And unresectable (stage 3 or 4, p = 0.079) PC 
from CP patients (Table 5).NGAL and its murine homologue Ngal have been proposed as components of the innate immune system [11?3]. In our earlier studies, we observed that overexpression of NGAL in PC cells inhibit invasion and metastasis and prevents angiogenesis [14]. The observation that NGAL levels are similar in CP and PC patients (Table 2) suggests that NGAL may be released as 
a part of the chronic inflammatory response that accompanies both diseases.Diagnosis Efficacy of NGAL, MIC-1 and CA19-Table 5. Comparison of Area under the ROC curve for NGAL, 22948146 MIC-1 and CA19-9 in the diagnosis of pancreatic cancer?.p-valueaGroups Stage 1/2 PC vs. HC ln CA19-9 ln NGAL+ln CA19-9 ln NGAL+ln CA19-9+ ln MIC1 Stage 3/4 PC vs. HC ln CA19-9 ln NGAL+ln CA19-9 ln NGAL+ln CA19-9+ ln MIC1 Stage 1/2 PC vs. CP ln CA19-9 ln MIC-1+ ln CA19-9* ln NGAL+ln CA19-9+ ln MIC1 Stage 3/4 PC vs. CP ln CA19-9 ln MIC-1+ ln CA19-9* ln NGAL+ln CA19-9+ ln MICAUC (SE)95 CI0.8 (0.06) 0.82 (0.05) 0.85 (0.05)0.69?.91 0.72?.93 0.75?.94 0.4 0.0.89 (0.05) 0.94 (0.03) 0.94 (0.03)0.80?.98 0.87?.00 0.89?.00 0.11 0.0.74 (0.06) 0.85 (0.05) 0.86 (0.04)0.62?.87 0.76?.94 0.77?.95 0.029 0.0.87 (0.04) 0.93 (0.03) 0.92 (0.03)0.79?.96 0.87?.99 0.86?.99 0.079 0.PC (pancreatic cancer), CP (chronic pancreatitis), AUC (area under the curve), SE (standard error). aP-value against CA19-9 alone.*Marker inclusion in combination tests was based on statistical significance of differentiation of individual biomarkers levels by multivariate analysis). ?PC patient samples were ?limited to treatment naive samples only for this analysis. doi:10.1371/journal.pone.0055171.tMIC-1 (also called as GDF-15 or NAG-1) is a member of the TGF-b family that was first identified as a protein secreted from macrophages in response to immune activation [15]. MIC-1 is also aberrantly expressed by several malignancies (including PC) and has emerged as target of p53 mediated transcription (role of MIC1 in cancer reviewed in [15]). Differential expression of MIC-1 was observed in SAGE (serial ML 264 site analysis of gene expression) libraries from six pancreatic cancer cell lines in comparison to nonneoplastic tissues [16]. Koopman and colleagues had reported earlier that MIC-1 was significantly better than CA19-9 in discriminating PC from HCs (AUC being 0.99 and 0.78, p = 0.003) but not from CP (AUC being 0.81 and 0.74 respectively, p = 0.63) [6]. They observed that the mean MIC-1 level in healthy controls, CP and PC was 0.76 ng/ml, 2.36 ng/ml and 5.4 ng/ml respectively. Further studies emphasized the diagnostic efficacy of MIC-1 equivalent to CA19-9 [6,7]. In our study, the mean plasma MIC-1 levels in these patient groups were 1.5 ng/ml, 1.6 ng/ml and 4.5 ng/ml (Table 2). In our sample set, at an optimal cut-off of .2.3 ng/ml, plasma MIC-1 was 62 sensitive and 63 specific in discriminating PC from HCs. At this cut-off, MIC-1 was 78 specific and 62 sensitive in differentiating PC from CP patients. Interestingly, the combined use of MIC-1 with CA 19-9 significantly improved the Rebaudioside A sensitivity and accuracy in differentiating resectable PC (Stage 1/2) patients from CP patients (AUC of 0.85, p = 0.029) in comparison to CA19-9 alone (AUC of 0.74), providing a promising approach for 23115181 PC diagnosis at an early stage. The significance of MIC-1 as a biomarker for PC will need to be investigated in larger patient cohorts. CA19-9 is a well-known molecular marker in PC. Biochemically, it