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Concentrating on molecular biomarkers in cancer research, Cancer Biomarkers publishes original research findings (and reviews solicited by the editor) on the subject of the identification of markers associated with the disease processes whether or not they are an integral part of the pathological lesion.
The disease markers may include, but are not limited to, genomic, epigenomic, proteomics, cellular and morphologic, and genetic factors predisposing to the disease or indicating the occurrence of the disease. Manuscripts on these factors or biomarkers, either in altered forms, abnormal concentrations or with abnormal tissue distribution leading to disease causation will be accepted.
Article Type: Editorial
DOI: 10.3233/CBM-2005-1101
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 1-2, 2005
Authors: Dixit, Rakesh | Srivastava, Sudhir
Article Type: Editorial
DOI: 10.3233/CBM-2005-1102
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 3-4, 2005
Authors: Groopman, John D. | Johnson, Denise | Kensler, Thomas W.
Article Type: Research Article
Abstract: The use of biomarkers in molecular epidemiology studies for identifying stages in the progression of development of the health effects of environmental agents has the potential for providing important information for critical regulatory, clinical and public health problems. Investigations of aflatoxins probably represents one of the most extensive data sets in the field and this work may serve as a template for future studies of other environmental agents. The aflatoxins are naturally occurring mycotoxins found on foods such as corn, peanuts, various other nuts and cottonseed and they have been demonstrated to be carcinogenic in many experimental models. As a …result of nearly thirty years of study, experimental data and epidemiological studies in human populations, aflatoxin B1 was classified as carcinogenic to humans by the International Agency for Research on Cancer. The long-term goal of the research described herein is the application of biomarkers to the development of preventative interventions for use in human populations at high-risk for cancer. Several of the aflatoxin specific biomarkers have been validated in epidemiological studies and are now being used as intermediate biomarkers in prevention studies. The development of these aflatoxin biomarkers has been based upon the knowledge of the biochemistry and toxicology of aflatoxins gleaned from both experimental and human studies. These biomarkers have subsequently been utilised in experimental models to provide data on the modulation of these markers under different situations of disease risk. This systematic approach provides encouragement for preventive interventions and should serve as a template for the development, validation and application of other chemical-specific biomarkers to cancer or other chronic diseases. This systematic approach provides encouragement for preventive interventions and should serve as a template for the development, validation and application of other chemical-specific biomarkers to cancer or other chronic diseases. Show more
DOI: 10.3233/CBM-2005-1103
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 5-14, 2005
Authors: Brott, D.A. | Jones, H.B. | Gould, S. | Valentin, J.P. | Evans, G. | Richardson, R.J. | Louden, C.
Article Type: Research Article
Abstract: Recently, there has been an increased incidence of vascular toxicity in pre-clinical toxicology studies. This is of concern because of the uncertain relevance and extrapolation of this finding to humans. In dogs, profound heart rate (HR) and mean arterial pressure (MAP) changes were considered surrogate markers for drug-induced vascular injury until the early 1990s when endothelin receptor antagonists (ETRA) did not significantly alter HR or MAP but induced identical lesions in the coronary arteries of dogs. Thus significant alterations in HR and MAP were found not to be a prerequisite for this lesion. Clinically, the potential for vascular injury coupled …with the lack of an unequivocal non-invasive diagnostic marker is an issue of concern to pharmaceutical companies and the regulatory authorities. Therefore, qualification and validation of biomarkers as diagnostic tools for drug-induced vascular injury would add great value to risk management and expedite the drug development process. This review focuses on the status, progress and future trends in vascular biology aimed at identification and development of diagnostic markers that are specific, sensitive and possess potential utility in both a pre-clinical and clinical setting. Show more
DOI: 10.3233/CBM-2005-1104
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 15-28, 2005
Authors: Lacour, Sandrine | Gautier, Jean-Charles | Pallardy, Marc | Roberts, Ruth
Article Type: Research Article
Abstract: Several important drug classes show pre-clinical hepatotoxicity or, in some cases hepatotoxicity in man in Phase III/IV not predicted by pre-clinical studies. This hepatotoxicity is associated with death of the parenchyma by both necrosis and apoptosis. Recent data have implicated molecular mediators of the immune response such as tumor necrosis factor α (TNFα), interleukin 1β(1L-1β) and interleukin 6 (IL6) in acute and chronic liver damage. These cytokines networks have been implicated in mediating the hepatic response to xenobiotics as diverse as PPAR ligands, acetaminophen and phenobarbitone. Thus, pro-inflammatory cytokines such as TNFα, IL1 β and IL6 are released into the …bloodstream both from the liver and from distal sites during hepatic toxic injury. Probably due to differences in the responses of rodent and human hepatocytes to cytokines, some clinical hepatotoxicities are not predicted by rodent models. However, the cytokine changes implicated in this human hepatic cell death could be manifest in rodent models and thus could be detected at the molecular level. Here we review the role of cytokines in different types of drug-induced liver injury and discuss whether these cytokine fingerprints are potential biomarkers of so-called idiosyncratic human liver toxicity. Show more
Keywords: drugs, hepatotoxicity, cytokines, biomarkers, inflammatory reaction
DOI: 10.3233/CBM-2005-1105
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 29-39, 2005
Authors: Heijne, Wilbert H.M. | Stierum, Rob H. | Leeman, Winfried R. | van Ommen, Ben
Article Type: Research Article
DOI: 10.3233/CBM-2005-1106
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 41-57, 2005
