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At least 757 records · Page 42Linked to original sources
PubMed2005

Mass spectrometry-based expression profiling of clinical prostate cancer.

The maturation of MS technologies has provided a rich opportunity to interrogate protein expression patterns in normal and disease states by applying expression protein profiling methods. Major goals of this research strategy include the identification of protein biomarkers that demarcate normal and disease populations, and the identification of therapeutic biomarkers for the treatment of diseases such as cancer (Celis, J. E., and Gromov, P. (2003) Proteomics in translational cancer research: Toward an integrated approach. Cancer Cell 3, 9-151). Prostate cancer is one disease that would greatly benefit from implementing MS-based expression profiling methods because of the need to stratify the disease based on molecular markers. In this review, we will summarize the current MS-based methods to identify and validate biomarkers in human prostate cancer. Lastly, we propose a reverse proteomic approach implementing a quantitative MS research strategy to identify and quantify biomarkers implicated in prostate cancer development. With this approach, the absolute levels of prostate cancer biomarkers will be identified and quantified in normal and diseased samples by measuring the levels of native peptide biomarkers in relation to a chemically identical but isotopically labeled reference peptide. Ultimately, a centralized prostate cancer peptide biomarker expression database could function as a repository for the identification, quantification, and validation of protein biomarker(s) during prostate cancer progression in men.

Biomarkers, Tumor↗
PubMed1995

Biomarkers used for the assessment of health hazards in populations living in the vicinity of communal and industrial waste dump sites.

The measure of individual hazard from exposure to environmental toxicants are the biomarkers which are indices of abnormalities within different biological systems that may be induced by hazardous agents of various chemical or biological nature. The biomarkers make it possible to "monitor" the processes within the organism from the moment of toxic agent penetration to the development of clinical symptoms. Biomarkers offer the possibility of early detection of phenomena which tend to be arranged in the sequence of pathogenic changes, usually not detectable by the conventional methods. Depending on the type of processes which accompany the effect of a specified harmful environmental agent on the human organism it may be determined with the aid of the biomarkers, which are then classified as exposure, health effect, and individual susceptibility. By integrating such concepts as exposure, health effect, and individual susceptibility, enhanced analysis of the problem of health risk in people exposed to environmental toxic agents has become possible.

Biomarkers↗
PubMed2026

Multimodal alignment improves generalizability of genomic biomarker prediction in computational pathology.

Computational pathology models that use digitized histopathology whole-slide images have the potential to become a cost-effective and scalable alternative to molecular assays for the prediction of genomic biomarkers, a key task in precision oncology. However, as new genomic biomarkers are discovered or quantified, large, labeled datasets must be prospectively collected to train new models. To address this challenge, we developed multimodal alignment for biomarker learning and generalization (MARBLE), a multimodal contrastive pretraining strategy that integrates structured biomarker knowledge into representation learning of histopathology images. MARBLE aligns histopathology-derived representations with representations of genomic biomarkers generated by a large language model (LLM) and a protein language model (PLM). This biologically informed alignment enables data-efficient generalization to novel, out-of-distribution biomarkers. Using the MSK-IMPACT cohort of over 40,000 patients across multiple biomarker panel versions, we design experiments grounded in real-world data to demonstrate the value of our proposed approach.

CP: computational biology↗
PubMed1998

Non-invasive detection of fecal protein kinase C betaII and zeta messenger RNA: putative biomarkers for colon cancer.