is the sialyl.And unresectable (stage 3 or 4, p = 0.079) PC from CP patients (Table 5).NGAL and its murine homologue Ngal have been proposed as components of the innate immune system [11?3]. In our earlier studies, we observed that overexpression of NGAL in PC cells inhibit invasion and metastasis and prevents angiogenesis [14]. The observation that NGAL levels are similar in CP and PC patients (Table 2) suggests that NGAL may be released as a part of the chronic inflammatory response that accompanies both diseases.Diagnosis Efficacy of NGAL, MIC-1 and CA19-Table 5. Comparison of Area under the ROC curve for NGAL, 22948146 MIC-1 and CA19-9 in the diagnosis of pancreatic cancer?.p-valueaGroups Stage 1/2 PC vs. HC ln CA19-9 ln NGAL+ln CA19-9 ln NGAL+ln CA19-9+ ln MIC1 Stage 3/4 PC vs. HC ln CA19-9 ln NGAL+ln CA19-9 ln NGAL+ln CA19-9+ ln MIC1 Stage 1/2 PC vs. CP ln CA19-9 ln MIC-1+ ln CA19-9* ln NGAL+ln CA19-9+ ln MIC1 Stage 3/4 PC vs. CP ln CA19-9 ln MIC-1+ ln CA19-9* ln NGAL+ln CA19-9+ ln MICAUC (SE)95 CI0.8 (0.06) 0.82 (0.05) 0.85 (0.05)0.69?.91 0.72?.93 0.75?.94 0.4 0.0.89 (0.05) 0.94 (0.03) 0.94 (0.03)0.80?.98 0.87?.00 0.89?.00 0.11 0.0.74 (0.06) 0.85 (0.05) 0.86 (0.04)0.62?.87 0.76?.94 0.77?.95 0.029 0.0.87 (0.04) 0.93 (0.03) 0.92 (0.03)0.79?.96 0.87?.99 0.86?.99 0.079 0.PC (pancreatic cancer), CP (chronic pancreatitis), AUC (area under the curve), SE (standard error). aP-value against CA19-9 alone.*Marker inclusion in combination tests was based on statistical significance of differentiation of individual biomarkers levels by multivariate analysis). ?PC patient samples were ?limited to treatment naive samples only for this analysis. doi:10.1371/journal.pone.0055171.tMIC-1 (also called as GDF-15 or NAG-1) is a member of the TGF-b family that was first identified as a protein secreted from macrophages in response to immune activation [15]. MIC-1 is also aberrantly expressed by several malignancies (including PC) and has emerged as target of p53 mediated transcription (role of MIC1 in cancer reviewed in [15]). Differential expression of MIC-1 was observed in SAGE (serial analysis of gene expression) libraries from six pancreatic cancer cell lines in comparison to nonneoplastic tissues [16]. Koopman and colleagues had reported earlier that MIC-1 was significantly better than CA19-9 in discriminating PC from HCs (AUC being 0.99 and 0.78, p = 0.003) but not from CP (AUC being 0.81 and 0.74 respectively, p = 0.63) [6]. They observed that the mean MIC-1 level in healthy controls, CP and PC was 0.76 ng/ml, 2.36 ng/ml and 5.4 ng/ml respectively. Further studies emphasized the diagnostic efficacy of MIC-1 equivalent to CA19-9 [6,7]. In our study, the mean plasma MIC-1 levels in these patient groups were 1.5 ng/ml, 1.6 ng/ml and 4.5 ng/ml (Table 2). In our sample set, at an optimal cut-off of .2.3 ng/ml, plasma MIC-1 was 62 sensitive and 63 specific in discriminating PC from HCs. At this cut-off, MIC-1 was 78 specific and 62 sensitive in differentiating PC from CP patients. Interestingly, the combined use of MIC-1 with CA 19-9 significantly improved the sensitivity and accuracy in differentiating resectable PC (Stage 1/2) patients from CP patients (AUC of 0.85, p = 0.029) in comparison to CA19-9 alone (AUC of 0.74), providing a promising approach for 23115181 PC diagnosis at an early stage. The significance of MIC-1 as a biomarker for PC will need to be investigated in larger patient cohorts. CA19-9 is a well-known molecular marker in PC. Biochemically, it is the sialyl.
