncology (ASTRO), American Association of Physicists in Medicine (AAPM), American College of Radiology (ACR), American College of Radiation Oncology (ACRO), manufacturers of medical radiation equipment and software developers and the regulated community has begun and will contribute to improved quality of care and patient safety. =20