We have developed a non-invasive method utilizing feces, containing sloughed colonocytes, as a sensitive technique for detecting diagnostic colonic biomarkers. In this study, we used the rat colon carcinogenesis model to determine if changes in fecal protein kinase C (PKC) expression have predictive value in monitoring the neoplastic process. Weanling rats were injected with saline or azoxymethane (AOM) and 36 weeks later fecal samples and mucosa were collected, poly A+ RNA isolated, and quantitative RT-PCR performed using primers to PKC betaII and zeta. Fecal PKC betaII and zeta mRNA levels were altered by the presence of a tumor, with tumor-bearing animals having a 3-fold higher (P < 0.05) PKC betaII expression as compared with animals without tumors. In addition, AOM-injection increased mucosal PKC betaII mRNA expression compared with saline controls. No effect of tumor incidence on mucosal PKC betaII expression was observed. In contrast, fecal PKC zeta expression was 2.5-fold lower (P < 0.05) in animals injected with azoxymethane versus saline. Since tumor incidence exerts a reciprocal effect on fecal PKC betaII and zeta mRNA expression, data were also expressed as the ratio between PKC betaII and zeta. The isozyme ratio was strongly related to tumor incidence, i.e. ratio for animals with tumors was 2.18 +/- 1.25, animals without tumors was 0.50 +/- 0.16, P = 0.025. We demonstrate that the expression of fecal PKC betaII and zeta may serve as a noninvasive marker for development of colon tumors. A sensitive technique for the detection of colon cancer is of importance since early diagnosis can substantially reduce mortality.

Animals↗
PubMed1995

Biochemical markers of neurotoxicity: research strategies and epidemiological applications.

A great deal of attention has been given in the past few years to the development and validation of biomarkers for non-cancer endpoints, to be used in human epidemiological studies. In this research, as they apply to the field of neurotoxicology, will be discussed. As biomarkers are often divided into indicators of exposure, effect and susceptibility, one example for each of these classes is presented. Measurements of hemoglobin adducts were developed as a way to monitor exposure to acrylamide (a peripheral neurotoxicant) in animals as well as humans, and have been successfully applied in a field study in occupationally exposed workers. Activity of monoamine oxidase B (MAO-B) in platelets was found to be inversely correlated with the levels of exposure to styrene, suggesting that this biochemical measurement may be a useful effect-related biomarker, though additional studies are needed to understand the mechanistic implications of these findings. Serum paraoxonase activity has been shown in animals to modulate the toxicity of organophosphorus insecticides. Studies in humans have lead to the identification of a genetic polymorphism for this enzyme and to define its underlying molecular basis. Epidemiological studies are needed to determine the relevance of this polymorphism in determining susceptibility to organophosphate toxicity.

Biomarkers↗
PubMed2006

Translational research in the pharmaceutical industry: from bench to bedside.

Current developments in basic discovery sciences have not been mirrored by the same level of progress in understanding the clinical basis of disease and ultimately the development of novel effective therapies. This can be improved by applying translational research throughout the late-stage discovery and exploratory development stages of drug development. A bi-directional dialogue between research scientists and clinicians concerning the biology of mechanism of action and clinical basis for disease will deliver biomarkers that enable drug development decisions to be made earlier and with increased confidence. Thus, we can better exploit the many targets that have been discovered through the mapping of the genome and other breakthroughs in medical sciences, such as the polyomic technologies.

Animals↗
PubMed2006

Microarrays as validation strategies in clinical samples: tissue and protein microarrays.

The widespread use of DNA microarrays has led to the discovery of many genes whose expression profile may have significant clinical relevance. The translation of this data to the bedside requires that gene expression be validated as protein expression, and that annotated clinical samples be available for correlative and quantitative studies to assess clinical context and usefulness of putative biomarkers. We review two microarray platforms developed to facilitate the clinical validation of candidate biomarkers: tissue microarrays and reverse-phase protein microarrays. Tissue microarrays are arrays of core biopsies obtained from paraffin-embedded tissues, which can be assayed for histologically-specific protein expression by immunohistochemistry. Reverse-phase protein microarrays consist of arrays of cell lysates or, more recently, plasma or serum samples, which can be assayed for protein quantity and for the presence of post-translational modifications such as phosphorylation. Although these platforms are limited by the availability of validated antibodies, both enable the preservation of precious clinical samples as well as experimental standardization in a high-throughput manner proper to microarray technologies. While tissue microarrays are rapidly becoming a mainstay of translational research, reverse-phase protein microarrays require further technical refinements and validation prior to their widespread adoption by research laboratories.

Animals↗
PubMed1993

The Malmo Diet and Cancer Study. Design and feasibility.