Authors: Betton, Graham R. | Kenne, Kerstin | Somers, Rebecca | Marr, Andrew
Article Type: Research Article
Abstract: Biomarkers of nephrotoxicity range from plasma and urine biochemistry, enzymic assays for brush border and lysosomal markers plus new protein markers by immunoassay. Because of the complexity of the nephron and regional sensitivity to xenobiotics, it is important to co-localise sites of marker release with pathological lesions. Han Wistar rats were treated p.o.for up to 14 days with compounds causing selective nephrotoxicity. Compounds used were cyclosporin A ,a signal transduction inhibitor and N-phenylanthranylic acid (NPAA). Plasma and urine was collected for biochemistry and urinalysis (including proteomics and metabonomics) and at termination kidneys were fixed for standard H&E pathology …and immunohistochemistry examinations for D28 k calbindin, calmodulin, phospho-erk, Cox 1, Cox 2 and other markers. Cyclosporin A treatment caused injury to the thick ascending limb (TAL) of the nephron and was associated with a down-regulation of calbindin protein expression in cortical distal tubules (mean score 75% reduction) and TALs (21% reduction). Inhibition of signal transduction used p-erk as a downstream marker of activity. P-erk was highly expressed in the collecting ducts and inhibition of signalling caused a 39% reduction in IHC score. There was no evidence of direct renal injury by there was a hypercalcaemia (9% increase) and hyperphosphataemia (24% increase) at 24 hrs post-dose and metastatic calcification by 7 days. NPAA treatment caused renal papillary necrosis in some treated rats (sometimes unilateral) with some secondary dilation of distal tubules. Unlike NSAID treatment, there was no evidence of Cox 1 or 2 dysregulation on IHC and the Cox1 positive interstitial cells did not loose integrity before the onset of necrosis. There were a number of urinary proteomic and metabonomic alterations which are being characterised. The 3 model nephrotoxicants studied demonstrated the linkage of protein expression on IHC to nephron segment-specific sites as important for urinary biomarker validation and linkage to mechanisms. Show more
DOI: 10.3233/CBM-2005-1107
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 59-67, 2005
Authors: Shaw, Martin
Article Type: Research Article
Abstract: Failure of drug candidates late in development is very expensive. This can be reduced by using more specific biomarkers of effect and toxicity during the preclinical and development testing. However, traditional toxicity tests have not been developed to study toxicology and so may lack sufficient sensitivity and specificity hence the search for new biomarkers using the many “–omics” technologies. Important aspects of useful biomarkers are that their origin is known and localised so that one knows what is being observed. Furthermore, biomarkers with a localised origin are less likely to be subject to background variation and have a wider dynamic …range. This paper will discuss how using biomarkers with a known cellular origin, toxic effects can be found earlier and at lower doses of compound. Show more
Keywords: glutathione S-transferase, GST, hepatotoxicity, nephrotoxicity, diabetes, renal papillary necrosis, acetaminophen, paracetamol, methotrexate, biomarkers
DOI: 10.3233/CBM-2005-1108
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 69-74, 2005
Authors: Stewart, Jane | Turner, Katie J.
Article Type: Research Article
Abstract: Inhibin B is a glycoprotein produced predominantly by Sertoli cells which regulates pituitary FSH release by a negative feedback loop. The regulation of inhibin B is complex with changes in the pattern of secretion occurring during development, and many factors such as FSH, testosterone, Sertoli cell proliferation and germ cell complement likely to contribute to overall production. Systemic inhibin B concentrations seem to reflect the extreme ends of spermatogenic status with high levels of inhibin B observed in normal, fertile individuals and lower levels of inhibin B in individuals with severe damage to the testis as a result of germ …cell depletion. Inhibin B has proved valuable in epidemiological studies exploring male infertility with data showing that inhibin B combined with FSH measurements has a higher positive predictive value for detecting male infertility than either alone. Inhibin B is proposed as a potential biomarker of testicular toxicity in rodent toxicity studies to compliment traditional endpoints. In pharmaceutical development, inhibin B might allow better linkage between animal study results and subsequent monitoring of testicular function in clinical trials. An international, intercompany project has been initiated to evaluate the overall suitability and limitations of inhibin B as a biomarker of testicular toxicity. Show more
DOI: 10.3233/CBM-2005-1109
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 75-91, 2005
Authors: Rockett, John C. | Kim, Sung J.
Article Type: Research Article
Abstract: A biomarker can be broadly defined as any biological index capable of being measured, which is associated with or indicative of a defined biological endpoint such as a developmental or disease stage. Identification and verification of anatomical, endocrine, cellular and molecular biomarkers is crucial for successful clinical diagnosis and treatment of toxicity and disease, as well as basic toxicological, epidemiological and other research. Various biomarkers of reproductive development and health have been identified, including those associated with pubertal development, adult reproductive health and pregnancy outcome. Herein we discuss those in situ biomarkers which have been more closely associated with toxicant …action on the reproductive system. Biomarkers of toxicant exposure and susceptibility are addressed, but the majority of the review focuses on those biomarkers which may prove useful for determining current pathophysiological status or predicting future adverse outcomes. In males these are primarily associated with altered spermatogenesis and sperm parameters, and in females with altered endocrine function. We conclude that although few robust in situ biomarkers are currently available which are specific for toxicant exposure, susceptibility or effect in reproductive systems, there is expectation that post-genomic technologies offer a new paradigm for identifying and verifying such biomarkers as may exist. Show more
DOI: 10.3233/CBM-2005-1110
Citation: Cancer Biomarkers, vol. 1, no. 1, pp. 93-108, 2005
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