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PubMed1998

Microsatellite instability associated with primary head and neck cancers and secondary esophageal cancers.

BACKGROUND: It is common that patients with head and neck cancers have secondary malignant neoplasm of esophageal cancer. METHODS: To know the genetic background of the development of these secondary cancers, we performed microsatellite assay at six loci and immunohistochemical analysis on head and neck cancers of eight patients with esophageal cancer and on those of 19 patients without esophageal cancer. RESULTS: Replication error (RER) at more than two loci was observed in two (25%) of eight double cancer patients, whereas it was not observed in the patients without the secondary cancer. Immunohistochemically, overexpression of cyclin D1 was detected in two (25%) of eight double cancer cases and in two (11%) of 19 non-double cancer cases, respectively, the incidence showing a higher tendency in the former. CONCLUSIONS: The results suggest that microsatellite instability may be implicated in the development of head and neck double cancers and that RER (+) phenotype may serve as a biomarker to predict the development of secondary esophageal cancer in patients with head and neck cancer.

Adult↗
PubMed2004

Genotypic and phenotypic biomarker profiles for individual risk assessment and cancer detection (lessons from bladder cancer risk assessment in symptomatic patients and workers exposed to benzidine).

There is a need for improved methods for detecting individuals at risk for cancer to target subsets of patients for more intensive individual screening and targeted cancer therapy and chemoprevention. One approach for accomplishing this objective is to detect premalignant molecular fingerprints in an organ at risk for cancer or to define biomarkers reflective of treatment selection and response. Bladder cancer is an excellent model for testing this approach; however, comprehending the strategy for biomarker selection and analysis is more complicated than is generally appreciated. The objective of this article is to provide a succinct overview of our experience with the selection of biomarkers for bladder cancer detection, first in symptomatic patients and then in high-risk cohorts of workers at risk for bladder cancer. Biomarker selection depends on multiple parameters, each of which must be optimized to enhance the utility of a biomarker for clinical application. Many markers that initially show promise fail in the clinical arena for a variety of reasons. Important parameters include when a biomarker is expressed in carcinogenesis (i.e., early vs. late), the sample type, and the method of analysis. These all contribute to the sensitivity, specificity, and ultimate clinical utility of a biomarker. New technologies/ support the notion that all diseases start in the cell, and Seymore West indicated the cell, under appropriate conditions, can function as a microcuvette for biophysical cytochemical analysis. Spectroscopy provides an accurate and sensitive method for quantitative single-cell proteomics. Improved and more stable fluorescence probes will enhance the utility of cellular chemistry, as will a rationale approach for biomarker selection based on the concepts of field cancerization, complemented by improved quantitative analysis of protein markers at the single-cell level. Our laboratory has developed a platform for single-cell proteomic analysis that can be applied to multiple basic science and clinical problems. Single-cell proteomics also facilitates the study of genetic instability and epigenetic signaling (stromal-epithelial interactions) in relation to cancer therapy and diagnosis. Because most cancers arise through multiple signaling pathways and are heterogeneous, the identification of appropriate biomarker profiles provides a number of strategic advantages over a single biomarker. Complex networks of signaling pathways lead to increased cell proliferation, decreased cell adhesion, cellular differentiation, genetic instability, and other functions associated with the malignant phenotype. The purpose of this presentation is to illustrate the fundamental concepts for selection and profile analysis of high-level phenotypic biomarkers developed for bladder cancer risk assessment, screening, and early bladder cancer detection.

Benzidines↗
PubMed2005

COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMT(L)) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia.

Adolescent↗
PubMed2004

The application of histo-cytopathological biomarkers in marine pollution monitoring: a review.

During the past two decades, a variety of histopathological alterations in fish and bivalves have been developed and used as biomarkers in pollution monitoring. Some of these have been successfully adopted in major national monitoring programmes, while others, although show promise, are still in the experimental stage. This paper critically reviews the scientific basis, cause and effect relationship, reliability, advantages and limitations of 14 histo-cytopathological biomarkers. The usefulness and practical application of each biomarker have been evaluated against a number of objective criteria including: ecological relevance, sensitivity, specificity, dose-response relationship, confounding factors, technical difficulties and cost-effectiveness.

Animals↗
PubMed2025

Ferroptosis in Oral Cancer: Mechanistic Insights and Clinical Prospects.

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management.

Humans↗
PubMed2001

Development of difluoromethyl-ornithine and Bowman-Birk inhibitor as chemopreventive agents by assessment of relevant biomarker modulation: some lessons learned.

