Contribution of 30 Biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: The MONICA, risk, genetics, archiving and monograph (MORGAM) biomarker project

Background— Cardiovascular risk estimation by novel biomarkers needs assessment in disease-free population cohorts, followed up for incident cardiovascular events, assaying the serum and plasma archived at baseline. We report results from 2 cohorts in such a continuing study.
Methods and Results— Thirty novel biomarkers from different pathophysiological pathways were evaluated in 7915 men and women of the FINRISK97 population cohort with 538 incident cardiovascular events at 10 years (fatal or nonfatal coronary or stroke events), from which a biomarker score was developed and then validated in the 2551 men of the Belfast Prospective Epidemiological Study of Myocardial Infarction (PRIME) cohort (260 events). No single biomarker consistently improved risk estimation in FINRISK97 men and FINRISK97 women and the Belfast PRIME Men cohort after allowing for confounding factors; however, the strongest associations (with hazard ratio per SD in FINRISK97 men) were found for N-terminal pro-brain natriuretic peptide (1.23), C-reactive protein (1.23), B-type natriuretic peptide (1.19), and sensitive troponin I (1.18). A biomarker score was developed from the FINRISK97 cohort with the use of regression coefficients and lasso methods, with selection of troponin I, C-reactive protein, and N-terminal pro-brain natriuretic peptide. Adding this score to a conventional risk factor model in the Belfast PRIME Men cohort validated it by improved c-statistics (P=0.004) and integrated discrimination (P<0.0001) and led to significant reclassification of individuals into risk categories (P=0.0008).
Conclusions— The addition of a biomarker score including N-terminal pro-brain natriuretic peptide, C-reactive protein, and sensitive troponin I to a conventional risk model improved 10-year risk estimation for cardiovascular events in 2 middle-aged European populations. Further validation is needed in other populations and age groups.

Novel biomarkers in early diagnosis of acute myocardial infarction compared with cardiac troponin T

Aims: To evaluate the role of novel biomarkers in early detection of acute myocardial infarction (MI) in patients admitted with acute chest pain.
Methods and results: A prospective study of 664 patients presenting to two coronary care units with chest pain was conducted over 3 years from 2003. Patients were assessed on admission: clinical characteristics, ECG (electrocardiogram), renal function, cardiac troponin T (cTnT), heart fatty acid binding protein (H-FABP), glycogen phosphorylase-BB, NT-pro-brain natriuretic peptide, D-dimer, hsCRP (high sensitivity C-reactive protein), myeloperoxidase, matrix metalloproteinase-9, pregnancy associated plasma protein-A, soluble CD40 ligand. A =12 h cTnT sample was also obtained. MI was defined as cTnT = 0.03 µg/L. In patients presenting <4 h of symptom onset, sensitivity of H-FABP for MI was significantly higher than admission cTnT (73 vs. 55%; P = 0.043). Specificity of H-FABP was 71%. None of the other biomarkers challenged cTnT. Combined use of H-FABP and cTnT (either one elevated initially) significantly improved the sensitivities of H-FABP or cTnT (85%; P = 0.004). This combined approach also improved the negative predictive value, negative likelihood ratio, and the risk ratio.
Conclusion: Assessment of H-FABP within the first 4 h of symptoms is superior to cTnT for detection of MI, and is a useful additional biomarker for patients with acute chest pain.

Proteomics Identification of Azaspiracid Toxin Biomarkers in Blue Mussels, Mytilus edulis

Azaspiracids are a class of recently discovered algae-derived shellfish toxins. Their distribution globally is on the increase with mussels being most widely implicated in azaspiracid-related food poisoning events. Evidence that these toxins were bound to proteins in contaminated mussels has been shown recently. In the present study characterization of these proteins in blue mussels, Mytilus edulis, was achieved using a range of advanced proteomics tools. Four proteins present only in the hepatopancreas of toxin-contaminated mussels sharing identity or homology with cathepsin D, superoxide dismutase, glutathione S-transferase Pi, and a bacterial flagellar protein have been characterized. Several of the proteins are known to be involved in self-defense mechanisms against xenobiotics or up-regulated in the presence of carcinogenic agents. These findings would suggest that azaspiracids should now be considered and evaluated as potential tumorigenic compounds. The presence of a bacterial protein only in contaminated mussels was an unexpected finding and requires further investigation. The proteins identified in this study should assist with development of urgently required processes for the rapid depuration of azaspiracid-contaminated shellfish. Moreover they may serve as early warning indicators of shellfish exposed to this family of toxins. Molecular & Cellular Proteomics 8: 1811-1822, 2009.

