Special Issue "Biomarkers 2011"

Guest Editor
Prof. Dr. Robert Bowser
Barrow Neurological Institute & St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013, USA
Website: http://path.upmc.edu/cmp/fac05.htm
E-Mail: bowserrp@upmc.edu
Phone: +1 602 406 8989
Fax: +1 602 406 6459

Dear Colleagues,

The expanding field of biomarkers continues to play important roles in the healthcare industry, basics sciences, and the pharmaceutical industry. Biomarkers are changing the way in which we diagnose and classify disease, as well as providing a means to monitor disease progression or the effects of therapy. In addition, biomarkers are providing new insights into mechanisms of disease and new therapeutic targets. Biomarkers may be any quantitative measure of cellular, biochemical, or genetic alteration that occurs in a physiologic condition. While genomic and proteomic biomarkers have been at the forefront for the past number of years, recent technologic advancements have enabled the development of additional metabolic and peptide based biomarkers to the study of disease states. However it is crucial to demonstrate clinical validation of the biomarker before determining the clinical utility of any biomarker or panel of biomarkers. This special issue on biomarkers for the International Journal of Molecular Sciences will highlight recent advancements in biomarker discovery efforts and their clinical utility.

Prof. Dr. Robert Bowser
Guest Editor

Submission

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• proteomics
• genomics
• metabolomics
• peptidomics
• mass spectrometry
• bioinformatics
• microarray
• 2D gel electrophoresis

Type of Paper: Review
Title: Looking to the Future: Biomarkers in the Management of Metastatic Pancreatic Cancer
Author: Jennifer Spratlin
Affiliation: Medical Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T5G 1Z2, Canada;
E-Mail: Jennifer.Spratlin@albertahealthservices.ca
Abstract: The incidence of pancreas cancer and pancreatic cancer mortality converge. There has been little advancement in the treatment of pancreas cancer since the acceptance of gemcitabine as the standard of care therapy. Unfortunately, efficacy of gemcitabine is dismal. While there is much discussion for the development of biomarkers to help direct therapy in this area, there is little action to move them into clinical practice. Herein, we review potential pancreatic cancer biomarkers and discuss the limitations in their implementation.

Type of Paper: Article
Title: Molecular Biomarkers for the Diagnosis of Primary Retinal Lymphoma
Authors: Yujuan Wang, Defen Shen, Vinson M. Wang and Chi-Chao Chan
Affiliation: Immunopathology Section, Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA;
E-Mail: chanc@nei.nih.gov (C.-C.C.)
Abstract: Primary retinal lymphoma (PRL) or primary intraocular lymphoma, a subtype of primary CNS lymphoma, often masquerades uveitis. The diagnosis of PRL requires an identification of lymphoma cells inside the eye, which is often challenging due to the frequent necrosis and admixing of PRL cells with reactive lymphocytes. Therefore, detection of IgH or TCR gene rearrangements provides molecular diagnosis of B- or T- lymphoma. We retrospectively evaluated molecular analyses of 213 cases with a clinical diagnosis of masquerade syndrome from 1998 to 2010. Using microdissection and PCR, 117 cases had IgH gene rearrangement, 7 cases had TCR gene rearrangement, and 89 cases were negative for these two gene arrangements. The molecular data confirmed the pathological diagnoses of PRL or uveitis. Cytokine levels in the vitreous were also measured in 103 of the 213 cases. A ratio of vitreous IL-10 to IL-6 greater than 1, suggesting PRL was found in 51/103 cases; 47/51 had the correct diagnosis. A ratio less than 1, suggesting uveitis was found in 52/103 cases; 37/52 confirmed the diagnosis. Moreover, the molecular data corresponded well with the clinical course of the diseases. The sensitivity and specificity of these molecular biomarker for the diagnosis of PRL are nearly 100%.

Type of Paper: Review
Title: Are Cerebrospinal Fluid Biomarkers Useful in Predicting the Prognosis of Multiple Sclerosis Patients?
Authors: Alberto Gajofatto, Matilde Bongianni, Maria Donata Benedetti and Salvatore Monaco
Affiliation: Department of Neurosciences, Sections of Clinical Neurology and Neuropathology, University of Verona, Verona, Italy;
E-Mail: salvatore.monaco@univr.it (S.M.)
Abstract: Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disorder of the central nervous system. Although many advances have been made in the comprehension of its pathogenesis, etiology is still unknown. The complexity of MS reflects in the extreme variability of the clinical course both between and within patients. Several prognostic factors have been suggested in large scale studies but predictions in the individual case are difficult to make. Cerebrospinal fluid (CSF) biomarkers, such as 14-3-3, tau, cystatin C and neurofilaments light protein, are promising sources of prognostic information with a good potential of quantitative measure, sensitivity, and reliability. However, none has showed sufficient reproducibility to be applied in the clinical practice. Here we review the current literature addressing the topic of CSF biomarkers as MS severity predictors.