The Malmö Diet and Cancer study is a 10-year prospective case-control study in 45-64-year-old men and women (n = 53,000) living in a city with 230,000 inhabitants. One objective is to clarify whether a western diet is associated with certain forms of cancer whilst taking other life-style factors into account. Another broad question is whether oxidative stress and the activity in DNA-repairing systems influence the impact of diet on the development of all or certain forms of cancer. The study is also to act as a resource available for testing new hypotheses emanating from other studies. Initially food intake, heredity, socio-economic factors, life-style pattern, occupational situation, previous and current diseases, symptoms and medications, will be determined. Viable lymphocytes, granulocytes, erythrocytes, and plasma/serum will be stored in a biological bank together with tumour specimens gathered from cases. The incidence and mortality of all cancer forms will then be followed for 10 years by existing registries. Data from the initial examination in these cases will then be compared with those of control subjects not having developed any form of cancer. A biomarker programme, utilizing the biological bank, has been developed and is aimed at finding predictors and/or precursors of cancer. A high participation rate (> 70%) and a high quality biological bank are prerequisites for a successful project. The experience gathered so far indicates that these goals are feasible.

Adult↗
PubMed2006

Multichannel reverse transcription-polymerase chain reaction microdevice for rapid gene expression and biomarker analysis.

A microdevice is developed for RNA analysis that integrates one-step reverse transcription and 30 cycles of PCR (RT-PCR) amplification with capillary electrophoresis (CE) separation and fluorescence detection of the amplicons. The four-layer glass-PDMS-glass-glass hybrid microdevice integrates microvalves, on-chip heaters and temperature sensors, nanoliter reaction chambers (380 nL), and 5-cm-long CE separation channels. The direct integration of these processes results in attomolar detection sensitivity (<11 template RNA molecules or approximately 0.1 cellular equiv) and rapid 45-min analysis, while minimizing sample waste and eliminating contamination. Size-based electrophoretic product analysis provides definitive amplicon-size verification and multiplex analysis. Multiplexed differential gene expression analysis is demonstrated on mdh and gyrB E. coli transcripts. RNA splice variant analysis of the RBBP8 gene is used to identify tumorigenic tissue. RT-PCR microdevice analysis of normal breast tissue RNA generates the expected 202-bp normal splice isoform; tumor breast tissue RNA samples generate a 151-bp amplicon signifying the presence of the tumorigenic splice variant. The ability to perform RNA transcript and splice variant biomarker analysis establishes our RT-PCR microdevice as a versatile gene expression platform.

Biomarkers, Tumor↗
PubMed2002

Effect of budesonide on the methylation and mRNA expression of the insulin-like growth factor 2 and c-myc genes in mouse lung tumors.

The use of surrogate end-point biomarkers could help in the development of chemopreventive agents. To define potential surrogate end-point biomarkers, the ability of budesonide to decrease mRNA expression of the insulin-like growth factor-2 (Igf-II) and c-myc genes and to cause the remethylation of the genes was investigated in lung tumors. Lung tumors were induced in female strain A mice by administering i.p. 16 mg/kg vinyl carbamate for 2 consecutive wk or by a single dose of 100 mg/kg benzo[a]pyrene (B[a]P). Thirty-four weeks later, the mice given vinyl carbamate received budesonide (0.6 or 2.4 mg/kg diet) for 7 d and then were killed. Mice were killed 24 wk after administration of B[a]P. The mRNA expression of the Igf-II and c-myc genes was increased in lung tumors relative to normal lung tissue. Budesonide decreased mRNA expression of both genes in tumors. The methylation status of 27 CpG sites in the differentially methylated region 2 in the Igf-II gene was determined with the bisulfite-treated DNA-sequencing procedure. The numbers of methylated CpG sites were 17-21 in normal lung (70.4 +/- 2.6%); 0-2, and 1-2 in lung tumors induced by vinyl carbamate and B[a]P (4.9 +/- 1.2% and 4.6 +/- 1.2%, respectively); and 4-5 or 7-16 in tumors after treatment with 0.6 or 2.4 mg/kg budesonide (16.0 +/- 1.2% and 46.2 +/- 5.1%, respectively). Thus, lung tumors had strikingly less methylated CpG sites than normal lung tissue, while even limited treatment with budesonide resulted in remethylation of the CpG sites in tumors. With HpaII digestion followed by Southern blot analysis, the internal cytosine of CCGG sites in the c-myc gene was found to be methylated in normal lung tissue, whereas some of the sites were unmethylated in lung tumors. Treatment for 7 d with budesonide resulted in the remethylation of these sites. In conclusion, mouse lung tumors showed decreased methylation of the Igf-II and c-myc genes that was associated with increased expression of these genes. Budesonide treatment caused remethylation and decreased expression of both genes. The results support the possibility of using decreased mRNA expression and remethylation of the Igf-II and c-myc genes as biomarkers for the efficacy of budesonide.

