Synthesis and biological evaluation of potent alphavbeta3-integrin receptor antagonists

INTRODUCTION: alpha(v)beta(3) Integrin is expressed in sprouting endothelial cells in growing tumors, whereas it is absent in quiescent blood vessels. In addition, various tumor cell types express alpha(v)beta(3) integrin. alpha(v)beta(3) Integrin, a transmembrane heterodimeric protein, binds to the arginine-glycine-aspartic acid (RGD) amino acid sequence of extracellular matrix proteins such as vitronectin and plays a pivotal role in invasion, proliferation and metastasis. Due to the selective expression of alpha(v)beta(3) integrin in tumors, radiolabeled RGD peptides and peptidomimetics are attractive candidates for tumor targeting. METHODS: A cyclic RGD peptide, a peptoid-peptide hybrid, an all-peptoid and a peptidomimetic compound were synthesized, conjugated with 1,4,7,10-tetraazadodecane-N,N',N',N'-tetraacetic acid (DOTA) and radiolabeled with (111)In. Their in vitro and in vivo alpha(v)beta(3)-binding characteristics were determined. RESULTS: IC(50) values were 236 nM for DOTA-E-c(RGDfK), 219 nM for DOTA-peptidomimetic, >10 mM for DOTA-all-peptoid and 9.25 mM for the peptoid-peptide hybrid DOTA-E-c(nRGDfK). (111)In-labeled compounds, except for [(111)In]DOTA-all-peptoid, showed specific uptake in human alpha(v)beta(3)-expressing tumors xenografted in athymic mice. Tumor uptake for [(111)In]DOTA-E-c(RGDfK) was 1.73+/-0.4% ID/g (2 h postinjection) and that of [(111)In]DOTA-peptidomimetic was 2.04+/-0.3% ID/g. Tumor uptake for the peptoid-peptide hybrid [(111)In]DOTA-E-c(nRGDfK) was markedly lower (0.45+/-0.07% ID/g). The all-peptoid [(111)In]DOTA-E-c(nRGnDnFnK) did not show specific uptake in tumors (0.11+/-0.04% ID/g). CONCLUSIONS: The peptidomimetic compound and the cyclic RGD peptide have a high affinity for alpha(v)beta(3) integrin, and these compounds have better tumor-targeting characteristics than the peptoid-peptide hybrid and the all-peptoid.     

Multiple imputation strategies for zero-inflated cost data in economic evaluations: which method works best?

Cost and effect data often have missing data because economic evaluations are frequently added onto clinical studies where cost data are rarely the primary outcome. The objective of this article was to investigate which multiple imputation strategy is most appropriate to use for missing cost-effectiveness data in a randomized controlled trial. Three incomplete data sets were generated from a complete reference data set with 17, 35 and 50 % missing data in effects and costs. The strategies evaluated included complete case analysis (CCA), multiple imputation with predictive mean matching (MI-PMM), MI-PMM on log-transformed costs (log MI-PMM), and a two-step MI. Mean cost and effect estimates, standard errors and incremental net benefits were compared with the results of the analyses on the complete reference data set. The CCA, MI-PMM, and the two-step MI strategy diverged from the results for the reference data set when the amount of missing data increased. In contrast, the estimates of the Log MI-PMM strategy remained stable irrespective of the amount of missing data. MI provided better estimates than CCA in all scenarios. With low amounts of missing data the MI strategies appeared equivalent but we recommend using the log MI-PMM with missing data greater than 35 %.     

Cerebral net exchange of large neutral amino acids after lipopolysaccharide infusion in healthy humans

Introduction  

Alterations in circulating large neutral amino acids (LNAAs), leading to a decrease in the plasma ratio between branched-chain and aromatic amino acids (BCAA/AAA ratio), may be involved in sepsis-associated encephalopathy. We hypothesised that a decrease in the BCAA/AAA ratio occurs along with a net cerebral influx of the neurotoxic AAA phenylalanine in a human experimental model of systemic inflammation.     

Surgery for colorectal cancer in Greece

Objective The aim of this study is to analyse our experience and assess the outcome of surgery for colorectal cancer with curative intent in Greece.Methods During the last 10 years,550 patients were treated for colorectal cancer with curative intent.291(52.9%) of the patients suffered from colonic cancer while 259(47.1%) were operated for rectal cancer.Tumour site,Astler?Coller and TNM classifications and surgical procedures were recorded.Total mortality,morbidity and 5?year survival were evaluated.Results Morbidity rate was 12.0% and mortality rate was 0.68% for colonic cancer surgery,whereas the overall five year survival rate was 77.9%.Morbidity rate was 16.9% and mortality rate was of 0.38% for rectal cancer patients.The overall five year survival rate was 79.6%.Conclusion Morbidity,mortality rate and 5?year survival after colorectal surgery in our department in Greece are comparable to those published in the international literature.