A major goal in the development of chemopreventive agents has been to develop markers that reflect the underlying process of carcinogenesis and which are modulatable by the agent under study. An important application of such markers will be to select cohorts that are at elevated risk for cancer development, which should allow use of smaller sample sizes in definitive phase III trials as well as shorter duration (and lower cost), without loss of statistical power. Susceptibility and surrogate end-point biomarkers are particularly important in this respect. Intermediate markers are probably best assessed in terms of proportionate rather than relative risk. The systematic development of difluoromethylornithine for use in chemoprevention against human cancer has involved pilot, phase IIa and IIb trials using participants with prior colonic polyps as the study group. A unique feature of the phase IIa study was the use of a dose de-escalation design which allowed selection of the lowest effective non-toxic dose of difluoromethylornithine. The phase IIb trial now in progress is using a combination of sulindac with difluoromethylornithine; the rationale for selection of markers for this study and for a randomized phase III registration trial is discussed. We also review the findings in phase I and IIa trials of Bowman-Birk inhibitor concentrate, in which patients with measurable oral leukoplakia are the study group.

Antineoplastic Agents↗
PubMedDate not supplied

Study design and data analysis in clinical and environmental models of nephrotoxicity.

Protocols for clinical studies of nephrotoxicity may include several elements. They include background information, study objectives, study design, data handling and analysis, organization and administration, and methods and definitions. Response variables used to indicate the development of clinically apparent renal disease should be clearly defined. Susceptibility factors such as diabetes, hypertension, cardiovascular disease, obesity, smoking history, and genetic factors may influence the development of renal disease and other health outcomes. These factors may also affect the pattern of abnormal biomarkers that appear during the development of renal disease. Some individuals who are normal by standard clinical criteria will be in various stages of disease development and will have abnormal biomarker levels. With all approaches, an adequate baseline assessment of biomarker values is critically important. Consistent findings among studies reinforce conclusions.

Biomarkers↗
PubMed2001

Executive Summary of the National Cancer Institute Workshop: Highlights and recommendations.

Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies. Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents (eg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens) in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group (PRG) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI, the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRG report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that can serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs.

Anticarcinogenic Agents↗
PubMed2005

The local hormonal environment and related biomarkers in the normal breast.

Recent developments in breast epithelial sampling techniques (nipple fluid aspiration, ductal lavage, and random fine needle aspiration) provide new opportunities for the acquisition of hormonal and cellular biomarker data in asymptomatic women, and thereby the possibility of developing a unified vision of how the hormonal environment of the breast may interact with the cellular expression of proteins, and with other evolving candidate markers of breast cancer risk. The purpose of this review is to integrate available information regarding cellular and breast fluid biomarkers of hormone action on the breast, to identify candidate biomarkers for studies of breast cancer risk and prevention. These include the estrogen receptors alpha and beta, markers of proliferative and apoptotic response, and protein markers of estrogen action in breast cells and nipple fluid. Studies of breast hormone levels in nipple aspiration fluid (NAF) show that estrone sulphate is present in large quantities in the normal breast, while the differences in serum ovarian steroids that are seen in pre- and postmenopausal women are blunted in NAF. The variability of several estradiol precursors in NAF over time is relatively small, a useful attribute of potential biomarkers of breast cancer risk, particularly if they are reversible with intervention in Phase 2 prevention trials. These studies are already providing new insights into the hormonal etiology of breast cancer, and should lead to the identification of robust, reversible biomarkers for use in breast cancer prevention studies.

Breast↗
PubMed1998

Neural development in the marsupial frog Gastrotheca riobambae.

The expression pattern of the tyrosine kinase gene Pag in whole-mount preparations of Gastrotheca riobambae embryos and the immunostaining of embryos against the proteins vimentin, NCAM, Pax-2, Hoxd9, and antigen 2G9 allowed detection of migrating streams of cranial neural crest (NC) cells, the isthmus, the hindbrain boundaries, rhombomeres, cranial nerves, and the developing spinal cord. Expression patterns of these genes and the basic neural morphology of Gastrotheca have been conserved in comparison with other vertebrates. However, as in Xenopus, a prominent stream of migrating cranial NC cells from rhombomere 5 was found in Gastrotheca embryos. By contrast, in chick embryos, premigratory NC cells from rhombomeres 3 and 5 undergo extensive apoptosis, which suggests that in anurans, apoptosis of the cranial NC may deviate from the chick pattern. The branchial-anterior and branchial-posterior masses of cranial NC cells, that populate the gill arches, are very large in G. riobambae. We cannot distinguish whether this feature corresponds to an anuran trait related to development of the tadpole pharyngeal skeleton, or is related to development of the peculiar external bell gills of this frog. This work provides the descriptive groundwork for lineage studies of the NC in G. riobambae embryos. Gastrotheca embryos are large and flat, have prominent streams of cranial NC cells, and develop very large external bell gills. These unique characteristics may facilitate future comparative analysis of the role of apoptosis in patterning the amphibian NC cell streams, and the contribution of the NC to development of the gills.