Adenocarcinoma↗
PubMed2005

Nicotinamide in relation to dietary nicotinic acid and nine other vitamins and larval development of Ceratitis capitata (Diptera: Tephritidae).

This study was undertaken to understand why Ceratitis capitata larvae reared on a diet fortified with nine vitamins except nicotinic acid had 100% mortality, while those reared on a 10-vitamin-free diet had 66% survival (Chang, C. L.; Li, Q. X. Ann. Entomol. Soc. Am. 2004, 97, 536-540). Our results showed that nicotinamide was detected at a level of 0.07 microg/g in second-instar larvae reared on the 10-vitamin-free diet and 0.30 microg/g in the corresponding spent diet, while it was not detected in either the larvae reared on the diet fortified with 707 microg/g of nine vitamins (nicotinic acid absent) or the corresponding spent diet. Nicotinamide was detected at concentrations of 0.13 and 0.15 microg/g in the larvae fed the diets that were fortified with 707 microg/g of nine other vitamins and 2 and 20 microg/g of nicotinic acid, respectively, but it was not found in the larvae fed the 0.2 microg/g of nicotinic acid diet. Nicotinamide was detected at concentrations of 0.44, 0.52, and 0.55 microg/g in the spent diets that were fortified with the nine vitamins (707 microg/g) and 0.2, 2, and 20 microg/g of nicotinic acid, respectively. Nicotinamide adenine dinucleotide (NAD) was in the live larvae, but not in the dead larvae. These findings indicate that dietary nicotinic acid is converted to nicotinamide, which, in turn, is used to synthesize NAD, and suggest a positive relationship between C. capitata larvae survival rates and concentrations of dietary nicotinic acid and nitcotinamide in the larvae as well as in the spent diets. The result shows that nicotinamide derived from supplemental nicotinic acid is essential for the development and survival of C. capitata larvae. Nicotinamide may be a biomarker for larval survival and development.

Animals↗
PubMed2005

Chemoprevention of melanoma: theoretical and practical considerations.

BACKGROUND: Chemoprevention refers to the use of agents to reverse, suppress, or prevent carcinogenic progression of cancer. The use of chemoprevention is an unexplored strategy in melanoma prevention. METHODS: A retrospective review of the literature was undertaken regarding the important elements in evaluating chemoprevention as a strategy in melanoma. RESULTS: Several considerations need to be addressed before a chemoprevention agent can be moved to a large randomized trial. Statins have both experimental and epidemiologic evidence to support their further development as candidate chemopreventive agents, but the evidence is insufficient to justify large-scale phase III studies. A strong scientific rationale, a systematic approach to chemoprevention agent development with rigorous chemoprevention designs, and careful selection of surrogate endpoint biomarkers are critical issues in developing a chemoprevention strategy. CONCLUSIONS: Addressing these relevant considerations will allow for the development of chemoprevention in melanoma.

Chemoprevention↗
PubMed2006

Bayesian detection of abnormal values in longitudinal biomarkers with an application to T/E ratio.

We developed a test that compares sequential measurements of a biomarker against previous readings performed on the same individual. A probability mass function expresses prior information on interindividual variations of intraindividual parameters. Then, the model progressively integrates new readings to more accurately quantify the characteristics of the individual. This Bayesian framework generalizes the two main approaches currently used in forensic toxicology for the detection of abnormal values of a biomarker. The specificity is independent of the number n of previous test results, with a model that gradually evolves from population-derived limits when n = 0 to individual-based cutoff thresholds when n is large. We applied this model to detect abnormal values in an athlete's steroid profile characterized by the testosterone over epitestosterone (T/E) marker. A cross-validation procedure was used for the estimation of prior densities as well as model validation. The heightened sensitivity/specificity relation obtained on a large data set shows that longitudinal monitoring of an athlete's steroid profile may be used efficiently to detect the abuse of testosterone and its precursors in sports. Mild assumptions make the model interesting for other areas of forensic toxicology.

