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Articles by R Harris
Total Records ( 3 ) for R Harris
  K Matthews , P. E Noker , B Tian , S. D Grimes , R Fulton , K Schweikart , R Harris , R Aurigemma , M Wang , M. N Barnes , G. P Siegal , A Hemminki , K Zinn , D. T Curiel and R. D. Alvarez

Purpose: The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma.

Experimental Design: Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects.

Results: Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD ± GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time.

Conclusions: These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.

  C. S Bonnet , M Aldred , C von Ruhland , R Harris , R Sandford and J. P. Cheadle

Clinical trials are underway for the treatment of tuberous sclerosis (TSC)-associated tumours using mTOR inhibitors. Here, we show that many of the earliest renal lesions from Tsc1+/– and Tsc2+/– mice do not exhibit mTOR activation, suggesting that pharmacological targeting of an alternative pathway may be necessary to prevent tumour formation. Patients with TSC often develop renal cysts and those with inherited co-deletions of the autosomal dominant polycystic kidney disease (ADPKD) 1 gene (PKD1) develop severe, early onset, polycystic kidneys. Using mouse models, we showed a genetic interaction between Tsc1 and Tsc2 with Pkd1 and confirmed an mTOR-independent pathway of renal cystogenesis. We observed that the Tsc and Pkd1 gene products helped regulate primary cilia length and, consistent with the function of this organelle in modulating cell polarity, found that many dividing pre-cystic renal tubule and hepatic bile duct cells from Tsc1, Tsc2 and Pkd1 heterozygous mice were highly misoriented. We therefore propose that defects in cell polarity underlie TSC and ADPKD-associated cystic disease and targeting of this pathway may be of key therapeutic benefit.

  D Eloire , P. J Somerfield , D. V. P Conway , C Halsband Lenk , R Harris and D. Bonnet

Zooplankton community composition and diversity have been analysed for the period 1988–2007 at the coastal station L4 off Plymouth in the Western Channel. The seasonal cycle of the total zooplankton was characterized by two peaks. The total zooplankton abundance did not show any long-term trend and its interannual variations were not directly related to changes in environmental conditions. However, different periods of change in total zooplankton abundance were observed that appeared to be consistently related to changes in sea surface temperature (SST) and wind. The number of taxa (22) contributing 80–90% of the total zooplankton abundance was consistent over the 20 years and their cumulative contribution to the community showed only small interannual variations. A significant long-term increase in species richness of the copepod community was detected and its maximum annual value was significantly related to annual average SST. There was evidence of long-term changes: numbers of Oncaea spp., Cirripede larvae, Calanus helgolandicus and Chaetognaths have increased, whereas numbers of Pseudocalanus elongatus, Temora longicornis, Acartia clausi, Evadne nordmanni, Appendicularians, Podon spp. and Ctenocalanus vanus have decreased. The use of indicator species to monitor hydroclimatic changes in the Western Channel is discussed.

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