Animals↗
PubMed2005

p53 autoantibodies predict subsequent development of cancer.

Because TP53 mutations can induce an immune response and can occur early in the carcinogenic process for some tumors, p53 autoantibodies may be useful biomarkers for risk of development of cancer. Using banked serum samples from an asbestosis cohort at high risk for cancer, we demonstrate for the first time a statistically significant relationship between p53 autoantibodies and the subsequent development of malignancy (hazard ratio [HR] = 5.5, 95% confidence interval [CI] = 2.8-10.9) with a positive predictive value of 0.76 and an average lead time to diagnosis of 3.5 years. p53 autoantibodies were also significantly associated with p53 alterations in the resultant tumors (kappa = 0.78, p = 0.01).

Asbestosis↗
PubMed2003

Molecular detection of von Hippel-Lindau gene mutations in urine and lymph node samples in patients with renal cell carcinoma: potential biomarkers for early diagnosis and postoperative metastatic status.

PURPOSE: Organ confined renal cell carcinoma can be cured in the majority of patients, whereas more extensive lesions have a poor prognosis. Therefore, the development of a useful biomarker for early diagnosis as well as postoperative metastatic status would contribute to the appropriate therapy for renal cell carcinoma. To diagnose renal cell carcinoma preoperatively we developed a novel urinary test and detected occult lymph node micrometastasis using a molecular approach. MATERIALS AND METHODS: Urine samples were obtained preoperatively from 27 patients with renal cell carcinoma and von Hippel-Lindau (VHL) gene mutations in the tumors, and were analyzed for VHL gene mutations using a nested single strand conformational polymorphism analysis. Lymph nodes without evidence of histological metastasis were obtained from 15 patients with renal cell carcinoma and VHL gene mutations, and analyzed for VHL gene mutations using mutation specific nested reverse transcription polymerase chain reaction method. RESULTS: In urine samples 5 of 27 VHL gene mutations (18.5%) were found and each mutation pattern was the same as that detected in each renal cell carcinoma. One lymph node micrometastasis was found. CONCLUSIONS: These data indicate the presence of detectable levels of tumor derived DNA in the urine of patients with renal cell carcinoma and suggest that nested single strand conformational polymorphism analysis of VHL gene of urine samples provides a possible tool for the early detection of renal cell carcinoma. Furthermore, mutation specific nested reverse transcription polymerase chain reaction is useful to detect occult lymph node micrometastasis and may predict patients at risk for local recurrence. These 2 combined approaches using VHL gene mutations may contribute to the total therapy for and prognosis of renal cell carcinoma.

Biomarkers, Tumor↗
PubMed2003

A novel approach toward development of a rapid blood test for breast cancer.

Mammography remains the diagnostic test of choice for breast cancer, but 20% of cancers still go undetected. Many serum biomarkers have been reported for breast cancer but none have proven to represent effective diagnostic strategies. ProteinChip mass spectrometry is an innovative technology that searches the proteome for differentially expressed proteins, allowing for the creation of a panel or profile of biomarkers. The objective of this study was to construct unique cancer-associated serum profiles that, combined with a classification algorithm, would enhance the detection of breast cancer Pretreatment serum samples from 134 female patients (45 with cancer, 42 with benign disease, 47 normal) were procured prospectively following institutional review board-approved protocols. Proteins were denatured, applied onto ProteinChip affinity surfaces, and subjected to surface enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry. The SELDI output was analyzed using Biomarker Pattern Software to develop a classification tree based on group-specific protein profiles. The cross-validation analysis of cancer versus normal revealed sensitivity and specificity rates of 80% and 79%, and for cancer versus benign disease, 78% and 83%, respectively. When 2 different chip surfaces were combined the sensitivity and specificity increased to 90% and 93%, respectively. The sensitivity and specificity of this technique are comparable to those of mammography and, if confirmed in a larger study, this technique could provide the means toward development of a simple blood test to aid in the early detection of breast cancer. The combination of SELDI ProteinChip mass spectrometry and a classification- and regression-tree algorithm has the potential to use serum protein expression profiles for detection and diagnosis of breast cancer.