Novel breast cancer biomarkers identified by integrative proteomic and gene expression mapping

Proteomic and transcriptomic platforms both play important roles in cancer research, with differing strengths and limitations. Here, we describe a proteo-transcriptomic integrative strategy for discovering novel cancer biomarkers, combining the direct visualization of differentially expressed proteins with the high-throughput scale of gene expression profiling. Using breast cancer as a case example, we generated comprehensive two-dimensional electrophoresis (2DE)/mass spectrometry (MS) proteomic maps of cancer (MCF-7 and HCC-38) and control (CCD-1059Sk) cell lines, identifying 1724 expressed protein spots representing 484 different protein species. The differentially expressed cell-line proteins were then mapped to mRNA transcript databases of cancer cell lines and primary breast tumors to identify candidate biomarkers that were concordantly expressed at the gene expression level. Of the top nine selected biomarker candidates, we reidentified ANX1, a protein previously reported to be differentially expressed in breast cancers and normal tissues, and validated three other novel candidates, CRAB, 6PGL, and CAZ2, as differentially expressed proteins by immunohistochemistry on breast tissue microarrays. In total, close to half (4/9) of our protein biomarker candidates were successfully validated. Our study thus illustrates how the systematic integration of proteomic and transcriptomic data from both cell line and primary tissue samples can prove advantageous for accelerating cancer biomarker discovery.

Discordant quantitative detection of putative biomarkers in nodal micrometastases of colorectal cancer: biological and clinical implications

Aims: Nodal expression of the carcinoembryonic antigen ( CEA), cytokeratin 20 ( CK20), and guanylyl cyclase C ( GCC) genes was measured in tandem in patients with colorectal cancer ( CRC) to assess whether there would be sufficient agreement between these markers in their ability to detect micrometastasis to qualify one of them as a universal marker, and whether frozen and paraffin wax embedded tissues would yield similar results.

Prognostic and Predictive Biomarkers in Resected Colon Cancer: Current Status and Future Perspectives for Integrating Genomics into Biomarker Discovery

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era. The Oncologist 2010; 15: 390-404

Biomarkers of fruit and vegetable intake in Human intervention studies a systematic review

Observational evidence consistently shows that consumption of a diet rich in fruit and vegetables may offer protection against diseases such as cardiovascular disease and cancer. Assessment of dietary intake is complex and prone to many sources of error. More objective biomarkers of fruit and vegetable intake are therefore of interest. The aim of this review is to examine the usefulness of the main biomarkers of fruit and vegetable intake to act as objective indicators of compliance in dietary intervention studies. A comprehensive search of the literature was conducted using six databases. Suitable papers were selected and relevant data extracted. The papers were categorized into 3 sub-groups: whole diet interventions; mixed fruit and vegetable interventions; and studies involving individual varieties of fruits or vegetables. Ninety-six studies were included in the review. Overall, the most commonly measured, and most consistently responsive, biomarkers were the carotenoids and vitamin C. Based on the results of this systematic review, it remains prudent to measure a panel of biomarkers in fruit and vegetable intervention studies. The only possible exception to this is “fruit only” intervention studies where assessment of vitamin C alone may suffice.

Imitating micelles as a way to control coordination self-assembly: cage-polymer switching directed rationally by solvent polarity or pH

Disguising a metal complex as a micelle by using amphiphilic phosphine ligands enables it to switch between a coordination polymer and a discrete cage in response to solvent polarity or pH; this medium-dependent behaviour of the complex is rational because it parallels that of true micelles.