Surrogate Marker For Detection Research Articles

Discovery of characteristic molecular signatures for the simultaneous prediction and detection of environmental pollutants

Gene expression data may be very promising for the classification of toxicant types, but the development and application of transcriptomic-based gene classifiers for environmental toxicological applications are lacking compared to the biomedical sciences. Also, simultaneous classification across a set of toxicant types has not been investigated extensively. In the present study, we determined the transcriptomic response to three types of ubiquitous toxicants exposure in two types of human cell lines (HepG2 and HL-60), which are useful in vitro human model for evaluation of toxic substances that may affect human hepatotoxicity (e.g., polycyclic aromatic hydrocarbon [PAH] and persistent organic pollutant [POP]) and human leukemic myelopoietic proliferation (e.g., volatile organic compound [VOC]). The findings demonstrate characteristic molecular signatures that facilitated discrimination and prediction of the toxicant type. To evaluate changes in gene expression levels after exposure to environmental toxicants, we utilized 18 chemical substances; nine PAH toxicants, six VOC toxicants, and three POP toxicants. Unsupervised gene expression analysis resulted in a characteristic molecular signature for each toxicant group, and combination analysis of two separate multi-classifications indicated 265 genes as surrogate markers for predicting each group of toxicants with 100 % accuracy. Our results suggest that these expression signatures can be used as predictable and discernible surrogate markers for detection and prediction of environmental toxicant exposure. Furthermore, this approach could easily be extended to screening for other types of environmental toxicants.

519 Predictors of Mortality in Individuals With Nonalcoholic Fatty Liver Disease (NAFLD) in the United States: Results From the Third National Health and Nutrition Examination Survey (NHANES III)

Background: Previous cross-sectional studies have shown that serum levels of cytokeratin fragments (CK18) are associated with the presence of steatohepatitis in individuals with nonalcoholic fatty liver disease (NAFLD). However, it is unknown if serial serum CK18 levels can predict longitudinal changes in liver histology in NAFLD. Aim: To determine the degree to which changes in serum CK18 associate with changes in liver histology over a 96-week period in adult patients with nonalcoholic steatohepatitis (NASH). Methods: Serum CK18 levels were measured at baseline and 16, 48, and 96 weeks in 231 of the 247 adults with NASH who participated in the PIVENS trial which investigated the efficacy of pioglitazone vs. vitamin E vs. placebo in non-diabetic individuals with histologically confirmed NASH over a 96-week period. Liver biopsies at baseline and after 96 weeks of treatment were centrally evaluated by the NASH CRN Pathology Committee. Multiple logistic (for categorical outcomes) and linear (for continuous outcome variables) regression models were used to determine the association between changes in histological features, ALT, and % collagen assessed by Sirius red staining, and change in CK18 levels, controlling for baseline CK18 levels and treatment group. Results: At baseline, CK18 levels among the 3 treatment groups were similar (placebo: 440± 350 U/L, vit E: 510± 350 U/L, and pioglitazone: 490± 410 U/L). Compared to placebo, serum CK18 levels among individuals treated with vit E were reduced at week 16 (mean change from baseline -160± 300 vs. -50 ±380 U/L, p= 0.02), week 48 (-220± 390 vs. -10± 370 U/L, p=0.009), and week 96 (-200± 400 vs. 30± 400 U/L, p=0.009). Similarly, compared to placebo, serum CK18 levels among individuals treated with pioglitazone were reduced at week 16 (mean change from baseline -240 ± 390 vs. -50± 380 U/L, p,=0.001), week 48 (-180± 370 vs. -10± 370 U/L, p=0.001, and week 96 (-260 ±400 vs. 30 ± 400 U/L, p=0.001). Strong correlations were seen with change in CK18 levels and the primary histologic endpoint, resolution of NASH, and individual histologic features of NASH (Table 1). In addition, change in CK18 levels strongly correlated with change in ALT levels (b=0.06, 95% CI: 0.04, 0.08; P,0.001).Percent collagen measurements were not related to change in CK18 (b=-0.17 %/100*U/L , 95% CI:-0.70, 0.37; P= 0.54). Summary: (1) Compared to placebo, treatment with vit E or pioglitazone had significant reduction in serum CK18 levels. (2) Changes in serum CK18 correlated with histologic improvement in non-diabetic adults with NASH treated with vitamin E or pioglitazone. Conclusion: Serum CK18 is a potential useful surrogate marker for detection of improvement in clinical trials.

Abstract 343: Molecular markers for detection of micrometastases in regional lymph nodes from patients undergoing surgery for non-small cell lung cancer