Type of Paper: Article
Title: Cerebrospinal Fluid Markers in Creutzfeldt-Jakob Disease
Authors: Gianluigi Zanusso, Michele Fiorini, Sergio Ferrari, Alberto Gajofatto, Annachiara Cagnin and Salvatore Monaco
Affiliation: Department of Neurosciences, Sections of Neuropathology and Clinical Neurology, University of Verona, Verona, Italy;
E-Mail: salvatore.monaco@univr.it (S.M.)
Abstract: Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest form of human prion diseases, accounting for about 90% of all cases. Current criteria for intra vitam diagnosis, include a distinct phenotype, periodic sharp and slow-wave complexes at EEG, and a positive 14-3-3 protein assay in the cerebrospinal fluid (CSF). In sCJD, the disease phenotype may vary, depending upon the genotype at codon 129 of the PRNP, a site of a common methionine /valine polymorphism, and two distinct  conformers of the pathological prion protein. Based on the combination between these molecular determinants, six different sCJD subtypes are recognized, each with distinctive clinical and pathologic phenotypes. We analyzed CSF samples from 95 subjects with definite sCJD to assess the sensitivity, specificity, and positive predictive value of 14-3-3 protein, total tau protein, phosphorylated tau, and amyloid beta peptide 1-42, either alone or in combination. While 14-3-3 assay and tau protein were the most sensitive indicators of sCJD, the highest sensitivity, specificity and positive predictive value were obtained when all the above markers were combined. The latter approach also allowed a reliable differential diagnosis with other neurodegenerative dementias.

Type of Paper: Article
Title: A SVM Based Meta-Analytic Approach for Simultaneous Gene Selection and Case Prediction in Alzheimer's Disease
Authors: Qian You ¹, Meeta Pradhan ², Amirali Jazayeri ¹ and Samiran Ghosh ³
Affiliations: ¹ Department of Computer and Information Science, IUPUI, USA
² School of Informatics, IUPUI, USA
³ Department of Psychiatry and Biostatistics, Weill Cornell Medical College, USA; E-Mail: sag2025@med.cornell.edu
Abstract: Motivation: The discovery of biomarkers, as well as classifying subjects in proper disease group is a ubiquitous task in any bioinformatics research. Over the last decade there is an exponential growth in bioinformatics research and related publications. This is also prompted by the increasing usage of publicly available data sets. Unfortunately these studies are heterogeneous in terms of analyzed biological construct, technology used and overall database organization, such that they can hardly be put together to do a single and more powerful analysis. This type of multi-study analysis by combining several data sets is termed as “Meta-analysis” in the literature. In this paper we present a very general framework for combining several studies under L1-norm support vector machine (SVM) framework. Results: L1-norm SVM has the computational advantage over many other competing classification algorithms. It also inherits the automatic feature selection property owing to its absolute norm penalty. Proposed L1-norm SVM with the multi-study generalization is first elucidated via an extensive simulation study. A new voting based strategy for choosing the optimum value of the tuning parameters, as well as feature selection is also explored. Next we apply our algorithm for classification and biomarker selection in combining several studies related to Alzheimer’s disease (AD). Using the pathway analysis software Pathway Studio, we analyzed the biomarkers with respect to their pathways and their inferences in literature with AD. Our methodology is able to identify already established as well as few new pathways and biomarkers of AD. The combined data set preserve most of the top voted biomarkers from separate data sets. Also we reveal some new set of candidate biomarkers only discovered when combining several studies together using our approach.
Keywords: Alzheimer’s disease; biomarker; classification; feature selection; genomics; SVM

Title: Advances in Carcinogenic Metal Toxicity and Potential Molecular Markers
Authors: Preeyaporn Koedrith and Young Rok Seo
Affiliation: Department of Life Science, Dongguk University-Seoul, 26 Pil-dong 3-ga, Jung-gu, Seoul 100-715, Republic of Korea; E-Mail: seoyr@dongguk.edu
Abstract: Metal compounds like arsenic, cadmium, chromium, cobalt, lead, mercury, and nickel are classified as carcinogens affecting human health through occupational and environmental exposure. However, underlying mechanisms involved in tumor formation are not well clarified. Interference of metal homeostasis may result in oxidative stress which represents an imbalance between production of free radicals and a biological system’s ability to readily detoxify reactive intermediates. This event consequently causes DNA damage, lipid peroxidation, protein modification and possibly symptomatic effects for various diseases including cancer. This review discusses predominant modes of action and numerous molecular markers. Attention is paid on metal-induced generation of free radicals, their phenomenon of oxidative stress, damage to DNA, lipid, and proteins, responsive signal transduction pathways with major roles in cell growth and development, and roles of antioxidant enzymatic and DNA repair systems. Interaction of non-enzymatic antioxidants (carotenoids, flavonoids, glutathione, selenium, vitamin C, vitamin E, and others) with cellular oxidative stress markers (catalase, glutathione peroxidase, and superoxide dismutase) as well as certain regulatory factors, including AP-1, NF-κB, Ref-1, and p53 are also reviewed. Dysregulation of protective pathways, including cellular antioxidant network against adverse effects of free radicals as well as DNA repair deficiency are related to oncogenic stimulation. This provides evidence that emerging oxidative stress-responsive regulatory factors and DNA repair proteins as putative predictive factors for tumor initiation and progression and understanding of their processes might be implicated in development of novel anticancer agents.
Keywords: carcinogenicity; DNA damage; DNA repair; genotoxicity; heavy metal; oxidative stress