The plasma peptidome preparation protocol was adapted from that of the urine peptidome analysis. The plasma samples were centrifuged at 3,000×g for 20 min at 10°C through Amicon Ultra centrifugal filtration devices (10 kDa cutoff; Millipore, Bedford, MA) pre-equilibrated with 10 ml Milli-Q water. The retentate (plasma proteome) was washed twice, brought to the final volume of 400 μl with 20 mM Tris-HCl (pH 7.5), and quantitated by the BCA protein assay (Pierce, Rockford, IL). The filtrate (plasma peptidome) containing the low MW naturally occurring peptides was processed with Waters Oasis HLB Extraction Cartridges (Waters Corporation, Milford, MA), and extracted with ethyl acetate. The resulting plasma peptide samples were quantified by the TNBS assay, as previously described [28] . Three nanomoles of peptides were fractionated by two-dimensional chromatography-a SCX column as the first and a RP column as the second dimension, and then subjected to extensive MSMS sequence identification involving a Thermo Finnigan LTQ-FTICR spectrometer.