Bayes Theorem↗
PubMed1996

Human metallothionein gene expression determined by quantitative reverse transcription-polymerase chain reaction as a biomarker of cadmium exposure.

Expression of the metallothionein (MT) gene in frozen human lymphocytes has been developed as a new molecular biomarker of heavy metal exposure. Workers at a Polish battery factory with high exposure to cadmium were monitored for airborne exposure and blood cadmium levels. A novel quantitative reverse transcription-PCR (RT-PCR) technique, making use of a homologous internal standard, was used to assess the level of MT-specific mRNA in frozen stored aliquots of blood samples taken from exposed and control workers. Results from this assay showed a statistically significant 2.5-fold increase in MT mRNA in exposed compared to control workers. The RT-PCR results also showed significant correlation with airborne cadmium, as registered on personal monitors and with blood cadmium levels. The results suggest that gene induction measured by quantitative RT-PCR is a promising approach for application as a biomarker of biologically effective dose in small samples of frozen tissues or cells.

Base Sequence↗
PubMed1997

DNA damage as an intermediate biomarker in intervention studies.

The development of sensitive assays for measurement of DNA damage in humans has great potential for enhancing intervention studies. Methods for DNA adduct measurement include immunoassays, [32p] postlabeling, high-performance liquid chromatography with fluorescence or electrochemical detection, and gas chromatography/mass spectroscopy. It is now well established that DNA adducts are a marker of exposure to various environmental, lifestyle, or occupational chemical carcinogens. Our own studies concentrate on immunologic detection of adducts by enzyme-linked immunosorbent assay (ELISA) of isolated DNA or quantitative immunohistochemical analysis of intact cells. Polycyclic aromatic hydrocarbon (PAH)-DNA adducts are elevated in blood cells of foundry and coke oven workers, individuals with high levels of exposure to environmental air pollution, and smokers. The study in smokers also found an inverse relationship between serum antioxidants and PAH-DNA, and is the basis for an ongoing antioxidant intervention. DNA adducts of PAH and 4-aminobiphenyl and oxidative DNA damage (8-oxo-deoxyguanosine) are being measured in blood mononuclear cells and exfoliated oral and bladder cells from subjects on antioxidants or placebo. Data on published intervention studies investigating oxidative damage and general aromatic DNA adducts measured by postlabeling are also summarized. These studies have already demonstrated that DNA adducts can be modulated by interventions and suggest that they can provide important mechanistic information in support of larger scale studies.

Animals↗
PubMed2025

Real-world deployment of a fine-tuned pathology foundation model for lung cancer biomarker detection.

Artificial intelligence models using digital histopathology slides stained with hematoxylin and eosin offer promising, tissue-preserving diagnostic tools for patients with cancer. Despite their advantages, their clinical utility in real-world settings remains unproven. Assessing EGFR mutations in lung adenocarcinoma demands rapid, accurate and cost-effective tests that preserve tissue for genomic sequencing. PCR-based assays provide rapid results but with reduced accuracy compared with next-generation sequencing and require additional tissue. Computational biomarkers leveraging modern foundation models can address these limitations. Here we assembled a large international clinical dataset of digital lung adenocarcinoma slides (N&#x2009;=&#x2009;8,461) to develop a computational EGFR biomarker. Our model fine-tunes an open-source foundation model, improving task-specific performance with out-of-center generalization and clinical-grade accuracy on primary and metastatic specimens (mean area under the curve: internal 0.847, external 0.870). To evaluate real-world clinical translation, we conducted a prospective silent trial of the biomarker on primary samples, achieving an area under the curve of 0.890. The artificial-intelligence-assisted workflow reduced the number of rapid molecular tests needed by up to 43% while maintaining the current clinical standard performance. Our retrospective and prospective analyses demonstrate the real-world clinical utility of a computational pathology biomarker.

Humans↗