Abstract PURPOSE: Lung cancer retains its status as the most common cancer in the world, with an estimated 1.5 million cases diagnosed in 2007, accounting for about 12% of all cancers. Identifying microscopic lynph-node metastases, could have clinical importance in selecting patients for adjuvant treatment. The purpose of this study wasis to Iidentify and evaluate molecular markers for detection of micrometastases in regional lymph nodes from patients undergoing surgery for non-small cell lung cancer. PATIENTS AND METHODS: Candidate micrometasis markers were selected based on digital transcript profiling in EST and SAGE databases, searching for transcripts with high levels in lung cancers and very low levels in normal lymph nodes. Surfactant protein C (SFTPC) and cytokeratin 19 (CK19) mRNA levels in tumor biopsies and resected regional lymp nodes (N=38) from 24 patients undergoing surgery for non-small cell lung cancer were measured by quantitative RT-PCR. A control material consisting of 22 normal mesenterial lymph nodes from patients undergoing surgery for benign colon disorders was analyzed in parallell. RESULTS: The median relative CK19SFTPC mRNA level in the non-small cell lung tumor biopsies were 446 times higher than the highest level in normal control lymph nodes. SFTPC mRNA was not detectable in the normal lymph nodes, whereas the tumor levels were high (Cq-values ranging from 17-25). Using the highest CK19 mRNA level in the normal lymph nodes as a cut-off, four out of five (80%) lymph nodes from patients with known lymph node metastases (by routine histology) had elevated CK19 levels. Accordingly, 5 (15%) of 33 lymph nodes from patients without known metastases (node-negative) had elevated levels of CK19 mRNA. SFTPC mRNA were detectable in 31 of the 33 lymph nodes from node-negative patients, although the median relative level was 7.1 times higher in the 5 lymph nodes from node-positive patients (P=0.002, Mann-Witney test). Elevated CK19 and SFTPC mRNA levels in regional lymph nodes without known metastases may reflect the presence of micrometastases. CONCLUSION: SFTPC and CK19 mRNA are promising surrogate markers for detection of micrometastases in regional lymph nodes from non-small cell lung cancer patients. However, clinical follow-up in a larger cohort is needed to eludicate the prognostic value of such findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 343. doi:10.1158/1538-7445.AM2011-343

Serum biomarker of diabetic peripheral neuropathy indentified by differential proteomics

At least one in four diabetic patients is affected by peripheral neuropathy. In this study, the MALDI-TOF-MS mass spectra of peptides and proteins were generated following WCX CLINPROT bead fractionation of 39 diabetic peripheral neuropathy (DPN), 39 diabetes mellitus (DM), and 35 control (CON) serum samples. The spectra were analyzed statistically using flexAnalysisTM and Clin-ProtTM bioinformatics software. Identification of the selected markers was performed and affinity bead-purified plasma protein was subjected to LTQ Orbitrap XL MS/MS analysis followed by Mascot identification of the peptide sequences. 89 differentially expressed peaks of serum proteins were identified. 17, 10 and 4 most significant peaks between CON vs. DM, CON vs. DPN, DM vs. DPN, respectively, were selected out using the ClinProTool software package and used to train a Supervised Neural Network. A veracity rate of 100% was obtained for all sets. Following this analysis, a 6631-Da marker was identified as a fragment of the Apolipoprotein C-I precursor. The peptides identified may have clinical utility as surrogate markers for detection and classification of DM and DPN.

Biomarker discovery and identification from non-small cell lung cancer sera

Currently, serum biomarkers might usually be thought not to be used for early detection of lung cancer by some researchers. In this study, we used a highly optimized ClinProt-matrix-assisted laser desorption/ionization time-of flight mass spectrometer (MALDI-TOF-MS) to screen non-small cell lung carcinoma (NSCLC) markers in serum. A training set of spectra derived from 45 NSCLC patients, 24 patients with benign lung diseases (BLDs) and 21 healthy individuals, was used to develop a proteomic pattern that discriminated cancer from non-cancer effectively. A test set, including 74 cases (29 NSCLC patients and 45 controls), was used to validate this pattern. After cross-validation, the classifier showed sensitivity and specificity, 86.20% and 80.00%, respectively. Remarkably, 100% of early stage serum samples could be correctly classified as lung cancer. Furthermore, the differential peptides of 1865Da and 4209Da were identified as element of component 3 and eukaryotic peptide chain release factor GTP-binding subunit ERF, respectively. The patterns we described and peptides we identified may have clinical utility as surrogate markers for detection and classification of NSCLC.

(1→3)-β-D-Glucan in Cereobrospinal Fluid is a Surrogate Marker for Detection and Therapeutic Response of Hematogenous Candida Meningoencephalitis

(1→3)-β-D-Glucan in Cereobrospinal Fluid is a Surrogate Marker for Detection and Therapeutic Response of Hematogenous Candida Meningoencephalitis

Differential exoprotease activities confer tumor-specific serum peptidome patterns

Recent studies have established distinctive serum polypeptide patterns through mass spectrometry (MS) that reportedly correlate with clinically relevant outcomes. Wider acceptance of these signatures as valid biomarkers for disease may follow sequence characterization of the components and elucidation of the mechanisms by which they are generated. Using a highly optimized peptide extraction and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS-based approach, we now show that a limited subset of serum peptides (a signature) provides accurate class discrimination between patients with 3 types of solid tumors and controls without cancer. Targeted sequence identification of 61 signature peptides revealed that they fall into several tight clusters and that most are generated by exopeptidase activities that confer cancer type-specific differences superimposed on the proteolytic events of the ex vivo coagulation and complement degradation pathways. This small but robust set of marker peptides then enabled highly accurate class prediction for an external validation set of prostate cancer samples. In sum, this study provides a direct link between peptide marker profiles of disease and differential protease activity, and the patterns we describe may have clinical utility as surrogate markers for detection and classification of cancer. Our findings also have important implications for future peptide biomarker discovery efforts.

Gamma-Glutamyltransferase as a Potential Surrogate Marker for Detection of the Non-A, Non-B Carrier State

Gamma-Glutamyltransferase as a Potential Surrogate Marker for Detection of the Non-A, Non-B Carrier State