Adult↗
PubMed2005

Preclinical drug safety analysis by chemogenomic profiling in the liver.

The economic hurdles of drug development and the emergence of genomic technologies such as chemogenomics are combining to shift the existing paradigms in preclinical drug development. Today, the information gleaned from high content molecular data has begun to augment traditional approaches to the assessment of drug safety. The optimal approach is a hybrid strategy employing chemogenomic data and gene expression-based biomarkers of drug efficacy and toxicity to supplement low content and insensitive methods for risk assessment and mechanistic evaluation of drug candidates. Large reference databases of chemogenomic data are essential to the derivation and validation of accurate and predictive gene expression biomarkers. An example of the development of a predictive biomarker for hepatic bile duct hyperplasia is described herein. As gene expression technologies improve, biomarkers will achieve higher throughput, and become more cost effective and increasingly accurate. This will elevate the value of chemogenomics in drug development, shift attrition to earlier in the process, and reduce the overall cost of drug development. Over the past 2 to 3 years, the transition of chemogenomics from a research tool to a decision-making tool has begun and regulatory agencies are anxiously awaiting implementation of this technology to make faster and more informed evaluations of potential drugs.

Animals↗
PubMed1996

Identification of needs in biomarker research.

Interest in the use of biological markers to evaluate future disease risk has increased greatly in recent years. Biomarkers are observable end points in a continuum of events leading from exposure to toxic agents to diseases that ultimately result from exposure. Because many significant diseases develop over long periods of time, methods for detecting early events that can predict risk are important for disease prevention. Biomarkers are generally categorized as detecting exposure, effects of exposure, or individual susceptibility to exposure. Although there has been significant progress in the technical development of biomarkers, implementation of their use in human populations has progressed much more slowly. We discuss four major needs in the development of biomarkers. First, new biomarkers need to be developed to fill gaps in our ability to observe steps in the continuum from exposure to disease. Second, the relationships between biomarker responses and disease pathology needs to be better understood. Third, the sensitivity, specificity, and variability of biomarkers need to be better characterized and they must be better validated as predictors of disease risk. Fourth, there are several societal impediments to the practical implementation of biomarker studies as public health tools. A common agreement among employers, employees, regulators, and the legal community must be established regarding appropriate and ethical uses and interpretation of biomarker data.

Biomarkers↗
PubMed2025

A clinically applicable method for early interstitial lung disease detection in incident rheumatoid arthritis cases: integration of protein biomarkers and clinical factors.

BACKGROUND: This study aimed to develop an early diagnostic method integrating proteomic biomarkers and clinical parameters for screening interstitial lung disease (ILD) in patients with newly diagnosed rheumatoid arthritis (RA) through a multi-phase research strategy. METHODS: A three-phase study was conducted: (1) Discovery: Tandem mass tag (TMT)-labeled quantitative proteomics with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyzed serum protein profiles in 5 RA-ILD and 5 RA-non-ILD patients, identifying candidates via bioinformatics. (2) Verification: Enzyme-linked immunosorbent assay (ELISA) validated candidates in an independent cohort (13 RA-ILD vs 14 RA-non-ILD). (3) Application: Biomarkers combined with clinical indicators (Krebs von den Lungen-6 [KL-6], age, sex) were evaluated in 110 patients (51 RA-ILD vs 59 RA-non-ILD) to build a predictive model. RESULTS: Proteomic analysis identified matrix metalloproteinase-3 (MMP3), von Willebrand factor (VWF), and other significantly differentially expressed proteins. ELISA validation confirmed that serum MMP3 and VWF levels were significantly higher in the RA-ILD group than in the RA-non-ILD group (p = 0.025 and 0.027, respectively). Expanded validation demonstrated superior diagnostic performance when combining MMP3 and VWF with KL-6 (area under the curve [AUC] = 0.90). The nomogram prediction model based on univariate analysis exhibited excellent discrimination (AUC = 0.89) and calibration. CONCLUSION: This systematic study from discovery to validation identified MMP3 and VWF as potential biomarkers for RA-ILD. The integrated predictive model combining these biomarkers with clinical parameters (KL-6, age, sex) provides a potential tool for early ILD screening in RA patients, offering novel strategies for early diagnosis and intervention of RA-ILD.

Humans↗